ALL’ACCORDO ECONOMICO
ECRETO DEL DIRETTORE GENERALE -ENM.EN4D4A1-MDEGNTdOel 27/06/2024 - Allegato Utente 1 (A01)
ALL’ACCORDO ECONOMICO
Il presente emendamento (il “Secondo Emendamento”) viene stipulato tra:
▪ Ipsen S.p.A. Società a Socio Unico - Società soggetta a direzione e coordinamento della Società Ipsen S.A., una società organizzata ed esistente ai sensi delle leggi italiane, con sede ad Xxxxxx (XX) xx Xxx xxx Xxxxx Xxxxxxxxx, 0 – Palazzo X0, Xxxxxxxxxxx Xxxx, X-00000, partita IVA 07161740159 e C.F. 05619050585, rappresentata dal Presidente, Dr.ssa Xxxxxxxx Xxxxxxx debitamente autorizzato a tal fine, di seguito “Ipsen”,
e
▪ Fondazione IRCCS “Istituto Nazionale dei Tumori”, con sede legale in xxx X. Xxxxxxxx, 0 -00000 Xxxxxx, codice fiscale: 80018230153, partita IVA: 04376350155, nella persona del suo Direttore Generale, Xxxx. Xxxxx Xxxxxx (di seguito il “Promotore”)
Ipsen e il Promotore sono di seguito denominati ciascuno singolarmente la “Parte” o collettivamente le “Parti”.
PREMESSO CHE:
(1) Ipsen e il Promotore hanno stipulato in data 27 maggio 2020 un accordo (l’”Accordo”) per la sponsorizzazione esterna dello studio “A phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in gastroenteropancreatic (GEP) and thoracic neuroendocrine tumour (NET): The LOLA trial” (lo «Studio») soggetto ai termini e alle condizioni ivi stabiliti.
(2) In data 29 aprile 2022, Ipsen e il Promotore hanno stipulato un primo emendamento all’Accordo in conformità al Decreto Ministeriale 17/12/2004 (il “Primo Emendamento”), finalizzato a modificare i termini relativi alla gestione delle procedure di farmacovigilanza e di audit.
(3) con l’entrata in vigore del Regolamento Europeo n. 2014/536 e del Decreto Ministeriale 30 novembre 2011, e a seguito di revisioni apportate al Protocollo di Studio, si è reso necessario ulteriormente modificare l’Accordo, come qui di seguito stabilito.
TANTO PREMESSO, SI CONCORDA quanto segue:
1. TEMPISTICHE DELLO STUDIO E PROTOCOLLO DI STUDIO
Le Parti concordano di sostituire l’Appendice 1 dell’Accordo con il testo di cui all’Allegato 1 al presente Secondo Emendamento.
2. PROSPETTO DEI PAGAMENTI
L’articolo 1.2 dell’Accordo viene integralmente sostituito dal testo di seguito riportato:
“Articolo 1.2 - PROSPETTO DEI PAGAMENTI”
I. PIANO DI FATTURAZIONE
Il Contributo è fissato in un importo complessivo di Euro 459.426,00 (quattrocentocinquantanovemilaquattrocentoventisei/00), esente IVA ai sensi dell’art. 2 comma 3 DPR 633/72, e sarà da fatturarsi come segue:
Traguardi intermedi di fatturazione | Importo del Fondo per lo Studio | Data prevista* |
Sottoscrizione del presente Contratto ad opera di entrambe le Parti per consentire al Promotore di iniziare lo Studio | 100000 | 31 gennaio 2020 |
Consegna di un report che attesta lo stato di avanzamento dello studio | 100000 | 19 dicembre 2021 |
Consegna di un report che attesta lo stato di avanzamento dello studio | 100000 | 14 Settembre 2022 |
Consegna di un report che attesta lo stato di avanzamento dello studio | 90000 | Dicembre 2023 |
Consegna di un report che attesta lo stato di avanzamento dello studio | 20000 | Dicembre 2024 |
Consegna di un report che attesta lo stato di avanzamento dello studio | 20000 | Settembre 2025 |
Saldo, al termine dello Studio dietro presentazione del Rapporto finale dello Studio | 29426 | Agosto 2026 |
*La tempistica (“Data prevista”) ha scopo meramente indicativo, restando invece ferma e vincolante la correlazione tra i “Traguardi intermedi di fatturazione” e l’erogazione dell’“Importo del Fondo dello Studio”.
Il Promotore dichiara che il Contributo verrà utilizzato unicamente per l’esecuzione dello Studio come previsto nel relativo Budget.
3. MODIFICA DEL PROTOCOLLO
Le Parti concordano di sostituire l’articolo 5.2 dell’Accordo con il testo di seguito riprodotto:
“5.2 - Modifica del Protocollo
Il Promotore potrà provvedere autonomamente ad apportare emendamenti al Protocollo che dovessero rendersi necessari ai fini della buona condotta dello Studio. Il Promotore
notificherà a Ipsen, con congruo anticipo, qualsiasi istanza al Comitato Etico avente ad oggetto un emendamento del Protocollo e/o del modulo di consenso informato. Il Promotore inserirà immediatamente qualsivoglia nuovo dato sulla sicurezza, fornito (ove applicabile) da Ipsen, nel Protocollo e nel modulo di consenso informato e richiederà tempestivamente l’approvazione da parte del Comitato Etico competente del Protocollo e/o del modulo di consenso informato aggiornato. L’erogazione del Contributo dipenderà dall’accettazione delle modifiche del Protocollo e/o del modulo di consenso informato da parte di Ipsen. Qualora venisse approvato dal competente Comitato Etico un emendamento del Protocollo e/o del modulo di consenso informato che modifica sostanzialmente il Protocollo iniziale e/o il modulo di consenso informato e detto emendamento non fosse coerente con il progetto iniziale che Ipsen ha accettato di finanziare, il Promotore, in persona dello Sperimentatore Principale, dovrà fornire a Ipsen le motivazioni della modifica affinché quest’ultima possa valutare se sussistano ancora le condizioni per la prosecuzione del supporto finanziario dello Studio. Prima della pubblicazione dei Risultati dello studio, Ipsen condividerà il Protocollo esclusivamente con i propri dipendenti, appaltatori o consulenti, non lo divulgherà a terzi e non lo renderà accessibile su siti web disponibili al pubblico o su altro forum pubblico, senza il previo consenso scritto del Promotore.”
4. RAPPORTI PERIODICI
Le Parti concordano di integrare l’articolo 6 dell’Accordo, inserendo il paragrafo 6.6 recante il testo di seguito riprodotto:
“6.6 Fatti salvi gli obblighi riguardo alle segnalazioni di sicurezza stabiliti all’articolo 8 che segue e nell’Appendice 6, il Promotore/lo Sperimentatore Principale dovrà inoltre fornire a Ipsen i rapporti periodici (a cadenza almeno semestrale) sullo stato di avanzamento dello Studio. I rapporti periodici predisposti dallo Sperimentatore conterranno come minimo le seguenti informazioni:
i. Aggiornamento sul numero di pazienti arruolati;
ii. Numero di pazienti esposti al Materiale dello Studio (totali cumulativi di pazienti esposti al Materiale dello Studio);
iii. Aggiornamento del piano di progetto (traguardi intermedi raggiunti e/o riprogrammati).”
Le Parti concordano di integrare l’Accordo inserendo, come Appendice 5 dell’Accordo stesso, il testo di cui all’Allegato 2 del presente Secondo Emendamento.
5. PUBBLICAZIONI SCIENTIFICHE E COMUNICAZIONI
Le Parti concordano di integrare l’articolo 7 dell’Accordo con il testo di seguito riprodotto:
“Nessuna delle Parti del presente Accordo può, in assenza del preventivo consenso scritto della parte interessata, utilizzare il nome o i marchi dell’altra Parte o di una delle sue Affiliate o di uno dei suoi dipendenti in relazione a comunicati stampa, pubblicità commerciale, documentazione promozionale o qualsiasi altra forma di pubblicità, salvo che ciò sia consentito dalla Legge applicabile. Il Promotore si impegna a non rispondere e a far in modo che lo Sperimentatore Principale non risponda a richieste di informazioni da parte di analisti finanziari relative al presente Accordo, allo Studio o al Contributo.”
6. FARMACOVIGILANZA
Le Parti concordano di sostituire l’articolo 8 dell’Accordo, come modificato dal Primo Emendamento, con il testo di seguito riprodotto:
“Articolo 8 - Farmacovigilanza
Il Promotore/lo Sperimentatore Principale rispetterà tutti gli obblighi di segnalazione in materia di farmacovigilanza applicabili allo Studio, in conformità al Protocollo, alle Leggi e ai Regolamenti applicabili, incluse, a titolo esemplificativo e non esaustivo, le norme di Buona pratica Clinica applicabili e/o le norme di Buone Pratiche di Farmacovigilanza (Good Pharmacovigilance Practices, GVP), nonché le disposizioni stabilite nell’Appendice 6”.
Le Parti concordano di integrare l’Accordo inserendo, come Appendice 6 dell’Accordo stesso, il testo di cui all’Allegato 3 del presente Secondo Emendamento.
7. RISOLUZIONE
Le Parti concordano di sostituire l’articolo 11 dell’Accordo con il testo di seguito riprodotto: “Articolo 11 – Risoluzione
11.1 Il presente Accordo può essere risolto sulla base di uno dei seguenti eventi di risoluzione:
• Cessazione anticipata dello Studio: qualora il Promotore, per qualsiasi motivo, ponesse termine allo Studio anticipatamente, il Promotore stesso potrà recedere dal presente Accordo dando un preavviso scritto di dieci (10) giorni a Ipsen per il tramite dello Sperimentatore Principale.
• Recesso anticipato da parte di Ipsen:
Ipsen può recedere dal presente Accordo dando un preavviso scritto di dieci (10) giorni al Promotore, qualora lo Studio non iniziasse nel termine essenziale di sei
(6) mesi dalla Data di efficacia del presente Accordo. Per le finalità di cui sopra, per inizio dello Studio si intende (i) la prima visita del primo soggetto o i dati raccolti relativamente al primo soggetto (se lo Studio è uno Studio clinico) o (ii) l’inizio della fase sperimentale (se lo Studio è uno studio preclinico).
Ipsen avrà il diritto di recedere dal presente Accordo, con effetto dalla data specificata nella sua comunicazione scritta al Promotore: (a) in caso di violazione da parte del Promotore/dello Sperimentatore Principale di una Legge applicabile o del Protocollo; (b) se in seguito a una modifica sostanziale del Protocollo, Ipsen stabilisce, a sua esclusiva discrezione, di non essere più interessata a fornire il Contributo; (c) per ragionevoli motivi commerciali o scientifici; (d) per ragioni di sicurezza legate all’uso del Materiale dello Studio.
• Risoluzione per inadempimento contrattuale: ciascuna Parte può risolvere il presente Accordo in caso di inadempimento dell’altra Parte delle disposizioni del presente Accordo e, nel caso di un inadempimento sanabile, non vi ponga rime- dio entro trenta (30) giorni dal ricevimento di una comunicazione scritta della Par- te adempiente, che fornisca tutti i dettagli dell’inadempimento e confermi l’intenzione di risolvere l’Accordo in assenza di rimedio.
11.2 In caso di risoluzione anticipata del presente Accordo, Xxxxx xxxx responsabile unicamente di fornire il Contributo solo fino alla data di efficacia della risoluzione. L’eventuale Contributo finanziario corrisposto anticipatamente sarà trattenuto solo in
ragione all’attività effettivamente svolta e l’eventuale eccedenza sarà restituita a Ipsen. Invece, il Promotore, su istruzione di Ipsen, dovrà restituire il Materiale dello Studio ad Ipsen o avviarlo alla distruzione e fornire apposita dichiarazione.
11.3 L’obbligazione in capo ad Ipsen, di cui all’Articolo 1 del presente Accordo, avente ad oggetto la fornitura del Materiale dello Studio cesserà alla scadenza o alla risoluzione anticipata del presente Accordo.
11.4 Al termine del presente Accordo, anche in caso di recesso o risoluzione, le Parti collaboreranno per effettuare una riconciliazione finanziaria al fine di confermare la coerenza tra il totale dei versamenti effettuati da Ipsen a titolo di Contributo e le milestone effettivamente raggiunte, il rispetto degli obblighi e delle responsabilità posti in capo alle Parti ai sensi del presente Accordo e del Protocollo. Le Parti convengono di effettuare eventuali adeguamenti (ad es. rimborso o pagamento supplementare) che risultassero giustificati da tale analisi. Il Promotore si impegna e provvede affinché lo Sperimentatore Principale si impegni a interrompere l’uso del Materiale dello Studio, di cui al presente Accordo, e fornire a Ipsen i risultati dello Studio in suo possesso in tale momento”.
8. DICHIARAZIONI E GARANZIE
Le Parti concordano di sostituire l’articolo 14 dell’Accordo con il testo di seguito riprodotto: “Articolo 14 – Dichiarazioni e garanzie
14.1 Il Promotore dichiara e garantisce (i) di avere il diritto, l’autorità e il potere legale di stipulare il presente Accordo e di adempiere gli obblighi in esso previsti; (ii) che il presente Accordo costituisce un valido vincolo legale e (iii) che non è parte di accordi che limitino o vietino la conclusione del presente Accordo. Il Promotore dichiara e garantisce, altresì, che lo stesso e/o lo Sperimentatore Principale non hanno interessi finanziari o di altra natura relativi ad Ipsen o all’esito dello Studio, che possano interferire con l’indipendenza del loro giudizio.
14.2 Ciascuna delle Parti garantisce, dichiara e conviene che provvederà affinché essa stessa e il proprio personale:
(a) adempiano le proprie obbligazioni di cui al presente Accordo con integrità, onestà e correttezza, sempre nel rispetto dei più alti standard etici;
(b) rispettino le Leggi applicabili, inclusi, a titolo esemplificativo, la legge n. 190/2012, i codici della Federazione internazionale dei produttori e delle associazioni farmaceutiche (IFPMA), della Federazione europea delle industrie e delle associazioni farmaceutiche (EFPIA) e di Farmindustria, la Convenzione sulla lotta alla corruzione di pubblici ufficiali stranieri nelle operazioni economiche internazionali dell’Organizzazione per la Cooperazione e lo Sviluppo economico (OCSE), la legge anti-corruzione britannica (UK Bribery Act), la legge francese Sapin II, la legge statunitense sulle pratiche anti-corruzione nel mercato estero (US Foreign Corrupt Practices Act) e altre leggi applicabili anti-corruzione;
(c) non offrano, promettano, facciano, autorizzino o forniscano, direttamente o per il tramite di terzi, alcun dono, pagamento o altro trasferimento di valore ad un funzionario pubblico o impiegato privato, al fine di influenzare o premiare qualsivoglia azione o decisione, intrapresa o presa da quest’ultimo nella sua veste ufficiale o professionale, allo scopo di ottenere o mantenere rapporti commerciali ovvero procurarsi un vantaggio indebito, con intenti corruttivi;
(d) non compiano alcuna azione che possa ragionevolmente indurre a credere che Ipsen effettui pagamenti indebiti a funzionari o altri soggetti;
(e) non offrano o ricevano alcun pagamento o altra agevolazione in cambio di servizi che il soggetto che effettua il pagamento ha il diritto di ricevere senza detto pagamento, ad eccezione della rara circostanza in cui il pagamento sia offerto per far fronte alla minaccia imminente di un grave danno fisico;
(f) non forniscano, offrano o promettano alcun dono o vantaggio, pecuniario o di altra natura, a persone abilitate a prescrivere o fornire prodotti farmaceutici né effettuino donazioni a soggetti o organizzazioni preposti all’acquisto di farmaci. Ai fini del presente articolo, per “donazione” si intende l’atto di fornire fondi, servizi o prodotti, senza in cambio alcun beneficio esplicito o implicito, se non generica gratitudine;
(g) implementino un’infrastruttura di compliance adeguata, in relazione allo Studio, che comprenda, a titolo esemplificativo, politiche e procedure, formazione e comunicazione, al fine di gestire e mitigare i rischi associati.
14.3 Le Parti si informeranno reciprocamente ed immediatamente qualora, in qualsiasi momento durante il periodo di validità del presente Accordo, vi sia un cambiamento delle loro rispettive circostanze, conoscenze o consapevolezze tali da non consentire a quella data il rinnovo di ciascuna delle garanzie innanzi rassegnate. La violazione di quanto previsto dal presente articolo costituisce grave inadempimento del presente Accordo ai sensi e per gli effetti di cui all'art. 1456 del Codice Civile, risultando pregiudicato il rapporto di fiducia tra le Parti.
Il Promotore conviene altresì di risolvere immediatamente qualsivoglia contratto con subappaltatori o terzi, in relazione allo Studio, qualora detto subappaltatore o terzo ovvero qualsivoglia socio, amministratore o rappresentante legale dello stesso sia inserito in un elenco ufficiale di sanzioni commerciali ed economiche. In tal caso, qualora il Promotore non risolva il contratto con detto subappaltatore o terzo, sarà facoltà di Ipsen risolvere immediatamente il presente Accordo, senza risarcire o indennizzare il Promotore in alcun modo.”
9. VARIE ED EVENTUALI
Le Parti concordano di integrare l’articolo 16 dell’Accordo con il testo di seguito riprodotto:
“Cessione: il Promotore e lo Sperimentatore Principale non cederanno il presente Accordo, né alcuno dei rispettivi diritti o obblighi in esso previsti, senza il preventivo consenso scritto di Ipsen. È facoltà di Ipsen cedere, delegare o trasferire il presente Accordo, o una parte di esso, in qualsiasi momento previa comunicazione scritta al Promotore.
Subappalto: In caso di subappalto, ill Promotore e lo Sperimentatore Principale rimarranno pienamente responsabili di tutte le attività affidate ai subappaltatori e rimarranno pienamente responsabili dell’adempimento di tutte le obbligazioni subappaltate di cui al presente Contratto. Il Promotore si assicurerà che qualsivoglia subappaltatore sia soggetto (i) agli obblighi di riservatezza in relazione alle Informazioni riservate di Ipsen, che siano almeno tanto vincolanti quanto quelli stabiliti nel presente Contratto, e (ii) all’obbligazione di trasferire al Promotore qualsivoglia diritto che detto subappaltatore potrebbe avere in relazione ad un’Invenzione, di modo che quest’ultimo possa adempiere le obbligazioni di cui all’Articolo 6 del presente Contratto.”
10. OBBLIGHI DEL PROMOTORE
Le Parti concordano di integrare l’Accordo inserendo l’articolo 20 recante il testo di seguito riprodotto:
“Articolo 20 – Obblighi e responsabilità del Promotore e dello Sperimentatore Principale
20.1 Il Promotore si assumerà la responsabilità dell’archiviazione di tutta la documentazione relativa allo Studio, in conformità alla Legge applicabile. Il Promotore conviene di non distruggere alcun registro o documento relativo allo Studio senza prima averne dato comunicazione scritta ad Ipsen.
20.2 Il Promotore dichiara che sia il Promotore sia lo Sperimentatore Principale hanno stipulato e manterranno, durante il periodo di efficacia del presente Accordo (e per i tre
(3) anni successivi a copertura delle richieste di risarcimento), una o più polizze assicurative sufficienti a coprire la propria responsabilità e la responsabilità del personale dello Studio, dei dipendenti e dei procuratori per tutte le perdite o i danni derivanti dallo Studio e/o dall’esecuzione del presente Accordo. Il Promotore fornirà a Ipsen, su richiesta, il certificato o i certificati di assicurazione attestanti tale copertura.
20.3 In caso di un danno cagionato a una persona nell’esecuzione dello Studio, il Promotore provvederà ad assistere il paziente dello Studio, sostenendone i costi, nel rispetto degli obblighi di assistenza sanitaria in capo al Promotore”.
11. INDENNIZZO
Le Parti concordano di integrare l’Accordo inserendo l’articolo 21 recante il testo di seguito riprodotto:
“Articolo 21 – Indennizzo
21.1 Lo Studio per il quale Ipsen fornisce il Contributo non è ideato, promosso o gestito da Ipsen e, pertanto, Ipsen non è in alcun modo responsabile per la conduzione dello Studio e, salvo quanto specificamente indicato di seguito, in nessun caso Xxxxx xxxx responsabile dell’uso, della manipolazione, della conservazione o dello smaltimento del Materiale dello Studio o dei materiali o delle attrezzature dello Studio da parte del Promotore, dello Sperimentatore Principale e/o di qualsivoglia membro del personale dello Studio. Il Promotore sarà responsabile di tutti gli atti od omissioni ad opera dello stesso, dello Sperimentatore Principale e del personale dello Studio nonché degli atti o delle omissioni colposi del personale dello Studio, derivanti dall’uso, dalla manipolazione, dalla conservazione o dallo smaltimento del Materiale dello Studio, dei materiali o delle attrezzature dello Studio. Il Promotore difenderà, manleverà e terrà indenne Ipsen e le sue Affiliate, nonché i rispettivi amministratori, direttori, impiegati, appaltatori, consulenti e procuratori (ciascuno una “Parte manlevata di Ipsen”) da ogni perdita, pretesa, risarcimento dei danni, richiesta, sentenza, accordo transattivo, responsabilità, costo e spesa (inclusi, a titolo esemplificativo, gli onorari e le spese legali, in misura ragionevole) derivante da qualsivoglia azione, procedura, arbitrato, causa legale o procedimento avviato da qualsivoglia autorità governativa o regolatoria o altra terza parte in relazione allo Studio, a condotta colposa o dolosa del Promotore, dello Sperimentatore Principale e/o di qualsivoglia membro del personale dello Studio, a qualsivoglia inadempimento da parte del Promotore di previsioni di cui al presente Accordo di cui al Protocollo o a qualsivoglia violazione delle Leggi applicabili da parte del Promotore, dello Sperimentatore e/o di qualsivoglia membro del personale di Studio.
21.2 Fatte salve le disposizioni del precedente Articolo 21.1, Ipsen terrà indenne e manlevato il Promotore, lo Sperimentatore Principale e qualsiasi membro del personale dello Studio (collettivamente, le “Parti manlevate del Promotore”) da qualsiasi perdita, pretesa, danno, responsabilità e costo derivante (i) da una condotta colposa o dolosa da parte di una Parte manlevata di Ipsen; o (ii) da violazione di una Legge o regolamento
applicabile da parte di una Parte manlevata di Ipsen; o (iv) dal mancato adempimento della Parte manlevata di Ipsen agli obblighi previsti dal presente Accordo. Resta in ogni caso salva la piena ed esclusiva responsabilità di Ipsen quale produttore del Materiale dello Studio di sua proprietà utilizzato nel corso dello Studio secondo le prescrizioni contenute nell’autorizzazione in commercio, come per legge. Inoltre, fatte salve le previsioni dell’Articolo 21.1 di cui al presente Accordo, Ipsen difenderà, manleverà e terrà indenne il Promotore, lo Sperimentatore Principale e qualsiasi membro del personale dello Studio da qualsiasi pretesa da parte di terzi e perdite e costi associati (incluse le spese legali in misura ragionevole) nella misura in cui tale pretesa derivi da difetti di fabbricazione del Materiale dello Studio fornito da Ipsen in base al presente Accordo, fatta eccezione per il caso in cui tale pretesa risulti (i) dall’utilizzo, ad opera della Parte manlevata del Promotore, del Materiale dello Studio in maniera non conforme al presente Accordo, al Protocollo e/o alle istruzioni scritte di Ipsen; o (ii) da una condotta colposa o dolosa di una Parte manlevata del Promotore; o (iii) dalla violazione di una Legge applicabile ad opera di una Parte manlevata del Promotore; o (iv) dal mancato adempimento ad opera della Parte manlevata del Promotore delle obbligazioni di cui al presente Accordo.
21.3 È fatto obbligo alla Parte che chiede l’indennizzo di comunicare alla parte responsabile qualsivoglia pretesa di terzi entro trenta (30) giorni dalla data di ricezione della stessa. La Parte tenuta a garantire l’indennizzo avrà il diritto di respingere quanto contestato, negoziare e tentare di risolvere la lite. Sarà facoltà della Parte indennizzata partecipare alla difesa in merito a dette questioni e, a tal fine, nominare, a proprie spese, un legale. Resta salvo il fatto che le decisioni definitive, in merito a tutti gli aspetti della contestazione degli addebiti, spettano alla Parte tenuta a indennizzare. La Parte che chiede l’indennizzo fornirà alla Parte tenuta ad indennizzare tutte le informazioni e l’assistenza, su ragionevole richiesta e a spese di quest’ultima. Nessuna Parte sarà responsabile per la composizione di una lite o azione legale, ovvero dalla stessa vincolata, qualora l'accordo sia raggiunto senza il consenso scritto della Parte stessa, purché, tuttavia, la Parte indennizzata non rifiuti o ritardi, in maniera irragionevole, la concessione di tale consenso.”
12. INTERDIZIONE
Le Parti concordano di integrare l’Accordo inserendo l’articolo 22 recante il testo di seguito riprodotto:
“Articolo 22 – Interdizione
22.1 Il Promotore e lo Sperimentatore Principale, ognuno per quanto di propria competenza, e/o a qualsivoglia membro del personale dello studio dichiarano e garantiscono di non essere soggetti a restrizioni o sanzioni legali o normative, e di non essere stati oggetto di inabilitazione da parte di autorità o altro organismo ufficiale e di non essere stati interdetti in base alle disposizioni di leggi o regolamenti di autorità pubbliche, sia all’interno sia all’esterno del Paese in cui viene condotto lo Studio (“Interdetto” o “Interdizione”). Nel caso in cui, durante il periodo di validità del presente Accordo, il Promotore/lo Sperimentatore Principale e/o qualsivoglia membro del personale dello studio (i) venga Interdetto o (ii) riceva da un’autorità di vigilanza una comunicazione di Interdizione o di avvio di procedimento volto all’Interdizione, il Promotore/lo Sperimentatore Principale dovrà darne sollecita comunicazione scritta a Ipsen.
22.2 Nel caso in cui il Promotore, ovvero lo Sperimentatore Principale e/o a qualsivoglia membro del personale dello studio venga Interdetto, il Promotore, ovvero lo Sperimentatore Principale e/o a qualsivoglia membro del personale dello studio, a seconda del caso, cesserà immediatamente tutte le attività relative al presente Accordo e
il presente Accordo sarà automaticamente risolto, senza ulteriori azioni o comunicazioni da parte di Ipsen. Nel caso in cui Ipsen riceva un avviso dal Promotore o dallo Sperimentatore Principale o venga a conoscenza in altro modo che (i) è stato avviato un procedimento volto all’Interdizione del Promotore o dello Sperimentatore Principale o (ii) è stata minacciata un’azione di Interdizione nei confronti del Promotore o dello Sperimentatore Principale, Ipsen avrà il diritto di risolvere il presente Accordo con effetto immediato.
22.3 Il Promotore e lo Sperimentatore Principale dichiarano che, per la conduzione dello Studio, non si avvarranno, a nessun titolo, dei servizi di un soggetto o di un ente che sia stato Interdetto. Nel caso in cui il Promotore o lo Sperimentatore Principale vengano a conoscenza dell’Interdizione o del rischio di Interdizione di qualsiasi persona fisica o giuridica che fornisce servizi direttamente o indirettamente correlati allo Studio, il Promotore o lo Sperimentatore Principale ne informerà immediatamente Ipsen la quale avrà il diritto di risolvere il presente Accordo con effetto immediato”.
13. DISPOSIZIONI GENERALI
13.1 Salvo quanto modificato con questo Secondo Emendamento, tutte le altre disposizioni dell'Accordo (così come già modificate e integrate con il primo emendamento) continuano ad essere pienamente valide e vincolanti per le Parti.
13.2 Le parole utilizzate in questo Secondo Emendamento con lettera iniziale maiuscola hanno lo stesso significato definito nell'Accordo, se non diversamente definito nel presente documento.
13.3 Questo Secondo Emendamento costituisce parte integrante dell'Accordo.
13.4 Questo Secondo Emendamento viene sottoscritto con firma digitale ai sensi dell’art. 24 del D. Lgs. 82/2005, giusta la previsione di cui all’art. 15, comma 2bis della Legge
n. 241/1990, come aggiunto dall’art. 6, D.L. 18/10/2012, n. 179, convertito in Legge 17/12/2012 n. 22. Le imposte e tasse inerenti e conseguenti alla stipula del presente Emendamento, ivi comprese l’imposta di bollo sull’originale informatico di cui all’art. 2 della Tabella Allegato A – tariffa parte I del DPR n. 642/1972 e l’imposta di registro devono essere versate, nel rispetto della normativa applicabile.
Il Finanziatore Società IPSEN S.P.A. Il Presidente Dr.ssa Xxxxxxxx Xxxxxxx Firmato digitalmente da: XXXXXXX XXXXXXXX Data: 06/05/2024 17:34:07 | Lo Sponsor Fondazione IRCCS Istituto Nazionale dei Tumori Il Direttore Generale Dr. Xxxxx Xxxxxx Per presa visione e accettazione: Lo Sperimentatore Principale Dr.ssa Xxxx Xxxxxxxx |
Firmato da:
XXXX XXXXXXXX
Codice fiscale: XXXXXX00X00X000X
Valido da: 27-09-2022 10:20:52 a: 27-09-2025 02:00:00
Certificato emesso da: InfoCert Qualified Electronic Signature CA 3, InfoCert S.p.A., IT Riferimento temporale 'SigningTime': 19-06-2024 11:01:51
Motivo: Approvo il documento
ALLEGATO 1
al Secondo Emendamento
“APPENDICE 1 - Tempistiche dello studio e Protocollo di studio”
APPENDICE 1
Tempistiche dello studio e Protocollo di studio
I. PIANO DI RECLUTAMENTO (dimensioni del campione dello studio)
Un massimo di 69 pazienti saranno reclutati entro il termine di 36 mesi a cui deve aggiungersi l’ulteriore periodo di FU di 6 mesi (e così, complessivamente, entro il termine di 42 mesi).
Il tasso di reclutamento atteso è di circa 1 paziente al mese.
II. TEMPISTICHE DELLO STUDIO
Traguardi intermedi dello Studio | Tempistiche previste |
Prima approvazione EC/IRB | 17 dicembre 2019 |
Prima visita del primo soggetto | 20 febbraio 2020 |
Prima visita dell’ultimo soggetto | 28 settembre 2025 |
Ultima visita dell’ultimo soggetto | 30 dicembre 2025 |
Rapporto finale dello Studio da consegnarsi a Ipsen | 30 agosto 2026 |
III. PROTOCOLLO
[Protocollo dello Studio]
A Study of Fondazione IRCCS Istituto Nazionale dei Tumori |
A Phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in gastroenteropancreatic (GEP) and thoracic neuroendocrine tumor (NET): The LOLA trial |
Protocol Number: LOLA Trial Eudract Number: 0000-000000-00
CLINICAL STUDY PROTOCOL
Indication: | Advanced or Metastatic well differentiated Gastro-Entero-Pancreatic and Thoracic neuroendocrine Tumors |
Phase: | II |
Sponsor | Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Under the aegis of Italian Association for Neuroendocrine Tumors (XX.X.XXX) |
Therapeutic Area: | Medical Oncology |
Contact |
Principal investigators: | Dr.ssa Xxxx Xxxxxxxx |
Responsible Investigator: | Prof Xxxxxxx G. de Xxxxx |
Sub-Investigators | Dr Xxxxxxxx Xxxxxxxx Dr Xxxxxx Xxxxxx Dr. Xxxxxxxx Xxxxxx |
Pathologist: | Dr. Xxxxxxx Xxxxxxxxx Dr. Xxxxxxx Xxxxxxxx Dr. Xxxxx Xxxxxxxxx |
Radiologists: | Dr. Xxxxxxx Xxxxxxx Dr. Xxxxx Xxxxxxxx |
Statisticians: | Dr. Xxxx Xxxxx Dr. Xxxxxx Xxxxx |
Data Management: | Dr. Xxxxx Xxxxxx La Porta |
Start-up and contract specialist | Dr. Xxxxxx Xxxxxxxx |
Pharmacy: | Dr. Xxxx Xxxxxx |
This study will be conducted according to the accepted standards of “Good Clinical Practice”
CONFIDENTIALITY STATEMENT: The information contained in this document is the property of Fondazione IRCCS Istituto Nazionale dei Tumori and therefore is provided to you in confidence for review by you, your staff, an applicable Ethics Committee/Institutional Review and regulatory authorities. It is understood that the information will not be disclosed to others without prior written approval from Fondazione IRCCS Istituto Nazionale dei Tumori, except to the extent necessary to obtain informed consent from those persons to whom the medication may be administered.
A Study of Fondazione IRCCS Istituto Nazionale dei Tumori |
A Phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in gastroenteropancreatic (GEP) and thoracic neuroendocrine tumor (NET): The LOLA trial |
Protocol Number: LOLA Trial Eudract Number: 0000-000000-00
CLINICAL STUDY PROTOCOL
Steering Committee (PI) | Dr. Xxxx Xxxxxxxx Dr. Xxxxxxxxx Xxxxxxx Dr. Xxxxxx Xxxxxxx Dr. Xxxx Xxxxxxx Dr. Xxxxx Xxx Xxxxxx Dr. Xxxxx Xxxxxxxxx Dr. Xxxxx Xxxxx Dr. Xxxxxxxxx Xxxxxx Dr. Xxxxxxxxx Xxxxx Dr. Xxxxx Xxxxxxxx Dr. Xxxx Xxxxxxxxxx |
Data Monitoring Committe | Xxxx. Xxxxxxxx Xxxxxxxxxx Dr. Xxxxxxxxx Xxxxx Xxxx. Xxxxxxx Xxxxxxx Xxxx. Xxxxxxxxxxx Xxxxxxxx Dr. Xxxx Xxxxxxxxx |
Reference Centre: s.c. Oncologia Medica 1, Fondazione IRCCS Istituto Nazionale dei Tumori, xxx X. Xxxxxxxx x. 0, 00000 Xxxxxx
Fondazione IRCCS Istituto Nazionale dei Tumori – Milano
PROTOCOL N° INT 240/19
APPROVATO DAL COMITATO ETICO FONDAZIONE IRCCS ISTITUTO TUMORI MILANO il 14/01/2020
A Phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in gastroenteropancreatic (GEP) and thoracic neuroendocrine tumor (NET): The LOLA trial
A Study of Fondazione IRCCS Istituto Nazionale dei Tumori
CLINICAL RESPONSIBLE SIGNATURE
Signature | Date |
prof.…………………………….. Responsible Investigator | |
/ / |
A Phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in gastroenteropancreatic (GEP) and thoracic neuroendocrine tumor (NET): The LOLA trial
A Study of Fondazione IRCCS Istituto Nazionale dei Tumori
[Multicenter Trial]
CLINICAL SITE SIGNATURE LIST
Signature | Date | |
Dr…………………………….. Principal Investigator | / / | |
Dr……………………………….. Sub-Investigator | / / | |
Dr……………………………….. Sub Investigator |
| / / |
Dr……………………………….. Sub Investigator |
| / / |
I have thoroughly read and reviewed the study protocol LOLA Trial.
Having read and understood the requirements and conditions of the study protocol, I agree to perform the clinical study according to the international good clinical practice principles and regulatory authority requirements for source document verification and auditing/inspection of the study. I agree to use the study material, including medication, only as specified in the protocol. I understand that any violation of the protocol may lead to early termination of the study. I agree to the following time schedule. The study will start on January 2020 and is foreseen to be completed by June 2023.
PROTOCOL SUMMARY
Title: | A Phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in gastroenteropancreatic (GEP) and thoracic neuroendocrine tumor (NET): The LOLA trial |
COORDINATING CENTER: | Medical Oncology Unit 1, ENETS Center of Excellence Fondazione IRCCS Istituto Nazionale dei Tumori Xxx X. Xxxxxxxx 0 00000 Xxxxxx, Xxxxx Telephone: x00-00-00000000 |
Number of centers: | 11 |
CLINICAL PHASE: | Phase II trial |
INDICATION: | Advanced or Metastatic well differentiated gastro-entero-pancreatic, thoracic and unknown primary tumor NET |
RATIONALE: | Cabozantinib is an inhibitor of multiple kinases, including VEGFR2, MET, RET and AXL, which has been recently approved for the treatment of advanced hepatocellularcarcinoma (HCC), medullary thyroid carcinoma (MTC) and advanced treatment-naïve renal cell carcinoma (RCC) patients with intermediate or poor risk or following prior vascular endothelial growth factor (VEGF)-targeted therapy. The safety and the activity of cabozantinib in NETs has been evaluated in a recent Phase II trial and presented at the ASCO GI meeting on 2017. Out of 61 patients with progressive, well differentiated, G1-2 carcinoid or pancreatic NET (pNET), cabozantinib has been administered at the dose of 60 mg/day. The primary endpoint was objective response rate (ORR) as measured by RECIST 1.1. 41 patients with carcinoid NET and 20 patients with pNET were accrued. Treatment with cabozantinib was associated with objective tumor responses and encouraging progression-free survival (PFS) in patients with advanced carcinoid and advanced pNET. 3/20 patients with pNET achieved partial response (PR) (ORR 15%); 15/20 had stable disease (SD). 6/41 patients with carcinoid achieved PR (ORR 15%); 26/41 had SD. Median PFS was 21.8 months in patients with pNET and 31.4 months in patients with carcinoid. While dose reduction was common (81%), treatment was tolerable. Grade 3/4 toxicity in ≥ 1 patient included hypertension (13%), hypophosphatemia (11%), diarrhea (10%), lymphopenia (7%), thrombocytopenia (5%), fatigue (5%), increased lipase or amylase (7 %). Concurrent somatostatin analogues (SSA) were allowed if stable dose was administered for two months. No significant cabozantinib-related toxicity has been reported in patients receiving concomitant somatostatin analogues. |
Further evaluation of cabozantinib is warranted in combination to efficacious drugs with a good profile of safety and tolerability. Lanreotide is a somatostatin analogue available in a long-acting formulation, conventionally administered every 28 days at the dose of 120 mg. Together with octreotide, it is considered the therapy of choice in the control of endocrine syndromes associated with NETs. A complete or partial clinical response to SSA therapy is generally achieved in at least 50% of patients with neuroendocrine syndrome. Data about the efficacy of lanreotide 120 mg in prolonging median PFS in GEP NET patients have been published in July 2014 in the NEJM, validating its anti-proliferative effects. These data show that in a population of 204 patients with non- functioning GEP-NET, naïve to previous somatostatin analogues treatment, there was a 53% risk reduction of death or disease progression after 24 months of treatment with lanreotide 120 mg/28 days compared to placebo (HR=0.47; 95% CI: 0.30-0.73; p<0.001). In other words, 65% of patients treated with lanreotide 120 mg/28 days vs 33% of patients treated with placebo had not progressed over the 2 years of treatment. The molecular anti-proliferative effect of somatostatin analogues is characterized by both direct and indirect anti-proliferative mechanisms, which may potentially improve clinical activity and efficacy of SSAs in combination to cabozantinib. Somatostatin analogues indirectly induce inhibition of growth factor secretion (GH, XXX-0, XXX, XXXX, XXX, XXXX, XXX, XXX), inhibition of angiogenesis by interaction with peritumoral vascular SST2 receptors, and immunomodulatory effects mediated by natural killer lymphocytes and monocytes. Directly, SSTR1-5 inhibit cell proliferation with a downregulation of the MAPK pathway and SSTR2/3 improve apoptosis by activation of p53/BAX. The primary or secondary mechanism of resistance to somatostatin analogues include compensatory over expression of growth factor receptors (IGF1R, VEGFR, PDGFR) and their intracellular effectors, the dysregulation and constitutive activation of Pi3K/ AKT/ mTOR and RAS/MAPK pathways and genetic aberration including mutation of XXXX, Xx0X, XXX0, XX0, XXX0. Overexpression of VEGF, PDGF and their receptors has been implicated in tumor angiogenesis in NETs. Receptor Tyrosine Kinases (RTKs) are implicated in deregulated/autocrine proliferation and survival of solid and hematologic cancer cells. Sunitinib is the only multitargeted tyrosine kinase inhibitor of angiogenesis approved for advanced NETs. In a Phase III study, sunitinib demonstrated an improvement in PFS and ORR versus placebo in patients with well- differentiated, advanced and/or metastatic pNETs. Similary to sunitinib, cabozantinib is an orally administered anti- angiogenetic small molecule that inhibits the tyrosine kinase enzymatic |
activities with particular affinity for VEGF2, MET, AXL, and RET receptors. Based on the efficacy and activity data from phase II and III trials on RCC, HCC, MTC and NET patients, due to its high-spectrum biological activity against multiple and non-redundant oncogenic pathways, cabozantinib may be superior to other angiogenesis inhibitors, especially in the treatment of rarer tumor histologies which are commonly associated with a worse prognosis and few available treatments. Although clinical experience of the combination of cabozantinib and somatostatin analogues in NETs is limited, the potential biological synergy and the favorable toxicity profile of lanreotide lead to evaluate the activity and safety of these drugs in combination, providing an opportunity for a novel therapeutic strategy for the treatment of subjects with NETs expressing somatostatin receptors. The biological rationale of the synergistic effects of cabozantinib in combination with lanreotide resides in the concomitant inhibition of intracellular signalling pathways associated with tumor cell proliferation, angiogenesis and immune modulation. The aim of this study is to define the safety and the activity of a concomitant treatment of cabozantinib plus lanreotide in progressive advanced GEP- NETs, thoracic and unknown origin NETs and to evaluate as secondary endpoint the possible impact on progression free survival and overall survival in treatment- naïve patients or in patients treated with maximum of one line before. Summary of the biological rationale of the synergistic effects of cabozantinib in combination with lanreotide • Vascular endothelial growth factor (VEGF) pathway inhibitors have activity in advanced neuroendocrine tumors (NETs) • Given the possible synergistic anti-angiogenic and anti-proliferative properties of lanreotide and the multi-kinase inhibitor cabozantinib, this combination might prove active in blocking multiple intracellular signal transduction pathways and achieve good response rates. - In vitro experiments indicate that SSAs may display anti-angiogenic properties by inhibiting the production and release of pro-angiogenic factors as well as expression of the relevant receptors. - In vivo, cabozantinib inhibits MET and VEGFR2. - cabozantinib directly provides dual inhibition of MET and VEGFR2 preventing the MET pathway from acting as an alternative pathway in the development of VEGF TKI resistance. - Recent studies have suggested that MET activation may also play a role in NET growth. |
- Increased expression of MET correlates with decreased overall survival (OS) in GEP-NETs. - Directly, somatostatin receptors (SSTR)1-5 inhibit cell proliferation through the downregulation of the MAPK pathway and SSTR2/3 improves apoptosis through the activation of p53/BAX. - Concurrent modulation of the SSTR and c-MET/VEGFR2 axes may therefore result in deepened suppression of the MAPK and PI3K/AKT/mTOR cascades. More in detail, functional interaction between the SSTR and MET/VEGFR cascades occur at multiple levels of signal transduction. SSTR2 and SSTR5, the most frequently expressed somatostatin receptors in well-to-moderately differentiated NETs, mediate inactivation of both tyrosine kinase receptor signaling and their downstream effectors, such as the Ras/MAPK and PI3K/AKT/mTOR pathways, resulting in cell cycle progression blockade and induction of apoptosis. - Most patients treated with a VEGF-targeted agent develop resistance as evidenced by disease progression. High expression of METor AXL is associated with poor prognosis and resistance to VEGFR inhibitors in preclinical models of several cancers, but no data are available for neuroendocrine tumors. Given the known oncogenic potential of MET and AXL and their upregulation along with VEGF as part of the underlying pathobiology of tumors, the assessment by immunohistochemistry of these two oncoproteins in addition to VEGFR2 may provide an insight on angiogenic regulation mechanisms in NETs, leading to additional anticancer strategies in NET patients, including more selective VEGFR-inhibition strategies. • Cabozantinib in combination with lanreotide may improve the immunogenicity of NETs or decrease the tumor-associated immunosuppressive phenotype either by acting directly on tumor pathways or interfering with immune responses througt the modulation of systemic immune response and tumor immune infiltate. • Correlation between objective responses and deregulation of crucial cell surface receptors and their downstream effectors, may reveal novel predictive biomarkers in NETs. • Clinical responses to new therapeutic combinations may translate into significant improvements in PFS and, hopefully, of OS. | |
OBJECTIVES: | Primary Objectives: • To demonstrate safety, tolerability and activity of cabozantinib and lanreotide association in patients with well differentiated GEP and thoracic NETs I stage |
• To evaluate the safety and tolerability of cabozantinib plus lanreotide. II and III stage (Co-primary objectives) • To evaluate the safety and tolerability of cabozantinib plus lanreotide. • To evaluate the activity of cabozantinib and lanreotide combination in terms of Objective Response Rate (ORR) according to the RECIST 1.1 criteria. Secondary Objectives: • To evaluate the Progression Free Survival (PFS) and Overall Survival (OS) | |
Exploratory Objectives | The exploratory objectives of this study are: To assess the immunohistochemical expression of MET, AXL, VEGFR2 with the aim to identify predictive or prognostic molecular targets. Translational evaluations will be performed with the aim to select and identify tissue biomarkers modulating treatment activity and/or safety. |
TRIAL DESIGN: | This is a multicenter, open-label, non-comparative, non-randomized, three- stage, phase II trial |
NUMBER OF PATIENTS: | 69 |
PATIENT POPULATION: | Patient with unresectable, advanced or metastatic neuroendocrine well differentiated GEPNET (pancreatic NET, Small Intestinal NET, stomach NET, colon and rectum NET), Thoracic NET (typical and atypical lung NET, thymus NET) and unknown origin NET with KI67 ≥ 10%. |
Inclusion criteria: | Each patient must meet all of the following inclusion criteria to be enrolled in the study: - voluntary written informed consent obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; - Patients with unresectable, advanced or metastatic neuroendocrine well differentiated GEP-NET (pancreatic NET (G2-G3), Small Intestinal NET, stomach NET, rectum NET) with Ki67 ≥ 10%. - Patients with unresectable, advanced or metastatic neuroendocrine well differentiated thoracic NET (typical and atypical lung NET, thymus NET) - Patients with unresectable, advanced or metastatic neuroendocrine well differentiated unknown primary NET with Ki67 ≥ 10%. - Locally advanced or metastatic disease documented as progressive by RECIST v1.1. on CT-scan or MRI at baseline and within 12 months prior to baseline. - disease that is not amenable to surgery with curative intent; |
- presence of at least one measurable target lesion for further evaluation according to RECIST v1.1; - age ≥18 years; - eastern Cooperative Oncology Group (ECOG) performance status 0 or 1(see APPENDIX I) - Octreoscan and/or PET 68Ga positive and/or IHC for SSTR2; - Advanced GEP, thoracic and unknown origin NET limited to the treatment of patients naïve or who have received a previous therapy for advanced disease or maximum 2 lines if any of these regimens include treatment with somatostatin analogs previously administered for a short period of time (less than 12 months for Octreotide and less than 6 months for Lanreotide) - Prior PRRT therapy must be completed at least 6 months prior to enrollement; - Prior treatment with somatostatin analogs, biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, and/or radiation must be completed at least 28 days prior to registration; - Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies must be completed at least 28 days prior to registration; - Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to National Cancer Institute (NCI) CTCAE, version 5.0, grade 1 or less; - Patients must have completed any major surgery at least two months prior to registration and any minor surgery (including uncomplicated tooth extractions) at least 28 days prior to registration; complete wound healing from major surgery must have occurred at least 1 month prior to registration, and complete wound healing from minor surgery must have occurred at least 7 days prior to registration - Functioning or non-functioning tumors; - all of the following laboratory test findings: - Hemoglobin > 9 g/dL (5.6 mmol/L) - WBC > 2,000/mm3 - Neutrophils > 1,500/mm3 - Platelets > 100,000/mm3 - AST or ALT < 3 x ULN (< 5 x ULN if liver metastases are present) - Total Bilirubin < 1.5 x ULN (except subjects with Xxxxxxx Syndrome, who can have total bilirubin < 3.0 mg/dL) - Adequate renal function, based upon meeting the following laboratory criteria: |
a . Serum creatinine ≤ 1.5 ´ upper limit of normal (ULN) or calculated creatinine clearance ≥ 40 mL/min using the Xxxxxxxxx-Xxxxx equation: (140 – age) × weight (kg)/(serum creatinine × 72 [mg/dL]) for males. (For females multiplied by 0.85) AND b. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g - Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis - PT-INR/PTT ≤ 1.5 x upper limit of normal. - Availability of a representative FFPE tumor specimen collected before starting treatment with cabozantinib and lanreotide that enables the definitive diagnosis of NET (the archival specimen must contain adequate viable tumor tissue to enable candidate biomarkers status; the specimen may consist of a tissue block or at least 10 unstained serial sections with 3 microns of thickness; for core needle biopsy specimens, at least two cores should be available for evaluation) - Female subjects of childbearing potential must not be pregnant at screening - Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception with a failure rate of < 1% per year (eg, barrier methods, including male condom or female condom with spermicidal gel, intrauterine devices, surgical male or female sterilisation) during the study and for 4 months after the last dose of study treatment - Female subject is either: post-menopausal for at least one year before the screening visit, or surgically sterilized, or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. - Male subject, even if surgically sterilized (ie, status postvasectomy), agrees to use an acceptable method for contraception during the entire study treatment period through 4 months after the last dose of cabozantinib. - Patients must be accessible for treatment and follow up as well as they must be willing and capable to comply with the requirements of the study. | |
Exclusion criteria: | Patients meeting any of the following exclusion criteria are not to be enrolled in the study: - Patients with undifferentiated, poorly differentiated GEP-NET, Thoracic or unknown primary NET; |
- Previous therapy for advanced disease > 1 line or > 2 line if any of these regimens include treatment with somatostatin analogs previously administered for a long period of time (more than 12 months for Octreotide and more than 6 months for Lanreotide) ; any medical adjuvant treatment must have been stopped at least six months before entry into the study; - Prior treatment with cabozantinib; - Prior treatment with any other tyrosine kinase inhibitors or anti- VEGF angiogenic inhibitors is permitted. Prior treatment with non- VEGF-targeted angiogenic inhibitors such as Everolimus is permitted; - Patients who stopped Everolimus or tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors treatment less than 4 weeks prior to the start of the study; - Patients with concomitant treatment with Interferon; - Patients previously treated with chemotherapy, loco-regional therapy (e.g., chemoembolization) or interferon with last administration less than 4 weeks prior to the start of the study or with toxicity not resolved to less or equal grade 1 at the start of the study; - PRRT therapy with last administration less than 6 months prior to inclusion in the study or with toxicity not resolved to less or equal grade 1 at the start of the study; - diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri; - history of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA see Appendix II); - prolongation of QT interval: Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances (e.g., hypokaliemia, family history of long QT Syndrome). Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms within 28 days before registration should be shown. Only subjects with a baseline QTcF ≤ 500 ms are eligible for the study. Note: If the QTcF was > 500 ms in the first ECG, a total of 3 ECGs were to be performed. If the average of these 3 consecutive results for QTcF was ≤ 500 ms, the subject met eligibility in this regard. |
- history of aneurysms and arterial dissections. The use of VEGF pathway inhibitors in patients with or without hypertension may favor the formation of aneurysms and / or arterial dissections. Before starting cabozantinib, this risk must be carefully considered in patients with risk factors such as hypertension or history of aneurysm. - poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]; - history of cerebrovascular accidents, including transient ischemic attack (TIA), history of thromboembolic events (including pulmonary embolism) or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible; - concomitant anticoagulation at therapeutic doses with oral anticoagulant (eg. Warfarin, direct thrombin and factor 10a inhibitors) or platelet inhibitors (eg. Clopidrogrel); - major surgery or trauma within 28 days prior to study entry; the presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major surgery); - known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before the start of the study. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of inclusion; - With the exclusion of inhaled steroids, chronic treatment with corticosteroids with dose superior of 10 mg/day methylprednisolone equivalent must be avoided; - evidence of active bleeding or bleeding diathesis and/or clinically- significant GI bleeding within 6 months before the first dose of study treatment; 3 months for pulmonary hemorrhage and patients with tumor invading or encasing any major blood vessels; - patients with GI disorders associated with a high risk of perforation or fistula formation; - major surgery within 2 months before to registration. Complete healing from major surgery must have occurred 1 month before registration. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before registration. Subjects with clinically relevant complications from prior surgery are not eligible - subjects with clinically relevant ongoing complications from prior radiation therapy; |
- positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness; - patients with complicated, symptomatic untreated lithiasis of the bile ducts; - any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures; - previous or ongoing treatment (except for adjuvant therapies) with any of the following anti-cancer therapies: chemotherapy, immunotherapy, target therapies, investigational therapy or hormonal therapy within 28 days or five half-lives of a drug (whichever is longer) prior to the first dose of cabozantinib plus lanreotide; - inability to swallow tablets; - rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. - previously identified allergy or hypersensitivity to to the study drugs and/or their excipients of the study treatment formulations; - concomitant use of strong inhibitor of CYP3A4 (i.e. information reported in session 4.5 of the protocol) | |
Duration of the study: | Trial expected duration (comprehensive of accrual, treatment and follow- up): 36 months (stage I plus stage II plus stage III). This should be added to a planned duration of follow up of 6 months since the enrolment of the last patient (resulting in a maximum of 42 months). |
TREATMENT ADMINISTRATION | Cabozantinib will be administered orally at a dose of 60 mg/day continuously in combination with Lanreotide 120 mg injection every 28 days. Both treatments will start the same day. |
Sample size, analysis methods: | This is an Italian, multicenter, open-label, double cohort, non comparative, non-randomized, three-stage, phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in GEP-NETs (Pancreatic NET, Small Intestinal NET, stomach NET, rectum NET), thoracic carcinoids (typical and atypical lung NET, thymus NET) and NETs of unknown origin. The two cohorts are identified according to the type of NET: pNETs and carcinoids including GEP-NETs (Small Intestinal NETs, stomach NETs, rectum NETs), thoracic carcinoids patients (typical and atypical lung NETs, thymus NETs) and NETs of unknown origin. For both cohorts the experimental treatment is the combination of cabozantinib plus lanreotide. The protocol will be designed according to three different stages. In the I stage the primary endpoints will be: safety and tolerabilitity in terms of the rate (%) of patients experiencing grade 3-5 toxicities according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. In the II/III stage the primary endpoints will be: safety and tolerability in terms of the rate (%) of patients experiencing grade 3-5 toxicities according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, and overall response rate. Enrollment in the pancreatic and carcinoid cohort will be competitive in the first stage. Sample Size calculation: I stage (i.e. run-in stage) : this stage aims to find the optimal dose of cabozantinib in combination with lanreotide. Starting dose of cabozantinib will be 60 mg plus lanreotide 120 mg. We will maintain fixed dose of lanreotide. Seven patients (both type of NET considered in inclusion criteria) will be enrolled. If grade 3-5 adverse events (AEs), excluded not clinically significant (NCS) laboratory abnormalities or clinically manageable and reversible G3 AEs within 7 days from their onset are observed in more than one patient, cabozantinib starting dose of 60 mg will be considered too toxic and ruled out (H0: % grade 3-5 toxicities < 5%; nominal p-value: 0.05; actual p- value: 0.044). In the latter case, 40 mg will be chosen as starting dose of cabozantinib. In the former case, 60 mg will be chosen as starting dose of cabozantinib. In order to preserve internal validity study enrollment will be re-started in the II stage. An interim safety analysis will be performed when all 7 patients will be observed on treatment for at least 8 weeks. If after the interim safety analysis observed in these 7 patients the combination of |
cabozantinib plus lanreotide will be consider too toxic (at the cabozantinib dose of 60 or 40 mg), the trial will be stopped. Otherwise other 10 patients will be accrued in stage II.
Follow up for safety and assessment for all stages will be every 3 cycles for each patient. Dose modification and AEs managements will be managed according to the latest version of SmPC.
Hypothesis 1
Starting dose | First dose level reduction | Second dose level dose reduction | Third dose level reduction |
60 mg daily (qd) | 40 mg daily (qd) | 20 mg daily (qd) | No dose reduction permitted |
Hypothesis 2
Starting dose | First dose level reduction | Second dose level dose reduction |
40 mg daily (qd) | 20 mg daily (qd) | No dose reduction permitted |
II-III stage: For each type of NET the optimal Xxxxx two-stage design will be used. For each type of NET the null hypothesis H0 that the true response rate is 5% will be tested against a one-sided alternative H1 that the true response rate is > 20%. Type I and II errors will be respectively equal to 5% and 20%.
For each type of NET, 10 patients will be accrued in the II stage. If no responses are observed in these 10 patients, the arm will be stopped. Otherwise other 19 patients will be accrued in stage III, for a total of 29 patients. The null hypothesis will be rejected if 4 or more responses are observed in 29 eligible patients.
Considering the drop out rate of 5% (i.e. eligible patients without the assessment of objective response) the maximum number of enrolled patients will be 69 (including the 7 patients enrolled in the stage I).
Safety: Safety is the other co-primary endpoint. We aim to statistically demonstrate that an unacceptable toxicity rate greater or equal to 20% is rejected using our data. The null hypothesis, to be rejected, is H0 : >20%. The alternative hypothesis, to be detected, is H0 : <5% (type I error will be equal to 5%, type II error will depend on the total number of enrolled patients). Because the statistical design is adaptive (i.e. a couple of Simon’s two stage designs are planned), the total number of patients that could be analyzed for safety is uncertain prior to study execution.
It could be 20 patients if both arms stop at the second stage, 39 (29+10) patients if only one arm stops at the second stage and 58 (29+29) patients if both arms are involved in the third stage. Thresholds to identify significant level at 5% and exact binomial test’s power will be determined based on the real number of patients to be analyzed [i.e. 0/20 (test’s power: 36%), 3/39 (test’s power: 87%) ; 6/58 (test’s power: 97%) are the maximum number of observed G3-G5 AEs to reject H0 : > 20% at a 5% significant level]. Overall survival (OS) will be pragmatically evaluated when all co- primary endpoints will be collected for each accrued and treated patients. |
INDEX
INTRODUCTION AND STUDY RATIONALE 23
1.1 Study rationale 23
1.2 Drug background of cabozantinib 31
1.2.2 Activity of Cabozantinib in the transgenic RIP-Tag2 mouse model of neuroendocrine pancreatic cancer 32
1.2.3 Non-clinical Toxicology 33
1.2.5 Clinical Data in Neuroendocrine Tumors 33
1.3 Safety pharmacology, toxicology and drug metabolism 34
1.3.5 Pharmacokinetics in special patient populations 35
1.4 Summary of safety profile 36
1.5 Drug background of lanreotide 38
1.5.2 Non clinical Toxicology 38
1.5.3.1 Clinical Data of efficacy in subjects with Neuroendocrine Tumors 39
1.6 Safety pharmacology, toxicology and drug metabolism 41
1.6.5 Pharmacokinetics in special patient populations 42
1.7 Summary of safety profile 42
2.1 Primary Objective 45
2.2 Secondary Objectives 45
2.3 Exploratory Objectives 45
STATISTICAL DESIGN 45
3.1 Selection of study population 48
3.3 Inclusion Criteria 48
3.4 Exclusion Criteria 50
4.1 Preparation, Handling and Storage of Drugs 51
4.2 Cabozantinib administration and dosage schedule 52
4.3 Lanreotide administration and dosage schedule 53
4.4 Dose Reduction and Treatment interruptions 53
4.5 Potential Drug Interactions, Excluded Concomitant Medications and Procedures 54
4.5.1 Potential Drug interactions with cabozantinib 55
4.5.2 Potential Drug interactions with lanreotide 56
4.6 Prohibited and Permitted Concomitant Medications and Procedures 57
4.7 Warnings, precaution and guidelines for management of potential cabozantinib and/or lanreotide Adverse Events 58
4.9 Termination of Treatment and/or Study Participation 68
STUDY ASSESSMENT AND PROCEDURES 69
5.2 Consent 69
5.3 Tissue specimen collection 69
5.4 Collection of clinicopathological and demographic data 71
5.5 Collection and Central Review of Imaging 71
5.6 Baseline and Screening procedures 72
5.7 Treatment period 74
5.9 Survival 76
RADIOLOGICAL TUMOR ASSESSMENT 76
6.1 Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 76
7.1 Adverse Event Definition 84
7.2 Serious Adverse Event Definition 84
7.3 Unlisted (Unexpected) Adverse Event 85
7.4 Adverse Drug Reaction 85
7.5 Serious Adverse Drug Reaction 85
7.6 Serious Unexpected Suspected Adverse Reaction (SUSAR) 85
7.8 Attribution Definitions 86
7.8.1 Intensity (Severity) Reporting and Attribution 86
7.9 Reporting procedure 86
8.0 All Adverse Events 86
8.1 Procedures for Reporting Serious Adverse Events (SAEs) 87
8.1.1 Emergency Medical Contacts 89
8.2 Serious Unexpected Suspected Adverse Reaction 89
8.3 Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 89
8.3.1 Pregnancy in Female Patients 89
8.3.2 Pregnancy in Female partners of Male Patients 90
8.4 Data Monitoring Committee and other external committees 90
8.4.1 Data Monitoring Commitee 90
8.4.2 Indipendent central review of imaging 90
STATISTICAL PROCEDURES 90
9.1 Accrual and sample size 90
9.2 Analysis population 91
9.3 Statistical analysis 91
9.3.1 Primary Endpoints 92
9.3.2 Secondary Endpoints 93
9.4 Safety analysis 93
9.5 Exploratory objectives analysis 94
9.6 Descriptive statistical analysis 94
9.7 Statistical software 94
STUDY MANAGEMENT 95
10.1 Study documentation 95
10.2 Protocol violation 95
10.3 Site inspections 95
10.4 Protocol amendments 95
10.5 Compliance with the protocol and protocol revisions 95
10.6 Monitoring 95
10.7 Source documentation 96
10.8 Records retention 96
10.9 Study drug records 96
10.10 Case report forms 96
10.11 Clinical study report and pubblications 97
ADMINISTRATIVE REQUIREMENTS AND ETHICAL CONSIDERATIONS 97
11.1 Good Clinical Practice 97
11.2 Institutional Review Board/Indipendent Ethics Committee 98
11.3 Patient Information and Informed Consent 98
11.4 Premature Closure of the Study 99
11.5 Confidentiality 99
11.6 Final Disclosure 100
APPENDICES 101
(Update with additional abbreviations/remove un-used abbreviations as necessary.)
Abbreviation | Definition |
°C | degrees Celsius |
μM | micromolar |
AE | adverse event |
ANC | absolute neutrophil count |
AUC AUC0-inf CLcr Cm Cmax | area under the plasma concentration-vs-time curve AUC from 0 h to infinity Creatinine clereance centimeter maximum plasma concentration |
CR | complete response |
CTCAE | (NCI) Common Terminology Criteria for Adverse Events |
dL | Deciliter |
DLT | dose-limiting toxicity |
DNA | deoxyribonucleic acid |
ECOG | Eastern Cooperative Oncology Group |
EOT | end of treatment |
FDA | Food and Drug Administration |
GCP | Good Clinical Practice |
GLP | Good Laboratory Practice |
Ht | Height |
ICH IC50 | International Conference on Harmonisation concentration associated with 50% inhibition |
IEC | independent ethics committee |
IND | Investigational New Drug |
IRB LS | Institutional review board least squares |
Kg | Kilogram |
m2 | square meters |
MedDRA Mg | Medical Dictionary for Regulatory Activities milligram |
Min | Minute |
mL | Milliliter |
mm3 | cubic millimeters |
mmol | millimole |
MTD | maximum tolerated dose |
NCI | National Cancer Institute |
Ng | nanogram |
nM | nanomole |
PFS | progression free survival |
PR | partial response |
RECIST | response evaluation criteria in solid tumors |
Abbreviation | Definition |
SAE | serious adverse event |
SD | stable disease |
SUSAR | suspected unexpected serious adverse reaction |
ULN | upper limit of normal |
w/w | weight-to-weight ratio |
WHO | world health organization |
Wt | Weight |
INTRODUCTION AND STUDY RATIONALE
1.1 Study rationale
Neuroendocrine tumors (NETs) are a heterogeneous group of slow growing rare malignant neoplasms that arise from diffuse neuroendocrine cells. These tumors are characterised by their capacity to secrete functional amines and peptides. The majority of NETs originate in the gastro-intestinal (GI) tract and in the pancreas and are therefore referred to as gastro-entero-pancreatic (GEP) NETs, and in the thorax. Some GEP NETs secrete bioactive substances that result in a clinical syndrome (e.g. a GEP NET derived from cells that produce and secrete serotonin resulting in carcinoid syndrome) while others do not. Approximately 80 to 90% of well and moderately differentiated GEP and thoracic NETs express somatostatin receptors on their cell surface that bind with high affinity to somatostatin analogues (SSAs). Once bound, SSAs inhibit the signal transmission pathways mediated by somatostatin receptors, causing a reduction in hormone and biogenic amine secretion that may improve tumor related symptoms and stabilise tumor growth (1). Surgery is the only potential cure when there is no metastatic spread. However, in about half of the patients, the tumors have metastatised at the time of diagnosis with 21% of those with well differentiated (Grade 1) tumors and 30% of those with moderately differentiated (Grade 2 or pNET G3) tumors having distant metastases (2-3). In the presence of metastatic disease, surgical resection of the primary tumor and debulking of the metastases can still be feasible but these procedures are most often only palliative and the majority of patients will require additional medical and/or interventional therapies.
Available medical and nuclear treatment options for unresectable disease include the use of Peptide Receptor Radiotherapy (PRRT), somatostatin analogs (which may relieve symptoms related to hormonal hypersecretion and produce antiproliferative effect), the mTOR ihnibitor Everolimus and Receptor tyrosine kinases (RTKs) inhibitor Sunitinib, all with proven efficacy on PFS in phase III trial.
The activity of cytotoxic chemotherapy is documented in metastatic pancreatic (p)NETs but not in patients with metastatic carcinoid tumors, where efficacy is also limited. In these latter patients, combinations of either streptozocin, oxaliplatin or temozolomide and capecitabine, appear to be inactive, and both regimens are associated with substantial toxicity (4). Thus, additional, effective systemic therapy for neuroendocrine tumors represents an unmet medical need.
Cabozantinib is an inhibitor of multiple kinases, including VEGFR2, MET, RET and AXL, which has been recently approved for the treatment of advanced hepatocellularcarcinoma (HCC), metastatic medullary thyroid cancer (MTC) and advanced treatment naïve renal cell carcinoma (RCC) patients with intermediate or poor risk or following prior vascular endothelial growth factor (VEGF)-targeted therapy (5).
Indeed, although limited data are available, cabozantinib seems to be able to modulate the systemic immune response and tumor immune infiltrate in cancer tissue promoting antitumor immunity by triggering an increased activity of anti-tumoral cytotoxic T cells and M1 macrophages and by decreasing immunesuppressive Tregs and myeloid derived suppressor cells (MDSCs) infiltrates (6). VEGF pathway inhibitors have shown activity in advanced neuroendocrine tumors (7-9). Recent studies have suggested that activation of the MET signaling pathway may also play a role in the growth of neuroendocrine tumors: a significant MET upregulation has been evidenced in GEP-NETs and in lung carcinoids, both at the mRNA and at the protein level (10).
MET protein overexpression in GEP-NETs has been detected in 17-33% of primary lesions and in up to 60% of metastatic sites, along with increased mRNA levels (10). Increased expression of MET correlates with increased Ki-67 proliferation index, increased risk of developing liver metastases and decreased overall survival (OS) in GEP-NETs (10,13-15). Despite no functionally relevant MET mutations in exons 2, 10, 14, 16, 17 and 19 have been detected (10,12-13). MET and/or its phosphorylated form have also been detected in typical and atypical lung carcinoids, with more than 80% of cases showing a strong expression (11).
In preclinical neuroendocrine tumor models, cabozantinib inhibits cell viability and decreases metastases and invasion (16-17). Although the presence of both MET and HGF has been observed in pNETs cell lines, suggesting autocrine stimulation, HGF staining on tumor tissue samples is mainly observed in the stroma, indicating a predominant role of tumor microenvironment in sustaining MET pathway paracrine activation (12).
Figure 1 Cabozantinib provides dual inhibition of MET and VEGFR2 preventing the MET pathway from acting as an alternative pathway in the development of VEGF TKI resistance
The clinical safety and the activity of cabozantinib in NETs has been evaluated in a recent Phase II trial and presented at the ASCO GI meeting on 2017 (18).
Cabozantinib was administered at the dose of 60 mg/day in 61 patients with progressive, well differentiated, G1-2 carcinoids or pNETs. The primary endpoint was objective response rate (ORR) as measured by RECIST 1.1. Forty-one patients with carcinoid and 20 pts with pancreatic NET were accrued.
Treatment with cabozantinib was associated with objective tumor responses and encouraging PFS durations in patients with advanced carcinoid and advanced pNET. Three out twenty (3/20) patients with pNET achieved partial response (PR) (ORR 15%); 15/20 had stable disease (SD). Six out of forty-one (6/41) patients with carcinoid achieved PR (ORR 15%); 26/41 had SD.
Median progression-free survival (PFS was 21.8 months in patients with pNET and 31.4 months in patients with carcinoid. Although dose reductions were common (81%), treatment was tolerable.
Grade 3/4 toxicity observed in ≥ 1 patients included hypertension (13%), hypophosphatemia (11%), diarrhea (10%), lymphopenia (7%), thrombocytopenia (5%), fatigue (5%), increased lipase or amylase levels (7 %). Concurrent somatostatin analogues were allowed if stable dose was administered for two months. No significant additional toxicity has been reported in patients receiving concomitant somatostatin analogues and cabozantinib. Further evaluation of cabozantinib is warranted in combination to efficaciuos drugs with a good profile of safety and tolerability.
Lanreotide is a somatostatin analogue available in a long-acting formulation, conventionally administered every 28 days at the dose of 120 mg. Together with octreotide, it is considered the therapy of choice in the control of endocrine syndromes associated with NETs. A complete or partial clinical response to SSA therapy is generally achieved in at least 50% of patients with neuroendocrine syndrome (1). Data about the efficacy of lanreotide 120 mg in prolonging median PFS in GEP NET patients have been published in July 2014 in the NEJM, validating its anti-proliferative effects. These data show that in a population of 204 patients with non-functioning GEP-NET, naïve to previous somatostatin analogues treatment, there was a 53% risk reduction of death or disease progression after 24 months of treatment with lanreotide 120 mg/28 days compared to placebo (HR=0.47; 95% CI: 0.30-0.73; p<0.001). In other words, 65% of patients treated with lanreotide 120 mg/28 days vs 33% of patients treated with placebo had not progressed over the first 2 years of treatment (19).
The molecular anti-proliferative effect of SSAs in NETs is characterized by both direct and indirect anti-proliferative mechanisms, which may potentially improve clinical activity and efficacy of SAAs in combination to cabozantinib (1).
Figure 2 Somatostatin analogues binding SSTR2-5 exert direct and indirect antiproliferative effects in NETs
Somatostatin analogues (lanreotide and octreotide) indirectly induce inhibition of growth factor secretion (GH, XXX-0, XXX, XXXX, XXX, XXXX, XXX, XXX) both from the neoplastic cell and the surrounding tumor matrix, (20) have immunomodulatory effects mediated by natural killer lymphocytes and monocytes (21) and induce inhibition of angiogenesis by interaction with peritumoral vascular SSTR2 receptors.
In this respect, the impact of SSAs on tumor related angiogenesis is of considerable relevance given the critical role of this biological phenomenon in neoplastic progression. In vitro experiments indicate that SSAs may display antiangiogenic properties by inhibiting the production and release of pro- angiogenic factors as well as expression of their receptors.
Thus, in immortalized HMEC (human dermal microvascular endothelial cells), vascular endothelial growth factor (VEGF) and vascular endothelial growth factor recep-tor-2 (VEGFR-2) expression and VEGF release are inhibited by SSTR1 agonists (22). Octreotide reduced the proliferation of HUVEC (human umbilical vein endothelial cells); moreover, in different animal models of experimental
angiogenesis octreotide was able to reduce the extent of neovascularization (23). Recently, it has been demonstrated that octreotide markedly reduces splanchnic neovascularization and VEGF expression in an animal model of portal hypertension; this effect, was linked to the presence of SSTR2 (24). Similarly, in the pancreatic cancer cell line PC-3, SSTR2 expression correlates with VEGF and matrix metalloproteinase-2 expression (25).
Somatostatine analogues are also indirectly able to trigger, through a Gαi mediated mechanism, the activity of protein phosphatases such as SHP-1, which are responsible of dephosphorylation and subsequent inactivation of membrane of Receptor Tyrosine Kinases (RTKs) (26) Figure 3.
Figure 3. (a) proposed intracellular effector pathways involved in SSTR-induced cell growth inhibition and apoptosis
SSTR1-5 inhibit cell proliferation through the downregulation of MAPK pathway mediated by SHP- 1 and PTPg phosphatases; moreover, SSTR2/3 improved apoptosis by activation of p53/BAX (26- 27). In addition, the simultaneous stimulation of XXXX 0 and 5 was shown to achieve significant inhibition of Ras activity (26,28) Figure 3.
SSTR2 has also been proven to downregulate the PI3K/AKT/mTOR pathway through SHP-1 mediated dephosphorylation of PI3K p85 subunit and inhibition of the serine/threonine kinase Akt; these effects result in decreased phosphorylation of downstream mTOR effectors p70S6K and 4E- BP1, negatively regulating protein synthesis and translation (26-29) Figure 3.
The primary or secondary mechanism of resistance to somatostatin analogues include compensatory overexpression of different growth fact receptors (IGF1R, VEGFR, PDGFR) and their intracellular effectors, the dysregulation and constitutive activation of the PI3K/AKT/mTORand RAS/MAPK pathways and genetic aberrations (such as mutations of PTEN, PI3K, TSC2, NF1, LKB1) (1).
Overexpression of VEGF, PDGF and their receptors has been implicated in tumor angiogenesis in NETs (7-9). RTKs are implicated in deregulated autocrine proliferation and survival of solid and hematologic cancer cells.
Sunitinib is the only multitargeted tyrosine kinase inhibitor of angiogenesis approved for advanced NETs. In a Phase III study, sunitinib demonstrated an improvement in PFS and ORR versus placebo in patients with well-differentiated, advanced and/or metastatic pNETs (7).
The role of sunitinib in advanced GEP-NETS and lung carcinoids is less known and it is currently limited to only one phase II trial (43 patients) showing a modest single agent activity in terms of ORR and a clinical case report (30).
Given these premises, a randomized phase II double-blind trial of sunitinib versus placebo in combination with lanreotide in patients with progressive advanced/metastatic midgut carcinoid tumors is currently ongoing (SUNLAND Trial NCT01731925).
Similary to sunitinib, cabozantinib is an orally administered anti-angiogenetic small molecule that inhibits the tyrosine kinase enzymatic activities with particular affinity for VEGF2, MET, AXL, and RET receptors.
Cabozantinib improved PFS in advanced renal cell carcinoma in first-line (vs sunitinib) (31) and in second-line (vs everolimus) in patients previously treated with antiangiogenic therapy (32).
Cabozantinib is also approved for progressive, metastatic medullary thyroid carcinoma (33) and hepatocellularcarcinoma (34). Cabozantinib was associated with objective tumor responses and encouraging PFS durations in phase II trial in patients with advanced carcinoid and advanced pNET (18).
On the basis of the efficacy and activity data from phase II and III trials in RCC, HCC, MTC and NET patients (18, 31-34), due to its high-spectrum biological activity against multiple and non- redundant oncogenic pathways, cabozantinib may be superior to other angiogenesis inhibitors especially in the treatment of rarer tumor histologies which are commonly associated with a worse prognosis and few available treatments.
Although there is limited clinical experience of the combination of cabozantinib and somatostatin analogues in NETs, the potential biological synergy and the favorable profile of toxicity of lanreotide lead to evaluate the activity and safety of these drugs in combination, providing an opportunity for a novel therapeutic strategy for the treatment of subjects with NET expressing somatostatin receptors. The biological rationale of the synergistic effects of cabozantinib in combination with lanreotide resides in the concomitant inhibition of intracellular signalling pathways associated with tumor cell proliferation, angiogenesis and immune modulation.
The aim of this study is to define the safety and the activity of a concomitant treatment of cabozantinib plus lanreotide in progressive advanced GEP NETs, (including pancreatic, small intestinal, stomach, rectum NETs), thoracic carcinoids patients (typical and atypical lung and thymus NETs) and NETs of unknown origin and to evaluate as secondary endpoint the possible impact on progression free survival and overall survival in treatment naïve patients or in patients treated with a maximum of one line before.
Summary of the biological rationale of the synergistic effects of cabozantinib in combination with lanreotide
• VEGF pathway inhibitors have activity in advanced NETs
- Given the possible synergistic anti-angiogenic and anti-proliferative properties of lanreotide and the multi-kinase inhibitor Cabozantinib, this combination might prove active to block multiple intracellular signal transduction pathways and achieve good response rates. In vitro experiments indicate that SSAs may display anti-angiogenic properties by inhibiting the production and release of pro-angiogenic factors as well as expression of the relevant receptors.
- In vivo cabozantinib inhibits MET and VEGFR2.
- Cabozantinib directly provides dual inhibition of MET and VEGFR2 preventing the MET pathway from acting as an alternative pathway in the development of VEGF TKI resistance.
- Recent studies have suggested that MET activation may also play a role in NET growth.
- Increased expression of MET correlates with decreased OS in GEP-NETs.
- SSTR1-5 directly inhibit cell proliferation through the downregulation of the PI3K/AKT/mTOR and Ras/MAPK pathways and SSTR2/3 improved apoptosis by activation of p53/BAX.
- Concurrent modulation of the SSTR and c-MET/VEGFR2 axes may therefore result in deepened suppression of the MAPK and PI3K/AKT/mTOR cascades.
More in detail, the functional interaction between the SSTR and MET/VEGFR cascades occur at multiple levels of signal transduction. SSTR2 and SSTR5, the most frequently expressed somatostatin receptors in well-to-moderately differentiated NETs, mediate the functional inactivation of both RTKs ignaling and their downstream effectors, such as the components of the Ras/MAPK and PI3K/AKT/mTOR pathways, resulting in cell cycle progression blockade and induction of apoptosis.
- Most patients treated with a VEGF-targeted agent develop resistance as evidenced by disease progression. High expression of METor AXL is associated with poor prognosis and resistance to VEGFR inhibitors in preclinical models of several cancers, but no data are available for neuroendocrine tumors. Given the known oncogenic potential of MET and AXL and their upregulation along with VEGF as part of the underlying pathobiology of NETs, the assessment by immunohistochemistry of these two oncoproteins in addition to VEGFR2 may provide an insight on angiogenic regulation mechanisms in NETs, leading to additional anticancer strategies in NET patients, including more selective VEGFR-inhibition strategies.
• Cabozantinib in combination with lanreotide may improve the immunogenicity of NETs or decrease thetumor-associated immunosuppressive phenotype either by acting directing on tumor pathways or interfering with immune responses througt the modulation of systemic immune response and tumor immune infiltate.
• Correlation between objective responses and RTK alterations and their downstream effectors may reveal novel predictive biomarkers in NETs.
• Clinical responses to new therapeutic combinations may translate into significant improvements in PFS and, hopefully, of OS.
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28. Pola S, Xxxxxxxx MG, Xxxxxxxxx LM Anti-migratory and anti-invasive effect of somatostatin in human neuroblastoma cells: involvement of Rac and MAP kinase activity. J Biol Chem. 2003 Oct 17;278(42):40601-6.
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1.2 Drug background of Cabozantinib
1.2.1 Pharmacology
Cabozantinib is a multi-targeted inhibitor of RTKs. The targets of cabozantinib include several RTKs known to play important roles in tumor cell proliferation and/or tumor neovascularization, namely VEGFR2 (also known as KDR), MET, AXL, and RET. Other recognized targets of cabozantinib
include ROS1, XXXX, XXXX, XXX0, XXXX0, and MER, two additional members of the VEGFR family (VEGFR1, VEGFR3), and the closely related RTKs KIT and FLT3. The mode of action for cabozantinib is similar to other drugs targeting RTKs: binding in a fully reversible manner to a region of the kinase domain (including the ATP-binding site) which forces the kinase activation loop into a pseudo-inactive conformation, thereby inhibiting subsequent catalytic activity (1). The cell-based target inhibition profile of cabozantinib is shown in Table 1.
Table 1: Inhibition of Key Protein Kinases by Cabozantinib in Cells
The concentrations associated with 50% inhibition (IC50) in biochemical kinase assays (Table 2) do not always translate evenly in vivo. For example, cabozantinib exhibits comparable potency against MET and VEGFR2 in cellular and in vivo assays, in spite of its apparent greater potency for inhibition of VEGFR2 in biochemical kinase assays. Data from pharmacodynamic experiments have shown that cabozantinib inhibits MET and VEGFR2 in vivo.
Oral administration of cabozantinib resulted in blockade of MET phosphorylation in human lung tumor xenografts grown in nude mice, blockade of MET phosphorylation in livers of mice, and blockade of VEGFR2 phosphorylation in mouse lung tissue. For both targets, the duration of action for cabozantinib was sustained, with > 50% inhibition observed for > 8 h post-dose at a single dose level of 100 mg/kg (2). In addition, oral administration of cabozantinib resulted in blockade of phosphorylation of mutationally activated RET in TT human MTC xenografts grown in nude mice (1). Treatment with cabozantinib results in anti-angiogenic effects in xenograft tumors, with disruption of the vasculature beginning within 24 h after administration, and is associated with pro- apoptotic effects. These effects translate into significant tumor growth inhibition or tumor regression after cabozantinib treatment in multiple tumor models including MTC, breast cancer, lung carcinoma, and glioblastoma (1,2).
IC50, concentration associated with 50% inhibition; MTC, medullary thyroid cancer; SEM, standard error of the mean. a Most frequent somatic mutation in MTC; associated with poor prognosis (3).
Table 2: Key Protein Kinase Inhibition by Cabozantinib in Biochemical Assays
1.2.2 Activity of Cabozantinib in the Transgenic RIP-Tag2 mouse model of neuroendocrine pancreatic cancer
In preclinical NET models, cabozantinib inhibits cell viability and decreases metastases and invasion (4-5). Inhibition of the VEGF signaling pathway alone was previously shown to result in more invasive tumors in the transgenic RIP-Tag2 mouse model of neuroendocrine pancreatic cancer, that spontaneously develops aggressive tumors (6). Treatment with cabozantinib for 3 weeks, from age 14 to 17 weeks, significantly prevented formation of liver metastases (Figure 4-A) in the RIP-Tag2 model compared with anti-VEGF treatment or vehicle alone. The number of liver metastases was 5- fold greater in anti-VEGF antibody-treated animals compared with vehicle-treated animals, and no liver metastases were detected in cabozantinib-treated animals (Figure 4-A). In addition, treatment with cabozantinib from age 14 to 20 weeks improved survival (Figure 4-B). Median survival was
14.7 weeks for vehicle-treated animals (n = 12) and 16.4 weeks for anti-VEGF antibody-treated animals (n = 7; P < 0.05 vs vehicle), and all cabozantinib-treated animals survived for the full 20 weeks of observation (n = 6; P < 0.05 vs vehicle and anti-VEGF antibody; Figure 4-B). These data suggest that dual inhibition of MET and VEGFR2 with cabozantinib leads to potent antitumor efficacy, including protection from metastatic tumor escape, which translates into survival advantages.
One of 7 mice in the cabozantinib group that died from a gavage injury at 3.5 weeks was excluded. * P < 0.05 anti-VEGF antibody vs vehicle # P <
0.05 cabozantinib vs anti-VEGF antibody. These results are adapted from Xxxxxxx et al. 2012 (5).
Figure 4 (A-B): RIP-Tag2 Model: Survival, Cabozantinib versus Vehicle
1.2.3 Non-clinical Toxicology
Cabozantinib nonclinical toxicology has been characterized in single- and repeat-dose studies in multiple species. Details can be found in the Investigator’s Brochure of the drug (1).
1.2.4 Clinical Data
In clinical studies, cabozantinib has been evaluated in multiple tumor types including medullary thyroid cancer, castration-resistant prostate cancer, ovarian cancer, breast cancer, hepatocellular carcinoma, nonsmall cell lung cancer, melanoma, differentiated thyroid cancer, renal cell carcinoma, and glioblastoma multiforme. To date, cabozantinib has demonstrated a broad spectrum of clinical activity in these tumor types and has been approved for the treatment of progressive metastatic medullary thyroid carcinoma, hepatocellular carcinoma, renal cell carcinoma. Consult the Investigator’s Brochure of the drug for more details. (1)
1.2.5 Clinical data in Neuroendocrine Tumors
Phase 2 ISS: Advanced Pancreatic Neuroendocrine and Carcinoid Tumors
Subjects with progressive, well-differentiated, grade 1 or 2 pancreatic neuroendocrine tumors or carcinoid tumors were enrolled in two parallel cohorts and treated with 60 mg cabozantinib qd (7). Reasons for discontinuation were disease progression or death (51%), withdrawal of consent or investigator decision (28%), and AEs (21%).
The ORR in the pNET cohort (20 subjects evaluable for tumor response) was 15% (95% CI: 5, 36), with 3 PRs and 15 SDs observed. The ORR in the carcinoid cohort (41 subjects evaluable for tumor response) was 15% (95% CI: 7, 28), with 6 PRs and 26 SDs observed. Median PFS was 21.8 months
(95% CI: 8.5, 32.0) in the pNET cohort and 31.4 months (95% CI: 8.5, not reported) in the carcinoid cohort. All subjects in each cohort were evaluable for safety.
Grade 3 or 4 AEs reported in one or more subjects were hypertension (13%), hypophosphatemia (11%), diarrhea (10%), lymphopenia (7%), thrombocytopenia (5%), fatigue (5%), and increased lipase or amylase (8%). Concurrent somatostatin analogues were allowed if stable dose was administered for two months. No significant toxicity in the safety of cabozantinib in patients receiving concomitant somatostatin analogues has been reported. Further evaluation of cabozantinib is warranted in combination to efficacious drugs with a good profile of safety and tolerability (1).
1.3 Safety pharmacology, toxicology and drug metabolism
1.3.1 Absorption
Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 2 to 5 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation (7). Repeat daily dosing of cabozantinib at the dose of 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.
A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken one hour after administration of cabozantinib. Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ) was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations (1,7).
1.3.2 Distribution
Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population- pharmacokinetic (PK) model, the volume of distribution (Vz) is approximately 212 L (SE: ± 2.7%). Protein binding was not altered in subjects with mild or moderately impaired renal or hepatic function (1).
1.3.3 Biotransformation
Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184- N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure.
Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalyzed human liver microsomal (HLM) incubation; in contrast, neutralizing antibodies to XXX0X0, XXX0X0, XXX0X0, XXX0X0, XXX0X00, XXX0X0 and CYP2E1 had no effect on cabozantinib metabolite formation. A
neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation (ie, a <20% reduction) (1).
1.3.4 Elimination
In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 healthy volunteers following oral administration of a range of doses from 20 mg to 140 mg, the plasma terminal half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was estimated to be 2.48 L/hr. Within a 48-day collection period after a single dose of 14C- cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine (1,7).
1.3.5 Pharmacokinetics in special patient populations
Renal impairment
Results from a study in patients with renal impairment indicate that the ratios of geometric least squares (LS) mean for plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 140.11%), for subjects with moderate renal impairment compared to subjects with normal renal function. Patients with severe renal impairment have not been studied.
Cabozantinib no dose adjustments are needed in patients with mild or moderate renal impairment. Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population (1,7).
Hepatic impairment
Results from a study in patients with hepatic impairment indicate that exposure (AUC0-inf) increased by 81% and 63% in subjects with mild and moderate hepatic impairment, respectively (90% CI for AUC0-inf: 121.44% to 270.34% for mild and 107.37% to 246.67% for moderate). Patients with severe hepatic impairment have not been studied. In patients with mild hepatic impairment no dose adjustment is required. Since only limited data are available for patients with moderate hepatic impairment (Child Xxxx B), no dosing recommendation can be provided. Close monitoring of overall safety is recommended in these patients. There is no clinical experience in patients with severe hepatic impairment (Child Xxxx C), so cabozantinib is not recommended for use in these patients (1,7).
Patients with cardiac impairment
There are limited data in patients with cardiac impairment. No specific dosing recommendations can be made (1).
Race
A population PK analysis did not identify clinically relevant differences in PK of cabozantinib based on race. No dose adjustment is necessary based on ethnicity (1).
Elderly patients
No specific dose adjustment for the use of cabozantinib in older people (≥ 65 years) is recommended (1).
Detailed information regarding the nonclinical pharmacology and toxicology of cabozantinib may be found in the Investigator broschure of the drug (1).
1.4 Summary of safety profile
The most common serious adverse reactions associated with cabozantinib are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%), and nausea (2%) (7).
The most frequent adverse reactions of any grade (experienced by at least 25% of patients) included diarrhoea (74%), fatigue (56%), nausea (50%), decreased appetite (46%), palmar-plantar erythrodysaesthesia syndrome (PPES) (42%), hypertension (37%), vomiting (32%), weight decreased (31%), and constipation (25%) (7).
Adverse reactions are listed in Table 3 according to MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness (7-9).
This study will be conducted in compliance with the protocol, applicable regulatory requirements, and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), guidelines.
MedDRA System Organ Class | Very Common | Common | Uncommon | Not Known |
Infections and infestations | abscess | |||
Blood and lymphatic disorders | anaemia tkíombocQtkcmia, | ⭲c"tíopc⭲ia lynphopenia | ||
Endocrine disorders | hypothyroidism | |||
Metabolism and nutrition disorders | decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia | dehydration, hypophosphataemia , hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinemia, hypoglycaemia hyperglycaemia, | ||
Nervous system disorders | dysgeusia, headache, dizziness | peripheral sensory neuropathy | convulsion, | cerebrovas cular accident |
Ear and labyrinth disorders | tinnitus | |||
Cardiac disorders | myocardial infarction | |||
Vascular disorders | hypertension, haemorrhage | deep vein thrombosis, venous and arterial thrombosis | aneurysms and arterial dissections |
hypertentio n crisis* ;hypertensi on with life threatening consequen ces” ** ; arterial embolism* ** | ||||
Respiratory, thoracic, and mediastinal disorders | dysphonia, dyspnea, cough | pulmonary embolism | ||
Gastrointestinal disorders | diarrhoea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, abdominal pain upper | gastrointestinal perforation, fistula, gastrooesophageal reflux disease, haemorrhoids, oral pain, dry mouth, glossodynia, dysphagia | Pancreatitis, | |
Hepatobiliary disorders | hepatic encephalopaty | hepatitis cholestatic Very rarely, Vanishing Bile Duct Syndrome (VBDS) *** | ||
Skin and subcutaneous tissue disorders | palmar-plantar erythrodysaesthesia syndrome, rash | pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change | ||
Musculoskeletal and connective tissue disorders | pain in extremity | muscle spasms, arthralgia | osteonecrosis of the jaw | |
Renal and urinary disorders | proteinuria | |||
General disorders and administration site conditions | fatigue, mucosal inflammation, asthenia, peripheral oedema | |||
Investigations | weight decreased, serum ALT, AST increased | ALP increased, creatinine increased, GGT increased, amylase increased, blood cholesterol and triglycerides increased, lipase increased, white |
blood cell count decreased | ||||
Injury, poisoning and procedural complications | wound complications |
*From Appendix K and L hypertention crisis listed as substantial change of Cabozantinib (XL184) Investigator’s Brochure, EXELIXIS 2021, v17.
** XL184 Investigator’s Brochure v18 2022 Summary of Changes
*** XL184 Investigator’s Brochure v19 2023 Summary of Changes
Table 3: Adverse reactions reported with cabozantinib
1.5 Drug background of lanreotide
1.5.1 Pharmacology
Lanreotide is a well-established peptide analogue of the natural hormone somatostatin, in which the biochemical stability of the peptide has been increased by incorporation of modified amino acids. Like native somatostatin, lanreotide inhibits the secretion of many hormones and has anti- proliferative activity (8).
Receptors for somatostatin are expressed on the surface of most NETs, and since somatostatin inhibits cell proliferation, the compound can also be used to treat these tumors. The therapeutic use of somatostatin is, however, limited by its short half-life of only 2 to 3 minutes. Therefore, synthetic SSAs with increased specificity and half-life duration have been developed for medicinal use.
Lanreotide is a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin. The compound is characterised by the presence of D-Tryptophan in the amino acid ring, increasing stability, and by the presence of D-beta Nal outside of this ring, which increases its selectivity. The terminal amine function reduces binding to central nervous system receptors. Lanreotide exhibits high affinity for the somatostatin Type 2 (SSTR2) and Type 5 (SSTR5) receptors found in the pituitary gland, GH secreting pituitary tumors, NETs and the digestive tract. The product has a much lower affinity for somatostatin Type 1, 3 and 4 receptors (8).
Activity at human SSTR2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine, and paracrine functions.
The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels. In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Lanreotide, plasma GH levels fall rapidly and are maintained for at least 28 days.
Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK).
In healthy subjects, lanreotide produces a reduction and a delay in postprandial insulin secretion, resulting in transient, mild glucose intolerance.
Lanreotide inhibits meal-stimulated pancreatic secretions, reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity.
Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects. In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide.
In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration.
Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis.
Lanreotide Autogel is approved for treatment of acromegaly, GEP NETs and symptoms associated with NETs and carcinoid syndrome (8).
1.5.2 Nonclinical Toxicology
Lanreotide nonclinical toxicology has been characterized in single- and repeat-dose studies in multiple species. Details can be found in the Investigator’s Brochure of the drug (8).
1.5.3 Clinical Data
The safety and efficacy of lanreotide has been demonstrated in subjects with acromegaly or GEP NETs. Different formulations of lanreotide (including lanreotide Autogel 120 mg every 28 days) also produced similar results in other indications including cardiac disorders, GI bleeding, diabetes, thyrotropic adenoma, digestive fistulae, ophthalmic Graves disease and paediatric studies, where the types and percentages of related serious adverse events (SAEs) across indications were broadly similar and no specific safety concerns were identified.
1.5.3.1 Clinical data of efficacy in Subjects with Neuroendocrine Tumors Control of Symptoms Associated with NETs
A phase III/IV, double-blind study (ELECT trial) assessed the efficacy of lanreotide administered at the dose of 120 mg every 28 days for the control of symptoms associated with NETs (diarrhoea and/or flushing). Least squares (LS) mean percentage of days on which s.c. octreotide was administered as rescue medication during the double-blind (DB) phase as a surrogate for symptom control, was significantly lower in favour of the lanreotide group (33.72% of days) compared with the placebo group (48.49% of days) (p=0.0165). The absolute difference in LS means (95% CI) was –14.76% (- 26.78%, -2.75%).
Results of the subgroup analyses confirmed the consistency of the results of primary efficacy variable. There was a reduction in mean percentage of days in which deep s.c. octreotide was administered as rescue medication irrespective of age, gender, race, ethnicity, time since diagnosis and BMI (except for BMI>30) supporting the robustness of the primary efficacy analysis. No statistically significant changes in QoL measures were reported; modest improvements in global health status (EORTC-
QLQ-C30) and GI and endocrine symptoms were observed for the lanreotide group compared with the placebo group.
For biochemical markers, subjects treated with lanreotide showed reductions from baseline in median values of CgA and 5-HIAA, while these biomarkers had increases in median values in the placebo group.
Overall, the results demonstrated that subjects who received lanreotide required octreotide, as rescue medication to treat the symptoms of carcinoid syndrome, for significantly fewer days compared subjects who placebo. These results indicate that lanreotide is beneficial in reducing rescue medication usage to control symptoms associated with NETs.
An international, non-interventional, cross-sectional phase IV study (SYMNET trial) has been conducted to assess NET subjects currently treated by lanreotide for history of carcinoid syndrome associated with episodes of diarrhoea. In total, 76% of the subjects were overall satisfied regarding control of their diarrhoea: 37% completely satisfied and 39% rather satisfied. Severe diarrhoea was reported for 49% of the subjects before treatment with lanreotide and for 10% of the subjects on the day of the visit. On the day of the visit 29% of the subjects had no diarrhoea compared to 8% at treatment initiation.
The assessment of change compared to the situation before treatment initiation was mostly positive: 79% of the subjects considered their situation better on the day of the visit, 13% perceived no change and 8% considered that they were in a worse situation.
The study confirmed in a real life setting the ability of lanreotide to control diarrhoea and flushes associated with NETs. Diarrhoea and other symptoms related to carcinoid syndrome were improved, with an overall decrease in stool frequency and in frequency and severity of flushes. Absence of diarrhoea, stool leakage, associated pain and flushes was observed for 51%, 75%, 68% and 49% of the subjects who experienced these symptoms at treatment initiation, respectively (8).
AntiProliferative Effect of Lanreotide in Subjects with Neuroendocrine Tumors
In the phase III, randomised, double-blind, placebo-controlled, multinational study CLARINET conducted in 204 subjects with GEP NETs, treatment with lanreotide 120 mg (N=101) administered as deep s.c. injections every 4 weeks for up to 96 weeks led to a longer PFS compared to placebo (mPFS greater than 96 weeks in the lanreotide group compared to 72 weeks with placebo, [p=0.0002]). Based on the Xxxxxx-Xxxxx estimates, 38% of subjects had progressed or died in the lanreotide group, compared with 78% of subjects in the placebo group. Treatment with lanreotide 120 mg reduced the risk of progression or death by 53% (Hazard Ratio = 0.47, 95% CI: 0.30, 0.73). Results from the open-label extension of CLARINET study, the OLE trial, showed that long-term treatment with lanreotide 120 mg led to a significant prolongation in PFS.
The median PFS for the 101 subjects treated with lanreotide 120 mg was 154.14 weeks (95% CI: 123.57, 237.43), whereas it was 72.00 weeks (95% CI: 48.43, 84.57) in 103 subjects who received placebo during the CLARINET Study, which corresponds to an improvement of 82.14 weeks.
Figure 4: Xxxxxx-Xxxxx Curves of Progression-Free Survival
Of the 32 subjects who had progressed in this trial on placebo treatment and were switched to lanreotide 120 mg in the extension Study, 20 subjects had subsequent PD and three subjects died.
The median time to subsequent PD or death during the OLE study was 76.14 weeks (95% CI: 40.29, 106.86). At the time of the final analysis, the median OS time was not reached in either treatment group.
The therapeutic effect in predefined subgroups was generally consistent with that of the overall population, with the exception of small subgroups in which CIs were wide. There were no significant between-group differences in quality of life or overall survival.
In conclusion, the antiproliferative activity of lanreotide Autogel was demonstrated and supports the registration of an antiproliferative effect of lanreotide and its inclusion in the treatment algorithm of subjects with GEP NETs (8).
1.6 Safety pharmacology, toxicology and drug metabolism
1.6.1 Absorption
Lanreotide is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the bloodstream (8).
1.6.2 Distribution
After a single, deep subcutaneous administration, the mean absolute bioavailability of lanreotide in healthy subjects was 73.4, 69.0, and 78.4% for the 60 mg, 90 mg, and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was
demonstrated with respect to AUC and Cmax, and showed high inter-subject variability. Lanreotide autogel (depot formulation) showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL at 60 mg. In patients with GEP-NETs treated with Lanreotide 120 mg every 4 weeks, steady state concentrations were reached after 4 to 5 injections and the mean trough serum lanreotide concentrations at steady state ranged from 5.3 to 8.6 ng/mL. Information from human studies regarding distribution of lanreotide is not available (8).
1.6.3 Biotrasformation
Indirect information regarding the metabolism of lanreotide is obtained from studies in special populations, which suggest that the kidney plays a more relevant role in the metabolism of lanreotide than the liver. No other clinical data regarding the metabolism of lanreotide are available (8).
1.6.4 Elimination
The urinary and faecal excretion of lanreotide is minimal and represents only a small fraction of lanreotide elimination while the recovery of unchanged lanreotide in faeces is indicative of biliary excretion. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion (8).
1.6.5 Pharmacokinetics in special patient populations
Renal Impairment
An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC was observed. Patients with acromegaly and with moderate to severe renal impairment should begin treatment with Lanreotide 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Lanreotide 120 mg every 6 or 8 weeks.
Mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment has no effect on clearance of lanreotide in patients with GEP-NETs based on a population PK analysis which included 106 patients with mild and 59 patients with moderate renal impairment treated with Lanreotide. GEP- NET patients with severe renal impairment (CLcr < 30 mL/min) were not studied (8). The recommended dose of lanreotide is 120 mg administered every 4 weeks by deep subcutaneous injection.
Hepatic impairment
In subjects with moderate to severe hepatic impairment, a 30% reduction in the clearance of lanreotide was observed. Mean residence time (MRT) and volume of distribution were increased in subjects with varying degrees of hepatic insufficiency.
Patients with acromegaly and with moderate to severe hepatic impairment should begin treatment with Lanreotide 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Lanreotide 120 mg every 6 or 8 weeks.
The effect of hepatic impairment on clearance of lanreotide has not been studied in patients with GEP-NETs (8).
Race
No clinically relevant interethnic differences were apparent in lanreotide PK in Caucasian, Asian, Black or Hispanic acromegalic subjects after deep s.c. administration of lanreotide. A covariate analysis indicated no effect of age, height, weight and gender on the PK profile of lanreotide Autogel although Cmax values were higher in men than in women (8).
Elderly
Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in MRT of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects. Age has no effect on clearance of lanreotide based on a population PK analysis in patients with GEP-NETs which included 122 patients aged 65 to 85 years with neuroendocrine tumors (8).
1.7 Summary of safety profile
Consistent with the known safety profile of SSA treatment, typical AEs were observed during treatment with lanreotide, the most common being: GI disorders (diarrhoea, abdominal pain, nausea, vomiting and constipation); and hepatobiliary disorders (cholelithiasis) (table 4).
Overall, undesirable effects reported by specific subjects enrolled in clinical trials suffering from GEP NETs and carcinoid syndrome treated with lanreotide, are: GI disorders, reported by over half of the subjects (55.8%) characterized by abdominal pain (23.0%), abdominal pain upper (11.9%), vomiting (14.6%), nausea (13.0%), constipation (10.1%) and flatulence (6.9%). Diarrhoea events were reported by 27.7% of subjects. Other most frequent AEs reported by >10% of these specific subjects included: fatigue (12.2%), and asthenia (10.8%), back pain (10.6%), headache (13.5%) and cholelithiasis
(10.8%), (see table 5).
Adverse reactions are listed in Table 4 and 5 according to MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness (10).
MedDRA system organ class | Very common | common | Uncommon | Post-marketing safety experience (frequency not known) |
Metabolism and nutrition disorders | hypoglycaemia, decreased appetite**, hyperglycaemia, diabetes mellitus | |||
Psychiatric disorders | insomnia* | |||
Nervous system disorders | dizziness, headache, lethargy** | |||
Cardiac disorders | sinus bradycardia* | |||
Vascular disorders | hot flushes* | |||
Gastrointestinal disorders | diarrhoea, loose stools*, abdominal pain | nausea, vomiting, constipation, flatulence, abdominal distension, | faeces discoloured* | pancreatitis |
abdominal discomfort, dyspepsia, steatorrhoea** | ||||
Hepatobiliary disorders | cholelithiasis | biliary dilatation* | cholecystitis | |
Muskuloskeletal and connective tissue disorders | musculoskeletal pain**, myalgia** | |||
Skin and subcutaneous tissue disorders | alopecia, hypotrichosis* | |||
General disorders and administration site conditions | asthenia, fatigue, injection site reactions (pain, mass, induration, nodule, pruritus) | |||
Investigations | ALAT increased*, ASAT abnormal*, ALAT abnormal*, blood bilirubin increased*, blood glucose increased*, glycosylated haemoglobin increased*, weight decreased, pancreatic enzymes decreased** | ASAT increased*, blood alkaline phosphatase increased*, blood bilirubin abnormal*, blood sodium decreased* | ||
Immune system disorders | allergic reactions (including angioedema, anaphylaxis, hypersensitivity) | |||
Infections and Infestations | injection site abscess |
* based on a pool of studies conducted in acromegalic subjects
** based on a pool of studies conducted in subjects with GEP-NETs
Table 5: summary of the undesirable effects of lanreotide for GEP NET and crcinoid syndromes patients
References
1. Cabozantinib (XL184) Investigator’s Brochure, EXELIXIS 2019, v15.
2. Xxxxx FM, Xxxx J, Xxx J, Xxxxxxxxx K, Xxx Y, Xx P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298-308.
3. Xxxxxxxxx T, Xxxxxx J, Xxxx HP, Xxxxxxx A, Xxxx HF, Xxxxxxxx W, et al. Prognostic value of codon 918 (ATG/ACG) RET protooncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. 2001;95:62–66.
4. Xxxxxxx C ,Xxxxxxx X, Spampatti M et al. Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for 'Off-Target' Effects Not Mediated by c-Met Inhibition. Neuroendocrinology. 2016;103(3-4):383- 401.
5. Xxxxxxx B, Ishiguro-Oonuma T, Xxx Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors Cancer Discov. 2012;2(3):270-287.
6. Xxxxx-Xxxxx M, Xxxxx E, Xxxxxx J, Xxxxxx T, Xxxxxxx H, Xxxxxxx F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009; 15:220-231.
7. Cabozantinib SmPC V.Sept 2019
8. 09/11/2021 Cabometyx - EMEA/H/C/004163 - IB/0025, product information last updated 01/12/2021 xxxxx://xxx.xxx.xxxxxx.xx/xx/xxxxxxxxx/xxxxx/XXXX/xxxxxxxxx
9. Cabozantinib (XL184) Investigator’s Brochure, EXELIXIS 2021, v17.
10. Lanreotide Investigator’s Brochure 2018, IPSEN, Version 20.0
STUDY OBJECTIVES
2.1 Primary Objectives:
The primary objectives of this study is to demonstrate safety, tolerability and activity of cabozantinib and lanreotide association in patients with well differentiated GEP, Thoracic and unknown primary NET
I stage
To evaluate safety and tolerability of cabozantinib plus lanreotide
II and III stage (Co-primary objectives)
To evaluate safety and tolerability of cabozantinib plus lanreotide.
To evaluate the activity of cabozantinib and lanreotide combination in terms of objective response rate according to the RECIST 1.1 criteria.
2.2 Secondary Objectives:
To evaluate clinical efficacy in terms of the progression free survival and overall survival.
2.3 Exploratory Objective :
Exploratory analyses will be conducted in order to identify possible predictors of outcomes in GEP and Toracic NETs receiving lanreotide plus cabozantinib, with the aim to select and identify tissue biomarkers modulating treatment activity and/or safety.
The exploratory objective of this study are:
- to identify the tissue expression level of MET, AXL, VEGFR2 by Immunoistochemistry
STATISTICAL DESIGN
This is an Italian, multicenter (6 participating Center), open-label, double cohort, non comparative, non-randomized, three-stage, phase II trial aiming to assess the safety and activity of the combination of cabozantinib with lanreotide in GEP, thoracic and unknown origin NET. Two cohorts of patients will be enrolled in the study according to different histotypes.
The first cohort includes pancreatic NET (pNET), the second cohort includes carcinoids with diagnosis of GEP NET (small intestinal, stomach, rectum NETs ), lung NETs (typical and atypical histotype, including thymus NET) and NET with unknown origin. For both cohorts the experimental treatment is the combination of cabozantinib plus lanreotide (see the section study treatments 4.1). The statistical design is adaptive, according to three sequential stages (see the study flow-chart depicted in figure 5).
Figure 5: Study design
The primary objective of the first stage (run-in stage) is to find the cabozantinib dose and to evaluate the safety and the tolerability of the combination. Starting dose of cabozantinib will be 60 mg plus lanreotide 120 mg. The dose of lanreotide will be fix (standard dose). No more than seven patients will be enrolled in the first stage. Every eligible histotype of NET will be enrolled in the first stage (i.e. competitive enrollment of histotypes will be used in the first stage).
If grade 3-5 (AE) toxicities (excluded clinically not relevant laboratory abnormalities according to NCI- CTCAE, version 5.0 or clinically manageable and reversible G3 AEs within 7 days from their onset are observed in more than one patient out of the first seven enrolled patients, cabozantinib starting dose of 60 mg will be considered too toxic and ruled out (H0: % grade 3-5 toxicities < 5%; nominal p-value: 0.05; actual p-value: 0.044). In the latter case, 40 mg will be chosen as starting dose of cabozantinib in the subsequent stage. In the former case, 60 mg will be chosen as starting dose of cabozantinib in the subsequent stage.
In order to preserve the internal validity of the study, outcome assessment will be re-started ex novo in the second stage (i.e. first and second stages are distinct phases of an operationally seamless, not inferentially seamless design (1). An interim safety analysis will be performed when all 7 patients will be observed on treatment for at least 8 weeks. If after the interim safety analysis observed in these 7 patients the combination of cabozantinib plus lanreotide will be consider too toxic (at the
cabozantinib dose of 60 or 40 mg), the trial will be stopped. Otherwise other 10 patients will be accrued in stage II.
In all stages, safety and activity assessment will be every three cycles for each enrolled patient.
A) Hypothesis 1
Starting dose | First dose level reduction | Second dose level dose reduction | Third dose level reduction |
60 mg daily (qd) | 40 mg daily (qd) | 20 mg daily (qd) | No dose reduction permitted |
B) Hypothesis 2
Starting dose | First dose level reduction | Second dose level dose reduction |
40 mg daily (qd) | 20 mg daily (qd) | No dose reduction permitted |
Table 6A-B: summary of the hypothesis 1 and 2 concerning dose level reduction of cabozantinib for adverse reactions.
II-III stages: for both cohorts, the optimal Xxxxx two-stage design (2) will be used. The primary endpoint of the second and third stages will be the ORR according to RECIST version 1.1. Co- primary endpoint will be treatment safety defined as percentage of grade 3-5 (AE) toxicities (excluded clinically not relevant laboratory abnormalities according to NCI- CTCAE, version 5.0 or clinically manageable and reversible G3 AEs within 7 days from their onset).
Secondary endpoints will be, PFS and OS.
The uninteresting antitumor activity (H0) is fixed in ORR < 5%. The useful antitumor activity to be detected (H1) is fixed in ORR > 20%. For both arms (pNET and carcinoids), 10 patients will be accrued in the stage II. If no responses are observed in these 10 patients, the arm will be stopped (nominal type II error = 0.20). Otherwise other 19 patients will be accrued in stage III, for a total of 29 patients. The null hypothesis will be rejected if 4 or more responses are observed in 29 eligible patients (nominal type I error = 0.05). Considering the drop out rate of 5% (i.e. eligible patients without the assessment of objective response) the maximum number of enrolled patients will be 69 (including the 7 patients enrolled in the stage I). Patients will receive study treatment until the evidence of disease progression or onset of unacceptable toxicity and consent withdraw.
Regarding the safety co-primary endpoint, the null hypothesis, to be rejected, is a percentage of adverse events greater or equal to 20% (i.e. H0 : > 20%, nominal type I error = 0.05) against an alternative hypothesis H1 : < 5%. Because the statistical design is adaptive (i.e. a couple of Simon’s two stage designs are planned after the first run-in stage), the total number of patients that could be analyzed for safety is uncertain prior to study execution. It could be 20 patients if both arms stop at the second stage, 39 (29+10) patients if only one arm stops at the second stage and 58 (29+29) patients if both arms are involved in the third stage. Thresholds to identify significant level at 5% and exact binomial test’s power will be determined based on the real number of patients to be analyzed [i.e. 0/20 (test’s power: 36%), 3/39 (test’s power: 87%) ; 6/58 (test’s power: 97%) are the maximum number of observed G3- G5 AEs to reject H0 : > 20% at a 5% significant level].
Duration of the study:
Trial expected duration (comprehensive of accrual, treatment and follow-up): 36 months (stage I plus stage II plus stage III).
This should be added to a planned duration of follow up of 6 months since the enrolment of the last patient (resulting in a maximum of 42 months).
References
1. 1 Maca J. et al. Drug Information Journal, vol.40: 463-473, 2006
2. Xxxxxxx Xxxxx Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 10 :1-10,1989.
STUDY POPULATION
3.1 Selection of study population:
Patient with unresectable, advanced or metastatic neuroendocrine well differentiated GEPNET (pancreatic NET, Small Intestinal NET, stomach NET, rectum NET), Thoracic NET (typical and atypical lung NET, thymus NET) and unknown origin NET with KI67 ≥ 10%.
3.2 Number of patients
The total number of patients to be enrolled on this study no more than 69. Enrollment is defined as the first day of cabozantinib plus lanreotide treatment (i.e. day 1 of cycle 1).
3.3 Inclusion criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
- voluntary written informed consent obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care;
- Patients with unresectable, advanced or metastatic neuroendocrine well differentiated GEP- NET (pancreatic NET (G2-G3), Small Intestinal NET, stomach NET, rectum NET) with Ki67
≥ 10%.
- Patients with unresectable, advanced or metastatic neuroendocrine well differentiated
thoracic NET (typical and atypical lung NET, thymus NET)
- Patients with unresectable, advanced or metastatic neuroendocrine well differentiated
unknown primary NET with Ki67 ≥ 10%.
- Locally advanced or metastatic disease documented as progressive by RECIST v1.1. on CT- scan or MRI at baseline and within 12 months prior to baseline.
- disease that is not amenable to surgery with curative intent;
- presence of at least one measurable target lesion for further evaluation according to RECIST v1.1;
- age ≥18 years;
- eastern Cooperative Oncology Group (ECOG) performance status 0 or 1(see APPENDIX I)
- Octreoscan and/or PET 68Ga positive and/or IHC for SSTR2;
- Prior PRRT therapy must be completed at least 6 months prior to enrollement;
- Advanced GEP, thoracic and unknown origin NET limited to the treatment of patients naïve or who have received a previous therapy for advanced disease or maximum 2 lines if any of these regimens include treatment with somatostatin analogs previously administered for a short period of time (less than 12 months for Octreotide and less than 6 months for Lanreotide)
- Prior treatment with somatostatin analogs, biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, and/or radiation must be completed at least 28 days prior to registration;
- Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies must be completed at least 28 days prior to registration;
- Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to National Cancer Institute (NCI) CTCAE, version 5.0, grade 1 or less;
- Patients must have completed any major surgery at least 2 months prior to registration and any minor surgery (including uncomplicated tooth extractions) at least 28 days prior to registration; complete wound healing from major surgery must have occurred at least 1month prior to registration, and complete wound healing from minor surgery must have occurred at least 7 days prior to registration
- Functioning or Non-functioning tumors;
- all of the following laboratory test findings:
- Hemoglobin > 9 g/dL (5.6 mmol/L)
- WBC > 2,000/mm3
- Neutrophils > 1,500/mm3
- Platelets > 100,000/mm3
- AST or ALT < 3 x ULN (< 5 x ULN if liver metastases are present)
- Total Bilirubin < 1.5 x ULN (except subjects with Xxxxxxx Syndrome, who can have total bilirubin < 3.0 mg/dL)
- Adequate renal function, based upon meeting the following laboratory criteria:
a. Serum creatinine ≤ 1.5 ´ upper limit of normal (ULN) or calculated creatinine clearance ≥ 40 mL/min using the Xxxxxxxxx-Xxxxx equation: (140 – age) × weight (kg)/(serum creatinine × 72 [mg/dL]) for males. (For females multiplied by 0.85)
AND
b. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g
- Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis
- PT-INR/PTT ≤ 1.5 x upper limit of normal.
- Availability of a representative FFPE tumor specimen collected before starting treatment with cabozantinib and lanreotide that enables the definitive diagnosis of NET (the archival specimen must contain adequate viable tumor tissue to enable candidate biomarkers status; the specimen may consist of a tissue block or at least 10 unstained serial sections with 3 microns of thickness; for core needle biopsy specimens, at least two cores should be available for evaluation)
- Female subjects of childbearing potential must not be pregnant at screening
- Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception with a failure rate of < 1% per year (eg, barrier methods, including male condom or female condom with spermicidal gel, intrauterine devices, surgical male or female sterilisation) during the study and for 4 months after the last dose of study treatment
- Female subject is either: post-menopausal for at least one year before the screening visit, or surgically sterilized, or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
- Male subject, even if surgically sterilized (ie, status postvasectomy), agrees to use an acceptable method for contraception during the entire study treatment period through 4 months after the last dose of cabozantinib.
- Patients must be accessible for treatment and follow up as well as they must be willing and capable to comply with the requirements of the study.
3.4 Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
- Patients with undifferentiated, poorly differentiated GEP-NET, Thoracic or unknown primary NET;
- Previous therapy for advanced disease > 1 line or > 2 lines if any of these regimens include treatment with somatostatin analogs previously administered for a long period of time (more than 12 months for Octreotide and more than 6 months for Lanreotide)
- Any medical adjuvant treatment must have been stopped at least six months before entry into the study;
- Prior treatment with cabozantinib;
- Prior treatment with any other tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors is permitted. Prior treatment with non-VEGF-targeted angiogenic inhibitors such as Everolimus is permitted;
- Patients who stopped Everolimus or tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors treatment less than 4 weeks prior to the start of the study;
- Patients with concomitant treatment with Interferon;
- Patients previously treated with chemotherapy, loco-regional therapy (e.g., chemoembolization) or interferon with last administration less than 4 weeks prior to the start of the study or with toxicity not resolved to less or equal grade 1 at the start of the study;
- PRRT therapy with last administration less than 6 months prior to inclusion in the study or with toxicity not resolved to less or equal grade 1 at the start of the study;
- diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri;
- history of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA see Appendix II);
- prolongation of QT interval: Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances (e.g., hypokaliemia, family history of long QT Syndrome). Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms within 28 days before registration should be shown. Only subjects with a baseline QTcF ≤ 500 ms are eligible for the study.
Note: If the QTcF was > 500 ms in the first ECG, a total of 3 ECGs were to be performed. If the average of these 3 consecutive results for QTcF was ≤ 500 ms, the subject met eligibility in this regard.
- history of aneurysms and arterial dissections. The use of VEGF pathway inhibitors in patients with or without hypertension may favor the formation of aneurysms and / or arterial dissections. Before starting cabozantinib, this risk must be carefully considered
in patients with risk factors such as hypertension or history of aneurysm.
- poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg];
- history of cerebrovascular accidents, including transient ischemic attack (TIA history of thromboembolic events (including pulmonary embolism) or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible;
- concomitant anticoagulation at therapeutic doses with oral anticoagulant (eg. Warfarin, direct thrombin and factor 10a inhibitors) or platelet inhibitors (eg. Clopidrogrel);
- major surgery or trauma within 28 days prior to study entry; the presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major surgery);
- known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before the start of the study. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of inclusion;
- With the exclusion of inhaled steroids, chronic treatment with corticosteroids with dose superior of 10 mg/day methylprednisolone equivalent must be avoided;
- evidence of active bleeding or bleeding diathesis and/or clinically-significant GI bleeding within 6 months before the first dose of study treatment; 3 months for pulmonary hemorrhage and patients with tumor invading or encasing any major blood vessels;
- patients with GI disorders associated with a high risk of perforation or fistula formation;
- major surgery within 2 months before to registration. Complete healing from major surgery must have occurred 1 month before initiation of the study. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before registration. Subjects with clinically relevant complications from prior surgery are not eligible;
- subjects with clinically relevant ongoing complications from prior radiation therapy;
- positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness;
- patients with complicated, symptomatic untreated lithiasis of the bile ducts;
- any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures;
- previous or ongoing treatment (except for adjuvant therapies) with any of the following anti- cancer therapies: chemotherapy, immunotherapy, target therapies, investigational therapy or hormonal therapy within 28 days or five half-lives of a drug (whichever is longer) prior to the first dose of Cabozantinib plus Lanreotide;
- inability to swallow tablets;
- rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption;
- previously identified allergy or hypersensitivity to to the study drugs and/or their excipients of the study treatment formulations;
- concomitant use of strong inhibitor of CYP3A4 (i.e. information reported in session 4.5 of the protocol)
-
STUDY TREATMENTS
4.1 Preparation, Handling and Storage of Drugs
As required by local regulations, any modifications to the plan for drug supply or storage will be communicated to the investigator. Study drug will be administered only to eligible patients under the supervision of the investigator or identified subinvestigator(s).
These study drugs (cabozantinib and lanreotide) will be provided by pharmaceutical company (IPSEN) and will be re-labeled at the Pharmacy of Fondazione IRCCS Istituto Nazionale dei Tumori in accordance with Ipsen instructions. The Sponsor will provide adequate supplies of cabozantinib, which will be supplied as 60-mg, 40-mg and 20-mg yellow film-coated tablets and lanreotide 120 mg autogel, prefilled syringe. The cabozantinib 60-mg tablets are oval, the 40-mg are triangle and the 20- mg tablets are round.
4.2 Cabozantinib administration and dosage schedule
In this protocol cabozantinib will be administered at the recommended dose of 60 mg once daily. Cabozantinib will be administered orally (tablets) at a dose of 60 mg/day continuously in combination with lanreotide 120 mg every 28 days. Both treatments will start the same day.
The start of study drug dosing should occur as soon after inclusion in the study, ie, within 24 hours if possible but no more than 3 days after. Subjects will take the tablet(s) once daily at bedtime except for Day 1 Week 1: the first dose of study treatment will be administered in the clinic so that each subject can be observed for initial tolerability. Subsequent doses will be self-administered at home. Any unused study treatment must be returned to the study site for drug accountability and disposal. The assigned starting dose is 60 mg cabozantinib given once daily, which should be maintained in the absence of treatment-emergent toxicity. Guidelines for these potential dose alterations are discussed in Section 4.4.
While on study treatment, subjects are to be instructed not to eat grapefruit, Seville oranges, or products made with these fruits (including juice, jams, or candies) while on study. See Section 4.5.1 for other potential drug interactions.
Study drug cabozantinib administration on Week1 Day 1 (W1D1)
On the first day of treatment, the subject should fast (with the exception of water) for at least 2 hours before receiving study drug. Required study examinations and blood draws should be done during this time, prior to any study treatment administration. Upon completion of the 2-hour fast, the subject should take the tablets with a minimum of 8 oz (240 mL) of water in the clinic and then continue to fast for 1 hour while under observation.
Subsequent cabozantinib dose administration
Subjects should fast (with the exception of water) for at least 2 hours after eating the evening meal before taking their dose of study drug. After the 2-hour fast and before going to bed, subjects are to take the tablets with a minimum of 8 oz (240 mL) water with no more food intake for at least 1 hour postdose. If the subject’s schedule requires taking cabozantinib during the day, the subject should be instructed to follow the same fasting recommendations.
Subjects should be instructed to not make up vomited doses or missed doses and to maintain the planned dosing schedule. Subjects should not make up for missed doses if more than 12 hours have elapsed after the time the subject would usually take study drug. In the event of missed doses, subjects should not take two doses to make up for the one the subject missed. If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.
4.3 Lanreotide administration and dosage schedule
Lanreotide is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. Each dose of the study treatment (per cycle) will be administered in the clinic every 28 days. The injection of lanreotide will be administered via the deep subcutaneous route in the superior external quadrant of the buttock. The injection site will be alternate between the right and left sides from one injection to the next. Investigators should remove lanreotide from the refrigerator 30 minutes prior to administration. Keep pouch sealed until just prior to injection.
4.4 Dose Reduction and Treatment Interruptions
Subjects will be monitored continuously for adverse events (AEs) while on study from the time of signing informed consent through 30 days after the date of the decision to permanently discontinue study treatment. Subjects will be requested to notify their physician immediately for any occurring AE.
Causality assessment of AEs should include at minimum confounding factors such as disease and concomitant medications. Adverse event severity will be categorized according to CTCAE v.5.0. The following criteria should be taken into consideration in decisions regarding dose modifications (reductions or interruptions):
- As a general approach all AEs should be managed with supportive care at the earliest signs of toxicity. Should this be ineffective, dose reductions or interruptions should be considered to prevent worsening of toxicity.
- The assigned cabozantinib starting dose for study treatment is 60 mg qd. When dose reduction is necessary, it is recommended to reduce to 40 mg daily, and then to 20 mg daily. Summary of cabozantinib dose reductions will be permitted (see section 3.0, table 6A-B):
60 mg qd to 40 mg qd (level 1)
40 mg qd to 20 mg qd (level 2)
- Dose reductions are recommended for events that, if persistent, could become serious or intolerable. Dose modification criteria for study treatments are shown in Table 7. Doses may be modified at any time on study treatment.
- Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities.
- If the subject recovers from his or her AEs to CTCAE v.5.0 Grade ≤ 1 or to the baseline value (or lower) and the AE was unrelated to study treatments, then study treatment may be restarted with no change in dose.
- If the subject recovers from his or her AEs to Grade ≤ 1 or to the baseline value (or lower) the toxicity was deemed possibly related to study treatments, then study treatment may be restarted at a reduced dose (see Table 6A-B for the schedule of dose reductions). Subjects receiving a daily cabozantinib dose of 20 mg may be restarted at the same dose if deemed safe at the discretion of the investigator. Subjects unable to tolerate a cabozantinib daily dose of 20 mg will discontinue study treatment.
- Dose modifications may also occur in the setting of lower grade toxicity than defined in Table 7, if the investigator feels it is in the interest of a subject’s safety.
- Dose interruptions of study treatment for any reason are allowed for up to 6 weeks. Restarting treatment after interruptions longer than 6 weeks may be allowed with approval of the Sponsor
- All treatment modifications should be entered into Case Report Form (CRF)s within 72 hours. Guidelines for the management of specific AEs such as GI disorders, hepatobiliary disorders, blood system disorders, constitutional disorders, skin disorders, hypertension, thromboembolic events, proteinuria, QTc prolongation, hemorrhagic events, GI perforation/fistula and non-GI fistula formation, and osteonecrosis of the jaw are provided in Section 4.7.
Adverse reaction and severity | Treatment modification |
Grade 1 and Grade 2 adverse reactions which are tolerable and easily managed | Dose adjustment is usually not required. Add supportive care as indicated. |
Grade 2 adverse reactions which are intolerable and cannot be managed with a dose reduction or supportive care | Interrupt treatment until the adverse reaction resolves to Grade ≤1. Add supportive care as indicated. Consider re-initiating at a reduced dose. |
Grade 3 adverse reactions (except clinically non- relevant laboratory abnormalities) | Interrupt treatment until the adverse reaction resolves to Grade ≤1. Add supportive care as indicated. Re-initiate at a reduced dose. |
Grade 4 adverse reactions (except clinically non- relevant laboratory abnormalities) | Interrupt treatment. Institute appropriate medical care. If adverse reaction resolves to Grade ≤1, re-initiate at a reduced dose. If adverse reaction does not resolve, permanently discontinue cabozantinib and/or lanreotide. |
- Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE)
Table 7: Recommended drugs dose modifications for adverse reactions
4.5 Potential Drug Interactions, Excluded Concomitant Medications and Procedures
The initiation of any non-protocol specific anti tumor therapy or surgery is considered an indication of disease progression whereby study treatment should be terminated. Patients who require initiation of biphosphonates during therapy should be evaluated carefully for possible disease progression before starting these treatments and accordingly with IB information about osteonecrosis of the jaw (see pag 67)
Prior and Concomitant Therapy
All medication, which is considered necessary for the patient’s welfare, and which is not expected to interfere with the evaluation of the study drug, may be given at the discretion of the Investigator. All concomitant medications (including start/stop dates, dose frequency, route of administration and indication) must be recorded in the patient’s source documentation, as well as in the appropriate pages of the CRF.
4.5.1 Potential Drug Interactions with Cabozantinib
Cabozantinib is a CYP3A4 substrate.
Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors or inducers.
Concurrent administration of cabozantinib with strong CYP3A4 inhibitors:
- Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Results from a clinical pharmacology study, showed that concurrent administration of cabozantinib with ketoconazole, resulted in a 38% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers.
- Co-administration of cabozantinib with others strong inhibitors of the CYP3A4 family (eg, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may increase cabozantinib concentrations.
- Grapefruit and Seville oranges may also increase plasma concentrations of cabozantinib.
- Strong CYP3A4 inhibitors and other drugs that inhibit CYP3A4 should be avoided because these drugs have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended. Please refer to the Xxxxxxxxx drug interaction tables for lists of substrates,
inducers, and inhibitors of selected CYP450 isozyme pathways (see xxxx://xxxxxxxx.xxxxx.xxx/xxxxxxxxx/xxxx/xxxxx.xxxx).
Concurrent administration of cabozantinib with strong CYP3A4 inducers:
- Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin
resulted in a decrease in cabozantinib plasma exposure.
- Co-administration of cabozantinib with strong inducers of the CYP3A4 family (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. Xxxx’x Wort) may significantly decrease cabozantinib concentrations.
- The chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended. Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who has been concurrently receiving a stable dose of cabozantinib, as this could significantly increase the exposure to cabozantinib.
Other drugs interaction with concurrent administration of cabozantinib:
- Co-administration of PPI esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.
- Protein Binding: Cabozantinib is highly bound (approximately 99.9%) to human plasma proteins. Therefore, highly protein bound drugs should be used with caution with cabozantinib because there is a potential displacement interaction that could increase free concentrations of cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic effect). Factors that influence plasma protein binding may affect individual tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound (eg, diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. Because warfarin is a highly protein bound drug with a low therapeutic index, administration of oral anticoagulants at therapeutic doses is not allowed in subjects receiving cabozantinib due to the potential for a protein binding displacement interaction.
- As food increases exposure levels of cabozantinib, fasting recommendations should be followed.
- Cabozantinib was an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.
- Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution.
- Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Additional details regarding potential drug interactions with cabozantinib can be found in the investigator brochure and SmPC Nov 2018.
4.5.2 Potential Drug Interactions with lanreotide
- The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered.
- Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly.
- Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels.
- The pharmacological gastrointestinal effects of lanreotide may reduce the intestinal absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine.
- Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary.
- Vitamin K absorption was not affected when concomitantly administered with lanreotide.
4.6 Prohibited and Permitted concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:
- Other anticancer treatments.
- Radiotherapy during study or within 4 weeks of start of study drug with the exception of brain radiotherapy according to the exclusion criteria.
- Major surgery during the treatment and/or within 4 weeks of start of study or during the treatment.
- Autologous bone marrow transplant or stem cell rescue within 4 months of study.
- Use of biologic response modifiers, such as G-CSF, within 3 week of study entry. [G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such
as febrile neutropenia when clinically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction.]
- Investigational drug therapy outside of this trial during or within 4 weeks prior to study entry.
- Prior exposure to the study drugs.
- Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
- Any condition that is unstable or could jeopardize the safety of the patients and their compliance in the study.
- Patients unable to swallow oral medications.
- Rifampicin.
- St. Xxxx’x Worth (Hypericum perforatum).
- With the exclusion of inhaled steroids, chronic treatment with corticosteroids with dose superior of 10 mg/day methylprednisolone equivalent is avoided;
- Erythropoietic-stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used based on a report of increased risk of tumor recurrence/progression associated with erythropoietin (Xxxxxx 2007). In patients taking chronic use, erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study.
- Therapeutic doses of oral anticoagulants (eg, warfarin or warfarin-related agents, thrombin or FXa inhibitors, antiplatelet agents such as clopidogrel) are not allowed.
The following medications and procedures are permitted during the study:
- Patients may receive palliative and supportive care for any underlying illness.
- Treatment with non-conventional therapies (e. g. herbs or acupuncture), and vitamin/mineral supplements is acceptable, if existing information that could not interfere with the drugs.
- Caution should be used in subjects receiving bisphosphonates (see section 4.7).
- Continuous use of Erythropoietin is permitted if the drug is undertaken within 2 months prior to the study or during the study.
- Best Supportive Care which may include analgesics, nutritional support, and other non-anti- neoplastics.
- All other medical conditions should be treated at the discretion of the investigator in accordance with local community standards of medical care.
- Antiemetics and antidiarrheal medications are allowed prophylactically according to standard clinical practice if clinically indicated.
- Granulocyte colony-stimulating factors are acceptable while the subject is enrolled in the study. However, these should not be administered prophylactically before initial treatment with study drug.
- Transfusions should be used in accordance with institutional guidelines.
- Hormone replacement and short-term systemic steroid treatment may be utilized as indicated by standard clinical practice while the subject is enrolled in the study. Chronic treatment with corticosteroids (dose of <10 mg/day methylprednisolone equivalent) is allowed.
- The protocol does not restrict the use of heparins at prophylactic doses. Therapeutic doses of heparins are allowed if clinically indicated for the management of advers events if the benefit outweighs the risk per the investigator’s discretion. During treatment with heparins, shuld be carefully evaluated the potential drug-drug interactions, and subjects need to be monitored on an ongoing basis for bleeding risk and signs of bleeding.
- Therapeutic doses of oral anticoagulants are prohibited.
- Antacids, H2 blockers, or proton-pump inhibitors should be taken at least 2 hours (preferably 4 hours) after taking study treatment but at least 14 hours before the next dose of study treatment if possible.
- Subjects with active HBV should be on appropriate antiviral therapy.
Potential drug interactions with cabozantinib and lanreotide are summarized in Section 4.5 and are discussed in more detail in the Investigator’s Brochure of the drugs.
4.7 Warnings, precautions, and guidelines for management of potential cabozantinib and/or lanreotide adverse events
The side effect profile of these drugs (cabozantinib and lanreotide) includes GI symptoms (such as nausea, vomiting, and diarrhea, mucositis/stomatitis, colelytiasis, malabsorption), fatigue/asthenia, anorexia, weight loss, skin disorders including palmar-plantar erythrodysesthesia (PPE) syndrome, elevated liver function tests (including alanine aminotransferase [ALT] and AST), increased pancreatic enzymes with rare cases of overt pancreatitis, hypothyroidism, iperglycaemia, ipercolesterolymia, as well as side effects associated with inhibition of VEGF signaling. The latter of
these include arterial and venous thrombotic events such as deep vein thrombosis (DVT), pulmonary embolism (PE), transient ischemic attack, and myocardial infarction; hypertension; hemorrhagic events; proteinuria, wound complications, and rare cases of GI perforation, fistulae formation and rectal/perirectal abscess, osteonecrosis, and reversible posterior leukoencephalopathy (RPLS). Please refer to the Investigator’s Brochure of the drugs for additional details.
As with all investigational products, unknown AEs may occur. Subjects should be monitored closely throughout their study participation for all AEs.
Please refer to the Investigator’s Brochure for additional practice guidelines and management recommendations for side effects potentially related to cabozantinib and lanreotide treatment; available information on potential risk of congenital, familial, and genetic disorders; and guidelines on management of cabozantinib overdose.
Gastrointestinal Disorders
The most common GI AEs reported in clinical studies with cabozantinib and/or lanreotide are diarrhea, abdominal pain, dyspepsia, stomatitis, and dysphagia.
Diarrhea
Subjects should be instructed to notify their physician immediately at the first signs of poorly formed or loose stool or an increased frequency of bowel movements. Administration of antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial management. Some subjects may require concomitant treatment with more than one antidiarrheal agent. When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, study treatment should be temporarily interrupted or dose reduced per Table 6A-B, 7.
In addition, general supportive measures should be implemented including continuous oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose- containing products, high fat meals and alcohol.
Nausea and Vomiting
Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and vomiting or as prophylaxis to prevent emesis, along with supportive care according to clinical practice guidelines. The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists and dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure- see Section 4.5). Caution is also recommended with the use of nabilone, which is a weak inhibitor of CYP3A4.
Stomatitis and Mucositis
Preventive measures may include a comprehensive dental examination to identify any potential complications before study treatment is initiated. Removal of local factors should be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis. During study treatment good oral hygiene and standard local treatments such as nontraumatic cleansing and oral rinses (eg, with a weak solution of salt and baking soda) should be maintained.
The oral cavity should be rinsed and wiped after meals, and dentures should be cleaned and brushed often to remove plaque. Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral culture if oral infection is suspected and treat infection as clinically indicated. When stomatitis interferes with adequate nutrition and local therapy is not adequately effective, dose reduction or temporary withholding of study treatment should be considered.
Hepatobiliary Disorders
Elevations of ALT, AST, and total bilirubin have been observed during treatment with cabozantinib and lanreotide.
A subject who has ALT, AST, and total bilirubin ≤ 3.0 X ULN at baseline and who develops
≥ Grade 3 elevated ALT, AST, or total bilirubin should have study treatment interrupted and the dose reduced as outlined in Tables Table 6A-B and Table 7.
Subjects on this study may enter the study with elevations of AST/ALT up to 5 X ULN at baseline. Elevations of aminotransferases when hepatic tumors are present may not require dose modifications if there are no progressive changes in the aminotransferases (less than a doubling) and if there are no progressive elevations in serum total bilirubin concentration or coagulation factors. Cabozantinib treatment should be interrupted when transaminase increases are accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation tests (eg, International Normalized Ratio [INR]). More frequent monitoring of transaminases should be considered and study treatment should be held until the etiology of the abnormalities is determined and these abnormalities are corrected or stabilize at clinically acceptable levels. If hepatic toxicity resolves during a temporary hold and was deemed related to study treatment, then study treatment may be restarted at a reduced dose. Study treatment should be discontinued if hepatic dysfunction is not reversible despite temporary interruption of study treatment.
Elevations > 3x ULN of ALT or AST concurrent with > 2xULN total bilirubin without other explanation can indicate drug-induced liver injury and drug should be permanently discontinued.
If possible, hepatotoxic concomitant medications should be discontinued in subjects who develop increased values of ALT, AST, or total bilirubin.
Evaluation of subjects with elevated transaminases or total bilirubin should be individualized and guided by the presence of specific risk factors such as illnesses which affect liver function (eg, infectious and non-infectious causes of hepatitis, liver cirrhosis, thrombosis of portal or hepatic vein), concomitant hepatotoxic medication, alcohol consumption, and cancer related causes. AEs which are based on hepatic dysfunction should be managed according to locally accepted clinical practice, including monitoring of appropriate laboratory functions.
Finally according to lanreotide IB, given the possibility to have an increased risk to develop gallbladder stones during treatment with lanreotide, subjects may need periodic monitoring. If complications of cholelithiasis are suspected, patients should discontinue lanreotide and be treated appropriately.
Hematological Disorders
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications have been observed after administration of cabozantinib and may be managed with dose interruptions and/or dose reductions. Use of granulocyte colony-stimulating factor support for neutrophil recovery
is allowed per investigator discretion in accordance with the American Society of Clinical Oncology Guidelines.
Complete blood counts with differentials and platelets should be performed during treatment on the schedule indicated in Appendix III. Subjects with hematologic toxicities may require additional or more frequent laboratory tests according to institutional guidelines.
Febrile neutropenia or evidence of infection associated with neutropenia must be assessed immediately and treated aggressively according to institutional guidelines.
Dose reductions or dose interruptions for anemia are not mandated but can be applied as clinically indicated. Supportive care such as red blood cell transfusions may be given as clinically indicated.
Fatigue, Anorexia, and Weight Loss
Fatigue has been reported during treatment with cabozantinib and/or lanreotide. Common causes of fatigue such as anemia, deconditioning, emotional distress (depression and/or anxiety), nutrition, sleep disturbance, and hypothyroidism should be ruled out and/or these causes treated according to standard of care. Individual nonpharmacological and/or pharmacologic interventions directed to the contributing and treatable factors should be given. Pharmacological management with psychostimulants such as methylphenidate should be considered after disease specific morbidities have been excluded. Note: Chronic use of modafinil should be avoided because of its potential to reduce cabozantinib exposure (see Investigator’s Brochure).
Dose reduction of study treatment should be considered when general or pharmacological measures have not been successful in reducing symptoms. Dose interruption may be considered for Grade ≥ 3 fatigue despite optimal management, at the investigator’s discretion.
Anorexia and weight loss should be managed according to local standard of care including nutritional support. Pharmacologic therapy such as megestrol acetate should be considered for appetite enhancement. Should these interventions prove ineffective, dose hold and reductions may be considered for Grade ≥ 3 anorexia or weight loss.
Skin Disorders. Palmar-plantar erythrodysesthesia (PPE) syndrome
PPE syndrome (also known as hand-foot syndrome), skin rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, and erythema have been reported in cabozantinib-treated subjects. All subjects on study should be advised on prophylactic skin care. This includes the use of hypoallergenic moisturizing creams, ointment for dry skin, and sunscreen with sun protection factor ≥ 30; avoidance of exposure of hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; use of thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects with skin disorders should be carefully monitored for signs of infection (eg, abscess, cellulitis, or impetigo).
Early signs of PPE syndrome include tingling, numbness, and slight redness or mild hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the palms and soles. The lateral sides of the fingers or peri-ungual zones may also be affected. Adequate interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas. Aggressive management of symptoms is recommended, including early dermatology referral. Treatment guidelines for PPE are presented in Table 8.
In the case of study treatment-related skin changes, the investigator may request that additional assessments be conducted with the subject’s consent. These assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until the skin changes resolve.
CTCAE v. 5.0 Grade Action To Be Taken for Treatment- emergent PPE Syndrome |
Grade 1 Study treatmenta may be continued at the current dose if PPE syndrome is clinically insignificant and tolerable. Otherwise, study treatmenta should be reduced to the next lower dose level. Start urea 20% cream twice daily AND clobetasol 0.05% cream once daily. Reassess at least weekly; if PPE syndrome worsens at any time or does not improve after 2 weeks, proceed to the intervention guidelines for Grade 2. |
Grade 2 Study treatmenta may be continued if PPE is tolerated. Study treatment should be dose reduced or interrupted if PPE is intolerable. Continue urea 20% cream twice daily and clobetasol 0.05% cream once daily and add analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) for pain control if needed. Reassess at least weekly; if PPE does not improve within 2 weeks or worsens or affects self-care, proceed to the intervention guidelines for Grade 3. |
Grade 3 Interrupt study treatmenta until severity decreases to Grade 1 or 0. Continue treatment of skin reaction with clobetasol 0.05% cream twice daily AND analgesics. Resume study drug at a reduced dose if PPE syndrome recovers to Grade ≤ 1. Discontinue subject from study if intolerable PPE syndrome recurs at a reduced dose or if PPE syndrome does not improve within 6 weeks. |
CTCAE, Common Terminology Criteria for Adverse Events; GABA, gamma-amino butyric acid; NSAID, non- steroidal anti- inflammatory drug; PPE, Palmar Plantar Erythrodysesthesia. a Study treatment includes both cabozantinib and matched placebo.
Table 8: Dose Modification Criteria and Recommended Guidelines for Treatment- emergent PPE Syndrome
Wound Healing and Surgery
VEGF inhibitors can cause wound healing complications and wound dehiscence which may occur even long after a wound has been considered healed. Therefore, surgical and traumatic wounds must have completely healed prior to starting study treatment and be monitored for wound dehiscence or wound infection while the subject is being treated with study drug.
Study treatment should be stopped at least 28 days prior to scheduled major surgery. The decision to resume study treatment after surgery should be based on clinical judgment of adequate wound healing. Study treatment should be interrupted for any wound healing complication. Study treatment should be discontinued in subjects with serious or chronic wound healing complications.
Hypertension
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been reported in subjects treated with cabozantinib.
Blood pressure should be monitored in a constant position at each visit (either sitting or supine). Treatment guidelines for hypertension are presented in Table 9. In general, subjects with known hypertension should be optimally managed prior to study entry. Decisions to decrease or hold the dose of study treatment must be based on blood pressure (BP) readings taken by a medical professional and must be confirmed with a second measurement at least 5 minutes following the first measurement. Other than for hypertension requiring immediate therapy, the presence of new or worsened hypertension should be confirmed at a second visit before taking therapeutic action. It is recommended that this second visit occurs within 1 week.
Criteria for dose modification and for the management of treatment-emergent hypertension |
Subjects NOT receiving optimized antihypertensive therapy ≥ 140 mm Hg (systolic) and < 160 mm Hg OR ≥ 90 mm Hg (diastolic) and < 100 mm Hg - Optimize antihypertensive treatment by adding new or additional antihypertensive medications and/or increase dose of existing medications. - Reduce study treatment by one dose level if optimal antihypertensive therapy (usually to include 3 agents) does not result in BP < 140 mm Hg systolic or < 90 mm Hg diastolic. - If subject is symptomatic treatment should be interrupted and can only be restarted once symptoms have resolved and BP is < 140 mm Hg systolic and < 90 mm Hg diastolic |
≥ 160 mm Hg (systolic) OR≥ 100mm Hg (diastolic) - Reduce study treatment by 1 dose leveor interrupt study treatment per Investigator discretion. Study treatment should be dose interrupted if upper limits of systolic BP (≥ 160 mm Hg) are sustained and not adequately manageable or if systolic BP is > 180 mm Hg or sustained diastolic BP > 100 mm Hg, or if subject is symptomatic Add new or additional antihypertensive medications and/or increase dose of existing medications and monitor subject closely for hypotension. If optimized antihypertensive therapy (usually to include 3 agents) does not result in BP < 160 mm Hg systolic or < 100 mm Hg diastolic, study treatment should be dose reduced further or interrupted. - . - Restart study treatment at the reduced dose and re-escalate only if BP falls to and is sustained at < 140 mm Hg systolic and < 90 mm Hg diastolic. |
Hypertension with life-threatening consequences (eg, malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated - Discontinue study treatment - Initiate appropriate medical management |
Table 9: Guidelines for the Management of Treatment-emergent Hypertension according to
Cabozantinib (XL184) Investigator’s Brochure guideline v18.0 2022
Thromboembolic Events
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by the malignancy or anticancer therapy. DVT and pulmonary embolism have been observed in clinical studies with cabozantinib, including fatal events. Subjects who develop a pulmonary embolism and/or DVT should have study treatment held until therapeutic anticoagulation is established. Refer to the individual protocol for guidance on anticoagulation medication use. Treatment with cabozantinib may be resumed in subjects with pulmonary embolism or DVT if it is determined that the event is uncomplicated and that the subject is deriving clinical benefit from cabozantinib treatment and that anticoagulation does not place them at a significant risk that outweighs the benefit of resuming treatment per discretion of the Investigator and according to individual protocols. Low molecular weight heparins (LMWH) are the preferred management for thrombotic events; oral anticoagulants (eg, warfarin, apixaban) are not permitted unless otherwise specified in study protocol.
Arterial thrombotic events (eg, TIA, MI) have been observed in studies with cabozantinib. Subjects should be evaluated for preexisting risk factors for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, hypertension, coronary artery disease, history of tobacco use, and cardiac and/or thromboembolic events that occurred prior to initiation of study treatment. Further treatment with cabozantinib should be discontinued in subjects who develop an acute MI, cerebral infarction, or any other clinically significant arterial thromboembolic complication.
The available cabozantinib data from clinical studies and postmarketing experience showed that arterial aneurysms and dissections may occur rarely during cabozantinib treatment. These events appear to primarily occur in the presence of hypertension (which is a known risk factor for this condition); however, in some events the presence of hypertension was not documented. Discontinuation of treatment with cabozantinib should be considered in subjects who develop aortic aneurysm and dissections.
Bibliography: Cabozantinib (XL184) Investigator’s Brochure guideline v18.0 2022
Proteinuria
Proteinuria is an anticipated AE with the inhibition of VEGFR pathway and has been observed in cabozantinib clinical studies; nephrotic syndrome has been reported with cabozantinib and other inhibitors of VEGFR pathway.
During each safety assessment visit, proteinuria will be quantified by measuring the urinanalysis or urinary dipstick performed by the local lab (see APPENDIX III). Management of proteinuria is presented in Table 10.
In the case of proteinuria, if the dipstick analysis shows proteinuria ≥ 3+, study treatment should be interrupted until the Urine Protein Creatinine Ratio (UPCR) results are available and more definitive management can be applied.
Severity of Proteinuria (UPCR) | Management of Proteinuria |
≤ 1 mg/mg (≤ 113.1 mg/mmol) | • No change in cabozantinib treatment or monitoring |
> 1 and < 3.5 mg/mg (> 113.1 and < 395.9 mg/mmol) | • Consider confirming with a 24-h protein assessment within 7 days. • No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine protein ≤ 2 g/24 h on 24-h urine collection. • Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine collection. Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg. Consider holding cabozantinib treatment if UPCR remains > 2 mg/mg despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart cabozantinib treatment at a reduced dose after a dose hold unless otherwise approved by sponsor. • Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 2 consecutive readings, UPCR monitoring can revert to protocol-specific times. (Second reading is confirmatory and can be done within 1 week of first reading.) If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is determined to be stable (< 20% change) for 1 month, check urine protein/creatinine per protocol or as clinically indicated. |
≥ 3.5 mg/mg (≥ 395.9 mg/mmol) | • Hold cabozantinib treatment pending repeat UPCR within 7 days and/or 24-h urine protein. • If ≥ 3.5 mg/mg on repeat UPCR, continue to hold cabozantinib treatment and check UPCR every 7 days. If UPCR decreases to < 2 mg/mg, restart cabozantinib treatment at a reduced dose and monitoring of urine protein/creatinine should continue weekly until the UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is determined to be stable (< 20% change) for 1 month, check urine protein/creatinine per protocol or as clinically indicated. |
Nephrotic syndrome | • Discontinue all study treatment |
UPCR = Urine Protein Creatinine Ratio
Table 10: Management of Treatment-emergent Proteinuria
Corrected QTc Prolongation
The effect of orally administered cabozantinib at 140 mg/day (FBE) on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled Phase 3 study in patients with MTC. A mean increase in QT interval corrected by Fridericia (QTcF) of 10-15 ms was observed at 4 weeks after initiating cabozantinib. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No cabozantinib treated patients had a QTcF > 500 ms.
Only subjects with a baseline QTcF ≤ 500 ms are eligible for this study. Subjects will have ECGs performed at times designated by the protocol (Section 5.7).
If at any time on study there is an increase in QTcF interval to an absolute value > 500 ms, within 30 minutes after the initial ECG, 2 additional ECGs must be performed each with intervals approximately 3 minutes apart.
If the average QTcF from the 3 ECGs is > 500 ms, the following actions must be taken:
• Withhold study treatment
• Immediately notify the Sponsor
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology evaluation and management
• Consider cardiology consultation for asymptomatic subjects for evaluation and management
• Check electrolytes, especially magnesium and potassium; correct abnormalities as clinically indicated
• Check concomitant medications for any medication that may have contributed to QT prolongation, and if possible, discontinue these medications (see xxxx://xxx.xxxxxxx.xxx)
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 ms
Study treatment may be restarted at a reduced dose level if all of the following conditions are met:
• Symptoms are determined to be unrelated to the QT interval prolongation
• The QTcF value > 500 ms is not confirmed by the central ECG laboratory or a QTcF
> 500 ms confirmed by the central laboratory returns to ≤ 500 ms
• Study treatment has been interrupted through a minimum of 1 week following the return of the QTcF to ≤ 500 ms
• Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 2 weeks for 1 month, then according to the protocol-defined time points.
Study treatment must be permanently discontinued if either of the following applies:
• Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation
• Recurrence of QTcF prolongation (confirmed by central ECG lab) after reinitiation of study treatment at a reduced dose
Hemorrhagic Events
Hemorrhagic events have been reported with approved drugs that inhibit the VEGFR pathway as well as with cabozantinib. In order to mitigate the risk of severe hemorrhage, subjects should be evaluated
for potential bleeding risk factors prior to initiating study treatment and monitored for bleeding events with serial complete blood counts and physical examination while on study. Risk factors for hemorrhagic events may include (but may not be limited to) the following:
• Tumor of the lung with cavitary lesions or tumor lesions which invade, encase, or abut major blood vessels. The anatomic location and characteristics of tumor as well as the medical history must be carefully reviewed in the selection of subjects for study treatment.
• Recent radiation or surgery
• Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases
• Underlying medical conditions which affect normal hemostasis (eg, deficiencies in clotting factors and/or platelet function, or thrombocytopenia)
• Concomitant medication with drugs which affect normal hemostasis
• History of clinically significant hemoptysis
Discontinue study treatment in subjects who experience a severe bleeding complication.
GI Perforation/Fistula and Non-GI Fistula Formation
GI perforation/fistula and non-GI fistula formation have been reported with approved drugs that inhibit the VEGFR pathway as well as with cabozantinib. Carefully monitoring for episodes of abdominal pain is mandatory, especially in subjects with known risk factors for developing GI perforation/fistula or non-GI fistula, to allow for early diagnosis. Such risk factors include (but may not be limited to) the following:
GI perforation/fistula:
• Intra-abdominal tumor/metastases invading GI mucosa
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis
• History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
• Prior GI surgery (particularly when associated with delayed or incomplete healing). Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be confirmed prior to initiating study treatment
Additional risk factors include concurrent chronic use of steroid treatment or nonsteroidal anti-inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and effectively managed.
Non-GI fistula:
Complications from radiation therapy have been identified as a possible predisposing risk factor for non-GI fistula formation in subjects undergoing treatment with VEGF pathway inhibitors (eg, bevacizumab). Subjects are excluded from this study if there are any clinically relevant ongoing complications from prior radiation therapy (ie, radiation esophagitis or other inflammation of the viscera).
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI perforation/fistula.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported with use of anti-angiogenic drugs and bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have been identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, smoking, dental or orofacial surgery procedures, and cancer disease itself. Osteonecrosis has been reported in subjects treated with cabozantinib, the details of which are provided in the current version of Investigator’s Brochure. As a preventive measure, invasive dental procedures should be avoided if possible. In cases where dental procedures are unavoidable, the risks and benefits of a dental procedure and the extent of the procedure as well as the risk of developing osteonecrosis of the jaw need to be considered when deciding on the duration of a temporary study treatment interruption. If clinically possible, study treatment should be held for approximately 4 weeks prior to a dental procedure and resumed after complete healing has occurred.
Subjects with any documented case of osteonecrosis should have study treatment interrupted, and appropriate clinical management should be initiated. Reinitiation of study treatment must be discussed with and approved by the Sponsor on a case-by-case basis.
Glycemic Metabolism and Electrolyte Abnormalities
According to IB of lanreotide, due to the possible or potential class effect of SSAs on glycoregulation, blood glucose levels should be monitored during the treatment, and any antidiabetic treatment should be prescribed accordingly.
Electrolyte abnormalities, including hypocalcemia, hypokalemia, hypomagnesemia, and hypophosphatemia have been noted in subjects treated with cabozantinib. In some cases these have been Grade 3 or 4 and/or serious.
Hypocalcaemia has been observed with cabozantinib at a higher frequency and/or increased severity (including Grade 3 and 4) in patients with thyroid cancer compared with patients with other cancers. Blood calcium level monitoring is recommended and, if needed, calcium replacement and/or cabozantinib dose modification should be performed as clinically indicated, especially in thyroid cancer patients.
Electrolyte values should be evaluated routinely. Deficits should be corrected when an electrolyte abnormality is noted in order to avoid worsening. Correction of electrolyte abnormalities should be accompanied by increased frequency of monitoring.
Bibliography: Cabozantinib (XL184) Investigator’s Brochure guideline v18.0 2022
4.8 Treatment Compliance
All drugs will be administered to eligible patients under the supervision of the investigator or identified sub-investigator(s).
The pharmacist will maintain records of drug receipt, drug re-label, and dispensing, including the applicable lot numbers and total drug administered in milligrams.
The investigator and the clinical data manager will maintain the study treatment accountability with accurate records of receipt of all study treatments including dates of receipt. In addition, accurate records will be kept regarding when and how much study treatment is dispensed and used by each subject in the study. Reasons for deviation from the expected dispensing regimen must also be recorded. At completion of the study, to satisfy regulatory requirements regarding drug accountability, all unused study treatment will be reconciled and destroyed according to applicable regulations.
4.9 Termination of Treatment and/or Study Participation
Patients will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The investigator also has the right to withdraw patients from the study for any of the following reasons:
- Intercurrent illness
- Occurrence of an unacceptable adverse event
- Patient request
- Protocol violations
- Non-compliance
- Administrative reasons
- General or specific changes in the patient’s condition unacceptable for further treatment in the judgment of the investigator
- Progressive disease at any time
STUDY ASSESSMENT AND PROCEDURES
5.1 Recruitment
Patients with a histological diagnosis of well-differentiated GEP, thoracic and unknow primary NETs that are anticipated to be treated with cabozantinib and lanreotide will be approached for consideration for study entry. Patients will be approached only once the appropriate official notification has been received by the chief investigator that the trial is open for recruitment.
5.2 Consent
Written informed consent will be obtained as a prerequisite for study entry. Consenting procedures will conform to GCP and local and national regulations. The patient will also consent to their general practitioner (GP) being informed of their participation in the study.
5.3 Tissue specimen collection and analisys
As mandatory inclusion criteria, the tissue submitted will be used to assess exploratory biomarkers. The tissue submitted should be a formalin-fixed, paraffin-embedded (FFPE) tumor specimen or 10 serial, freshly cut, unstained slides accompanied by an associated pathology report. Cytological samples are not acceptable.
Representative FFPE tissue samples will be collected from the primary tumor and/or any previous metastatic tissue specimens, so that further analysis may be performed on that/those tissue sample(s) as appropriate.
The samples will be received, processed and centrally analysed by the Department of Pathology of Fondazione IRCCS Istituto Nazionale dei Tumori under the responsibility of Dr. Xxxxxxx Xxxxxxx, Director of Pathology Division 1 (MM).
Tissue will be removed from a representative tumor block and tissue cores and sections will be subsequently be prepared for the immunohistochemistry analysis and further testing as appropriate. The tumor tissue were classified according to revision by two blinded experienced pathologist (Dr. Xxxxxxx Xxxxxxx -MM-; Dr. Xxxxx Xxxxxxxx -LC-) to select representative sections (tumor and normal) for TMA (tissue micro-array) construction (Dr. Xxxxxxxx Xxxxxxxx -GC- Research Biologist and Xxxxxxxx Xxxxxxx -GG- Lab Technician).
The TMA blocks were done containing 2 representative areas of each primary cancer of NET tissue, metastatic tissue, and when available the normal counterpart (1 mm diameter core).
Analysis on biomarkers is exploratory by nature and will be performed retrospectively after the main study analysis is completed. Xxxxxx received in excess to that required by this study will be returned to the histopathology department from where it was originally requested.
The tumor tissue will be analyse by immunohistochemistry to determine VEGFR2, MET, AXL expression level, based on published procedures (1-9).
In addition, tumor tissue (archival or recently biopsied) obtained at enrollment whenever needed, may be used to explore other potentially pathway components or modulators associated with the mechanism of action of cabozantinib as predictive biomarkers.
Assesment of VEGFR2 IHC status
Formalin-fixed paraffin-embedded tumor blocks will be analysed using anti-VEGFR2 antibody (clone 55B11, Cell Signaling, Danvers, MA) (1). All immunostained slides will be reviewed by an experienced immunopathologist (MM) to assess VEGFR2 expression in tumor vasculature and cells. One score will be scored per patient. Different scoring approaches will be examined for vessels and tumor cells. Briefly, a case will be interpreted as VEGFR2 positive in tumor vasculature if endothelial cells in 10% or more of the tumor stromal blood vessels exhibit unequivocal immunoreactivity for VEGFR2. An assessment of the level of intensity of tumor cell staining (range of 0, no staining; 1+, weak staining; 2+, moderate staining; 3+, intense staining) will be made objectively by the study pathologist after screening the entire area of the stained tissue section. Observations will be made in the tumor cell cytoplasmic and nuclear compartments simultaneously. For each level of staining intensity, the percentage of tumor cells staining for that intensity will be determined. The value of each staining level (0, 1, 2 or 3) will be multiplied by the respective percentage of tumor cells at that intensity level. A total VEGFR2 H-score represents the sum of the three scores, reported on a continuous scale of 0– 300 (see below Table 11) (1-3).
Unique patient ID (CPID) | Diagnosis (AN) | Vascular endotheliu m Positive (VP)/ Negative (VN) | VEGFR2, Cyt/Nuc, 1+ (%) | XXXXX0, Xxx/Xxx 2+ (%) | VEGFR2, Cyt/Nuc, 3+ (%) | Total Cyt/Nuc, H-score |
001 | pNET | VP | 10% | 4% | 0 | 18 |
Table 11: Immunohistochemical expression of VEGFR2 in tumor vascular endothelial cells and tumor cells
VEGFR2 staining levels will be summarised by assessment type (e.g., neoplastic vessels, tumor cytoplasmic membrane, and so on). For those assessment types where there is a sufficient distribution of staining values, marker results will be categorised as low or high using the median H-score value as the cutoff, or by using H-score = 0 vs > 0 (2).
Assesment of MET IHC status
Subjects will be evaluated for baseline tumor MET status (high, low/negative, or unknown) based on IHC analysis. Formalin-fixed paraffin-embedded tumor blocks will be analysed using the SP44 antibody (Ventana Medical Systems, Inc, Tucson, AZ, USA) and MET status will be categorised as positive or negative based on a cutoff of ≥50% of tumor cells stained 2 + or 3 + for positive status (4- 6).
Assesment of AXL IHC status
Formalin-fixed paraffin-embedded tumor blocks will be analysed using the anti-Axl antibody (dilution 1:50, Cat #AF154 R&D Systems, Minneapolis, MN) at room temperature for 2 hours. Normal breast tissue, that will be used as a positive control, shows membranous Axl staining of luminal ductal cells with variable cytoplasmic staining (7).
The score used will be the sum of the percentage of cytoplasm positive cells (negative, 0%–<1% positive cells; 1, 1%–10% positive cells; 2, >10%–50% positive cells; 3, >50% positive cells) and the
staining intensity (0, negative; 1, weak; 2, moderate and 3, strong). Samples with scores 0 to 2 will
be considered negative for AXL expression and those with score 3 to 6 will be considered positive for AXL expression, as previously described for receptor tyrosine kinase immunohistochemistry analysis (7-8). All cases will be scored by two pathologists (MM, LC).
References
1. Xxxxxx TR, Xxxxxxx AD, Xxxxxxxxx DM, et al. Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung. PLoS One 2013;8:e80292
2. Xxxxx CS, Xxxxxxxxx J, Xxxxxxxx J, et al. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2- targeted antibody ramucirumab. Br J Cancer 2016;115:974–82.
3. Xxxxxxx S, Xxxxxxx A, Xxxxxxxxx H, Xxxxxx Y, Xxxxx H, Xxxxxx T, Xxx T, Xxxxx A, Xxxxxxx T, Xxxxx EM, Xxxxxxxxxxxxxxx S, Xxxxx A, Xxxxxx T, Xxxxxxx K. Efficacy and safety of ramucirumab-containing chemotherapy in patients with pretreated metastatic gastric neuroendocrine carcinoma. ESMO Open. 2018 Nov 1;3(7):e000443.
4. Choueiri TK, Xxxxxxxx B, Xxxxxx T, Xxxxxx NM, Xxxxxxxxxx PN, Xxxx BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17(7):917e27.
5. Xxxxxxx A, Xxxxxxx L, Xxxxxxx I, Xxxxxxx X, Xxxxxxxx S, Xxx Xxxxxxx JL, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo- controlled phase 2 study. Lancet Oncol 2013;14(1):55e63.
6. Xxxxxx DR, Xxxxx XX, Xxxxxx RA, Xxxxxx DB, Xxxxxxxxxxx Xx JH, Xxxxxxxxxxxx Xx XX, et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2013;31(32):4105e14.
7. D’Xxxxxxx TM, Xxxxxx X, Xxxx Z, Xxx Y, Xxxx P, Xxxx SJ. Axl receptor tyrosine kinase expression in breast cancer. J Clin Pathol 2014;67:690–6.
8. X.X. Xxxxx et al. Urologic Oncology: Seminars and Original Investigations 36 (2018) 11.e13–11.e21
5.4 Collection of clinicopathological and demographic data
Initial data will be collected on a study-specific eCRF to summarise information regarding the individual patient’s case. This will enable correlation of clinicopathological and demographic data with data from the biological studies performed. The eCRF will include information on: age, date of diagnosis, site of disease, stage at presentation, sites and diagnosis of metastatic disease, histological features at presentation, treatment, response to treatment, date of progressive disease, date of death, specific features of past medical history and family history.
5.5 Collection and Central Review of Imaging
CD-ROM copies of the CT or RMN scans (with contrast unless contraindicated) performed at baseline and during treatment until disease progression according to RECIST v1.1 will be send within 28 days at the Coordinating Data Center (s.c. Oncologia Medica 1 Fondazione IRCCS Istituto Nazionale dei Tumori, xxx Xxxxxxxx 0, 00000 Xxxxxx Xxxxx) for Central Review. The CD-ROM will be send at the courtesy attention of Dr.ssa Xxxx Xxxxxxxx (Principal investigator of the study, xxxx.xxxxxxxx@xxxxxxxxxxxxxx.xx.xx)
Sites should follow their local privacy practices to de-identify all subject identifying information (name, medical record number, act.) prior to submitting images to Coordinating Center.
Upon receipt, the Coordinating Center will verify that this information has been completely redacted, and, if necessary, will redact any remaining identifying information.
CD-ROM copies of the CT scans will be collected and centrally analysed by the Department of Radiology of the Fondazione IRCCS Istituto Nazionale dei Tumori under the responsibility of Dr. Xxxxxxx Xxxxxxxxx.
The CT scans will be reported according to evaluation by two experienced radiologist (Dr. Xxxxx Xxxxxxxxx -CS-; Dr. Xxxxxxx Xxxxxxxx -TC-) to perform a blinded Central Review of imaging in order to assess ORR and PFS according to RECIST vers 1.1 of the combination.
5.6 Baseline and Screening procedures
Pre-treatment evaluation will only be performed after the subject has agreed to participate and has signed and dated the informed consent document. No treatment or trial-related procedures will be initiated before the signed consent has been obtained. Imaging may be done before obtaining informed consent if done routinely. Subjects will not be required to undergo additional scanning if suitable images taken within 4 weeks of treatment period or inclusion in the study are available. Pre- treatment evaluations will be performed according to the eligibility criteria. If the subject is eligible for the study, the parameters at the screening visit showing subject health status, including blood values, will be recorded in the eCRF.
The following procedure and evaluations will be performed at screening (as per clinical practice) (see Appendix III)
A) The following evaluations will be performed within 28 days prior to treatment period
- Sign informed consent: enrolment in the study is defined as the signing of the Informed Consent. The Informed Consent Document must be signed prior to any study related procedures.
- Subject registration and subject number assignment
- Review inclusion and exclusion criteria and confirm eligibility
- Demographics
- Record disease history
- Record medical history
- Record concomitant medications / therapy
- Record previous anti-cancer treatments (prior and current)
- Perform full physical examination
- Within 28 days prior to start of study drug radiological assessment should be performed. This radiological evaluation must include a CT or MRI of the chest, abdomen and pelvis and should meet the standard of care for imaging of lesions in the respective organ system(s) at baseline. All additional suspected sites of disease should be imaged. CT or MRI of the head must be conducted to rule out brain metastasis.
- Appropriate radiological evaluation (e.g. bone scan) should be obtained if bone metastases are suspected.
- Within 6 months prior to the start of study drugs, nuclear assessment should be performed. This radiological evaluation must include a 68GA-PET or Octreoscan and must be conducted to rule out SSTR2-5 negativity. In case of negativity of SSTR2-5 expression
by nuclear assesments, tissue IHC evaluation of SSTR2 is allowed. The inclusion of the patient will be allowed if IHC analysis show a positive stain for SSTR2.
- 12-lead electrocardiogram (ECG) with evaluation of QTcF calculated by the Fridericia formula. Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms within 28 days before registration should be shown. Only subjects with a baseline QTcF
≤ 500 ms are eligible for the study.
- Note that : If the QTcF was > 500 ms in the first ECG, a total of 3 ECGs were to be performed. If the average of these 3 consecutive results for QTcF was ≤ 500 ms, the subject met eligibility in this regard.
- A multigated acquisition (MUGA) scan or a cardiac echocardiogram (ECHO) should be obtained. A MUGA scan or cardiac ECHO taken within 4 weeks prior to inclusion in the study is acceptable. Additional MUGA or cardiac ECHO should be requested when clinically indicated.
- Archival or recently biopsied tumor tissue.
B) The following evaluations will be performed within 7 days prior to treatment period
- Clinical Examination
- ECOG-PS
- Record vital signs: blood pressure, heart rate, respiratory rate, temperature, height (cm) and weight (kg)
- Red blood cell count (RBC), haemoglobin, hematocrit, platelet count, white blood cell count (WBC). WBC should include differential neutrophil, lymphocyte, monocyte, basophil and eosinophil counts.
- Electrolyte panel: sodium, potassium, chloride magnesium and corrected calcium.
- Chemistry panel: Aspartate Amino-Transferase (AST), Alanine Amino-Transferase (ALT), bilirubin (total and direct), alkaline phosphatase, uric acid, total proteins, albumin, calcium, lipase, amylase (amylase and lipase only at the screening), phosphate, Lactic Dehydrogenase (LDH), glucose, creatinine, Glomerular filtration rate (GFR)
- Thyroid function tests: FT3, FT4, TSH.
- Coagulation panel: Prothrombin Time (PT) or the International Ratio of PT (PT-INR), and Partial Thromboplastin Time (PTT).
- HBa1C, insulin, HDL/LDL-cholesterol, triglycerids, B12 cianocobalamine, D-vitamin, PTH.
- Cromogranine A, NSE,
- HBV anti-core antibody, HBV surface antigen (Hbs Ag), and antibodies anti - HCV
- HBV DNA or HCV RNA, only in subjects who have documented HBV or HCV positivity at baseline
- Urine or serum pregnancy test for women of childbearing potential (must be negative).
- Urinalysis or Urinary dipstick: (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen). 24 hours proteinuria is requested if protein are positive at urinanalysis or urinary dipstick.
- Any sign or symptom that begins, or is ongoing after enrolment (even if prior to start of study medication) must be documented on an Adverse Event page using the version 5.0 NCI CTCAE guidelines. Any medical conditions must be recorded on the Medical History page.
5.7 Treatment period
The treatment period (cycles) extends from the day of first treatment with cabozantinib and lanreotide to 4 weeks (28 days) until progression or unaccetable toxicity or consent withdraw.
A) Treatment period for all patient enrolled in Stage I-II-III Assessments to be performed at (cycle 1 day 1) (cycle 2 day 1):
To evaluate tolerability, clinical assessments, laboratory testing (chemistry, hematology tests) and AEs will be performed every 2 weeks for the first 8 weeks of treatment
- Perform full physical examination
- ECOG-PS
- Record vital signs: blood pressure, heart rate, respiratory rate, temperature, height (cm) and weight (kg)
- Blood draw for hematology, chemistry and urine evaluations. Only for cycle 1 day 1, these examinations could be the same executed at baseline if performed within 7day prior to the start of study treatment, according to baseline and screening section (see section 5.6).
- Record AEs, SAEs
- Record concomitant medications/therapy
- Drug accountability/dispensing
Assessments to be performed at (cycle 1 day 14) – (cycle 2 day 14):
To evaluate tolerability , clinical assessments, laboratory testing (chemistry, hematology tests) and AEs will be performed every 2 weeks for the first 8 weeks of treatment
- Perform full physical examination
- ECOG-PS
- Record vital signs: blood pressure, heart rate, respiratory rate, temperature, height (cm) and weight (kg)
- Blood draw for hematology, chemistry and urine evaluations (CBC, chemistries, Pregnancy test, Thyroid function test, Coagulation test, Urinanalysis) see appendix III.
- Record AEs, SAEs
- Record concomitant medications/therapy
- Drug accountability/dispensing
B) Assessments to be performed at each cycle:
- Perform full physical examination
- ECOG-PS
- Record vital signs: blood pressure, heart rate, respiratory rate, temperature, height (cm) and weight (kg)
- Blood draw for hematology, chemistry and urinary evaluations (CBC, chemistries, Pregnancy test, Thyroid function test, Coagulation test, Urinanalysis) see appendix III.
- Record AEs, SAEs
- Record concomitant medications/therapy
- Drug accountability/dispensing
C) Assessments to be performed every 3 cycles
- Perform full physical examination
- ECOG-PS
- Record vital signs: blood pressure, heart rate, respiratory rate, temperature, height (cm) and weight (kg)
- Blood draw for hematology, chemistry and urine evaluations (CBC, chemistries, Pregnancy test, Thyroid function test, Coagulation test, Urinanalysis) see appendix III.
- Other blood text including HbA1c, insulin, HDL/LDL-cholesterol, triglycerids B12- cianocobalamin, D-vitamin, PTH, Chromogranine A, NSE. (see appendix III).
- Record AEs, SAEs
- Record concomitant medications/therapy
- Drug accountability/dispensing
- A chest/abdominal/pelvic CT scan or MRI (time window for the scans is +/- 28 days). The same imaging modalities used at baseline have to be used for disease assessment. A subject who experiences radiological progression at CT scan can be discontinued. CT or MRI of the head must be conducted only in the presence or in the suspect of brain metastases.
- Appropriate radiological evaluation (bone scan etc.) should be obtained in the presence or in the suspect of bone metastases
- 12-lead electrocardiogram (ECG) with QTC evaluation
- ECHO or MUGA if clinically indicated.
- HBV DNA or HCV RNA only in subjects who have documented HBV or HCV positivity at baseline;
D) End of treatment visit:
When a patient is to be taken off treatment, the following assessment should be done 30 days (+/- 7 days) after study treatment has stopped:
- Brief medical history and complete physical examination including review of all organ systems, examination of pertinent organ systems,
- Record vital signs: blood pressure, heart rate, respiratory rate, temperature, height (cm) and weight (kg)
- Blood draw for hematology, chemistry and urine evaluations (CBC, chemistries, Pregnancy test, Thyroid function test, Coagulation test, Urinanalysis) see appendix III.
- Other blood text including HbA1c, insulin, HDL/LDL-cholesterol, triglycerids, B12- cianocobalamin, D-vitamin, PTH, Chromogranine A, NSE (see appendix III).
- Record AEs, SAEs
- Record concomitant medications/therapy
- ECOG performance status.
- HBV DNA or HCV RNA (only in subjects who have documented HBV or HCV positivity at baseline);
- For patients who discontinue for reasons other than Disease Progression, tumor measurements and evaluation of tumor response of all measurable lesions should be performed according to RECIST criteria.
5.8 Follow up
After study drug treatment ends, patients will be evaluated approximately every 3 months to determine follow-up. All patients who are discontinued from study drug for any reason other than disease progression will continue to have tumor assessments as per the schedule and until the patient has documented disease progression determined by the local radiologist and/or the investigator or until the initiation of new anticancer therapy.
5.9 Survival
Patients who discontinued therapy due to progression of disease should be evaluated for “survival” every 3 months in order to define if the patient is alive and the subsequent therapies.
RADIOLOGICAL TUMOR ASSESSMENT
Response and progression will be evaluated in this study using the updated international criteria proposed by RECIST (Response Evaluation Criteria in Solid Tumors) committee (Xxxxxxxxxx EA et al., Eur J Cancer 2009).
6.1 Response Evaluation Criteria in Solid Tumors (RECIST v 1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST) (Xxxxxxxxxx EA et al), Version 1.1 are presented below, with slight modifications and the addition of explanatory text as needed for clarity.
Measurability of tumor at baseline definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows.
a. Measurable Tumor Lesions
Tumor Lesions. Tumor lesions must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:
• 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (CT/MRI scan slice thickness/interval no greater than 5 mm)
• 10-mm caliper measurement by clinical examination (lesions that cannot be accurately measured with calipers should be recorded as non-measurable)
• 20 mm by chest X-ray
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).
At baseline and in follow-up, only the short axis will be measured and followed. See also notes below on “Baseline Documentation of Target and Non-Target Lesions” for information on lymph node measurement.
b. Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal masses/abdominal organomegaly identified by physical examination that is not measurable by reproducible imaging techniques.
c. Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular comment, as outlined below.
Bone lesions:
• Technetium-99m bone scans (T-99m), sodium fluoride−positron emission tomography (NaF-PET) bone scans, or plain films are not considered adequate imaging techniques to measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered measurable lesions if the soft tissue component meets the definition of measurability described above.
• Blastic bone lesions are non-measurable.
Cystic lesions:
• Lesions that meet the criteria for radiographically defined simple cysts should not be considered malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts.
• Cystic lesions thought to represent cystic metastases can be considered measurable lesions if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions.
Lesions with prior local treatment:
• Tumor lesions situated in a previously irradiated area or in an area subjected to other loco- regional therapy are usually not considered measurable unless there has been demonstrated progression in the lesion. Study protocols should detail the conditions under which such lesions would be considered measurable.
Target lesions: specifications by methods of measurements
a. Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as close as possible to the treatment start and never more than 4 weeks before the beginning of the treatment.
b. Method of Assessment
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during study. Imaging-based evaluation should always be the preferred option.
Clinical Lesions
Clinical lesions will be considered measurable only when they are superficial and ≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion is suggested.
Chest X-Ray
Chest CT scan is preferred over chest X-ray, particularly when progression is an important endpoint, since CT scan is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung.
CT, MRI
CT is the best currently available and reproducible method to measure lesions selected for response assessment. This guideline has defined measurability of lesions on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the study should be guided by the tumor type under investigation and the anatomic location of the disease. For patients who develop contraindications to contrast after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should also be based on the tumor type and the anatomic location of the disease and should be optimized to allow for comparison with the prior studies if possible. Each case should be discussed with the radiologist to determine if substitution of these other approaches is possible and, if not, the patient should be considered not evaluable from that point forward. Care must be taken in measurement of target lesions on a different modality and interpretation of non-target disease or new lesions since the same lesion may appear to have a different size using a new modality.
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology
The utilization of these techniques for objective tumor evaluation cannot generally be advised.
Tumor response evaluation. Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, it is necessary to estimate the overall tumor burden at baseline and to use this as a comparator for subsequent measurements. Measurable disease is defined by the presence of at least one measurable lesion, as detailed above.
Baseline documentation of target and non-target lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline. This means in instances where patients have only one or two organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), respectively, will be recorded. Other lesions (albeit measurable) in those organs will be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and be representative of all involved organs but, additionally, should lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement, in which circumstance the next largest lesion that can be measured reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures that may be visible by imaging even if not involved by tumor. As noted above, pathological nodes that are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, an abdominal node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the node measurement. All other pathological nodes (those with short axis ≥ 10 mm
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should not be recorded or followed.
Lesions irradiated within 4 weeks prior to Cycle 1, Day 1 may not be counted as target lesions.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be included in the sum, then, as noted above, only the short axis is added into the sum. The baseline sum of diameters will be used as a reference to further characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the electronic-Case Report Forms (eCRF) (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
Response criteria
a. Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor response for target lesions.
• Complete response (CR): disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
• Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters
- Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
• Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study
b. Special Notes on the Assessment of Target Lesions
• Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement recorded (measured in the same anatomical plane as the baseline examination), even if the nodes regress to < 10 mm on study. This means that when lymph nodes are included as target lesions, the sum of lesions may not be zero even if CR criteria are met since a normal lymph node is defined as having a short axis < 10 mm.
• Target Lesions That Become Too Small to Measure
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an exact measure and may report them as being too small to measure. When this occurs, it is important that a value be recorded on the CRF as follows:
- If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm.
- If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned and BML (below measurable limit) should be ticked. (Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable size when
normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this circumstance as well and BML should also be ticked.)
However, to reiterate, if the radiologist is able to provide an actual measure, that should be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
• Lesions That Split or Coalesce on Treatment.
When non-nodal lesions fragment, the longest diameters of the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer separable, the vector of the longest diameter in this instance should be the maximal longest diameter for the coalesced lesion.
c. Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the group of non-target lesions. Although some non-target lesions may actually be measurable, they need not be measured and, instead, should be assessed only qualitatively at the timepoints specified in the protocol.
• CR: disappearance of all non-target lesions and (if applicable) normalization of tumor marker level) All lymph nodes must be non-pathological in size (< 10 mm short axis).
• Non-CR/Non-PD: persistence of one or more non-target lesion(s) and/or (if applicable) maintenance of tumor marker level above the normal limits
• PD: unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
d. Special Notes on Assessment of Progression of Non-Target Disease
• When the Patient Also Has Measurable Disease
In this setting, to achieve unequivocal progression on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. The designation of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
• When the patient has bone lesions at baseline
When a bone scan is the sole indicator of progression, progression in bone will be defined as when at least two or more new lesions are seen on bone scan compared with screening. In situations where the scan findings are suggestive of a flare reaction or apparent new lesion(s) that may represent trauma, these results must be confirmed with other imaging modalities such as MRI or fine-cut CT to constitute progression. Only a single new bone lesion on bone scan is required for progression if the lesion can be correlated on CT or MRI.
e. New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments on detection of new lesions are important. There are no specific criteria for the identification of new radiographic lesions; however, the finding of a new lesion should be unequivocal, that is, not attributable to differences in scanning technique, change in imaging modality, or findings thought to represent something other than tumor (for example, some “new” bone lesions may be simply healing or flare of preexisting lesions). This is particularly important when the patient’s baseline lesions show PR or CR. For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan.
New osteoblastic bone lesions identified on plain films, CT, or MRI will not be considered progression in an otherwise stable or responding subject if, in the opinion of the physician, the osteoblastic lesion appears to be healing or a response to therapy.
Evaluation of response
a. Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table 12 provides a summary of the overall response status calculation at each timepoint for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 13 is to be used.
Target Lesions Non-Target Lesions New Lesions Overall Response | |||
CR | CR | No | CR |
CR | Non-CR/non-PD | No | PR |
CR | Not evaluated | No | PR |
PR | Non-PD or not all evaluated | No | PR |
SD | Non-PD or not all evaluated | No | SD |
Not all evaluated | Non-PD | No | NE |
PD | Any | Yes or no | PD |
Any | PD | Yes or no | PD |
Any | Any | Yes | PD |
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease.
Table 12 Timepoint Response: Patients with Target Lesions (with or without Non-Target Lesions)
b. Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable at that timepoint. If only a subset of lesion measurements are made at an assessment, usually the case is also considered not evaluable at that timepoint, unless a convincing argument can be made that the
contribution of the individual missing lesion(s) would not change the assigned timepoint response. This would be most likely to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and, during the study, only two lesions were assessed, but those gave a sum of 80 mm; the patient will have achieved PD status, regardless of the contribution of the missing lesion.
If one or more target lesions were not assessed either because the scan was not done or the scan could not be assessed because of poor image quality or obstructed view, the response for target lesions should be “unable to assess” since the patient is not evaluable. Similarly, if one or more non-target lesions are not assessed, the response for non-target lesions should be “unable to assess” except where there is clear progression. Overall response would be “unable to assess” if either the target response or the non-target response is “unable to assess,” except where this is clear evidence of progression as this equates with the case being not evaluable at that timepoint.
OR at First Timepoint | OR at Subsequent Timepoint | Best OR |
CR CR CR CR PR SD, PD, or PR a CR SD SD, provided minimum duration for SD was met; otherwise, PD CR PD SD, provided minimum duration for SD was met; otherwise, PD CR NE SD, provided minimum duration for SD was met; otherwise, NE PR CR PR PR PR PR PR SD SD PR PD SD, provided minimum duration for SD was met; otherwise, PD PR NE SD, provided minimum duration for SD was met; otherwise, NE NE NE NE | ||
OR =Overall response; CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease must have reappeared after CR). Best response would depend on whether the minimum duration for SD was met. However, sometimes CR may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR, at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best response is PR.
Tab 13 Best Overall Response When Confirmation Is Required
b. Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” size (< 10 mm), they may still have a measurement reported on scans.
This measurement should be recorded even though the nodes are normal in order not to overstate progression should it be based on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a total sum of “zero” on the eCRF.
Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to document objective progression even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response;
it is a reason for stopping study therapy. The objective response status of such patients is to be determined by evaluation of target and non-target disease as shown in Tables 12-13.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment progression is confirmed, the date of progression should be the earlier date when progression was suspected.
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple passes with large core needle) of a new lesion or an existing solitary progressive lesion that following serial sectioning and pathological examination reveals no evidence of malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary progressive lesion will not constitute disease progression. The subjects must be stop the treatment with cabozantinib at least 28 days before major or minor surgery.
In studies for which patients with advanced disease are eligible (i.e., primary disease still or partially present), the primary tumor should also be captured as a target or non-target lesion, as appropriate. This is to avoid an incorrect assessment of CR if the primary tumor is still present but not evaluated as a target or non-target lesion.
ADVERSE EVENTS AND SAFETY
7.1 Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug.
7.2 Serious Adverse Event Definition
Serious adverse event (SAE) means any untoward medical occurrence that at any dose:
• Results in death.
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe).
• Requires inpatient hospitalization or prolongation of an existing hospitalization.
• Results in persistent or significant disability or incapacity (disability is defined as a substantial disruption of a person’s ability to conduct normal life functions).
• Is a congenital anomaly/birth defect.
• Is a medically important event. This refers to an AE that may not result in death, be immediately life threatening, or require hospitalization, but may be considered serious when, based on appropriate medical judgment, may jeopardize the patient, require medical or surgical intervention to prevent one of the outcomes listed above, or involves suspected transmission via a medicinal product of an infectious agent. Examples of such medical events