Exploratory Objectives. The exploratory objective of the First part (Part A) of this study is • To investigate the relationship between plasma AZD5363 exposure and plasma concentrations of exploratory biomarkers and efficacy. Biomarkers may include, but are not restricted to, somatic mutation or amplification of genes on the PI3 kinase and related pathways in cfDNA. • To obtain a p reliminary assessment of AZD5363 treatment effect by quantitative change in circulating tumour cells (CTCs). • To investigate the concordance of PIK3CA mutation status between per-patient analyses of blood and archival tumour tissue samples. • To explore changes in WHO performance status in patients treated with AZD5363 in combination with weekly paclitaxel compared with weekly paclitaxel plus placebo. • To collect optional matched pre-and post- treatment tumour biopsy samples to conduct assessment of the PD effect of therapy compared to baseline. • To collect and store archival tumour samples and analyse surplus blood or tissue, for potential future exploratory research into factors that may influence development of cancer and/or response to AZD5363 (where response is defined broadly to include efficacy, tolerability or safety). Biomarkers may include, but are not restricted to, somatic mutation or amplification of genes on the PI3 kinase and related pathways, PTEN protein expression and AKT protein expression. This exploratory analysis will be reported separately. • To obtain blood samples for deoxyribonucleic acid (DNA) extraction for future exploratory research into genes/genetic variation that may influence response (i.e., distribution, safety, tolerability and efficacy) to AZD5363 treatment and/or susceptibility to cancer. This exploratory analysis will be reported separately.
Exploratory Objectives. Compare the detection of local and metastatic disease using [68Ga]FAPI-46 PET to a composite of clinical, radiological (i.e. CT, MR) and/or 18F-FDG PET and histopathological reference in patients with resectable or borderline resectable PDAC.
Exploratory Objectives. 1. Evaluate the difference in disease progression according to RECIST 1.1 vs iRECIST (Appendix 5) criteria.
2. Assess the utility of a Patient Personalized Clinical Benefit (PPCB) phone based application.
3. Assess the association between improvement in symptoms as recorded by the Patient Personalized Clinical Benefit (PPCB) with progression at 6 months by RECIST 1.1.
4. To assess any changes in tumor and/or tissue texture on imaging in both arms of the trial.
5. To monitor and compare the gut microbial communities in both arms of the trial.
Exploratory Objectives. To examine the efficacy of aramchol in improving imaging-based biomarkers associated with changes in NAFLD
Exploratory Objectives. Patients must have platinum-resistant disease:
Exploratory Objectives. ● The pharmacokinetics (PK) of LB-100 and etoposide ● The biomarkers relevant to LB-100 and the disease state as well as their correlation to clinical outcomes
Exploratory Objectives. Frequency tables that include the proportion of patients who achieved clinical remission will be used to describe the proportion of patients that achieved clinical remission within the 12-month period. Clinical remission will be defined as meeting all the following: • No clinically significant asthma exacerbations during the 12-month period and; • No OCS use for asthma at the 12-month period and; • ACQ-5 < 1 at the end of 12-month period; and • Lung function stabilisation (no decline of ≥100 mL lung function measured using FEV1 compared to baseline) at 12 months. The change from baseline in FeNO will estimate the mean difference in FeNO at 1-, 3-, 6- , and 12-months and will use mixed effects models for repeated measures when appropriate (a similar approach as the one used for the primary objective). The change from baseline in FEV1 will estimate the mean difference in FEV1 at 1-, 3-, 6- , and 12-months and will use mixed effects models for repeated measures when appropriate (a similar approach as the one used for the primary objective). The change from baseline in blood eosinophil values will estimate the mean difference in blood eosinophil values from baseline and the ratio to baseline for blood eosinophil values at 1-, 3-, 6-, and 12-months. Both estimates will use mixed effects models for repeated measures when appropriate (a similar approach as the one used for the primary objective). Depending on data availability, exploratory objectives may only be described (as described in Section 3.7.1)
Exploratory Objectives. The exploratory objectives of this study are to examine the potential mechanisms of GSH by: ▪ Evaluating changes in circulating GSH levels and in levels of other redox intermediates which are co-regulated with GSH (GSSH, cysteine, cystine, redox ratios and potential for the GSH and cysteine couples) ▪ Evaluating changes occurring in up to 180 metabolites including acylcarnitines, amino acids, biogenic amines, monosaccharides, sphingolipids and glycerophospholipids as a result of changes in GI function associated with GSH administration.
Exploratory Objectives. To assess PRO using the EORTC QLQ-C30, EQ-5D-5L, and Patient Global Impression of Severity (PGIS) questionnaires • To evaluate concentrations of MIRV, TAb, DM4 and S-methyl DM4, using sparse sampling • To assess the immunogenicity of MIRV via anti-drug antibodies (ADAs) • To evaluate potential biomarkers in blood and tumor tissue predictive of response to MIRV
Exploratory Objectives. To identify potential biomarkers including BRCA status, homologous recombination repair (HRR) gene status, HRD score, PD-L1 expression, and other disease-related or treatment-related biomarkers that would associate with tumor responses to the combination of TSR-042, bevacizumab, and niraparib based on the molecular profile of tumor tissue, blood, and optional ascitic fluid samples. • To evaluate the evolution of the molecular profile of the tumor and tumor microenvironment in response to treatment.
