Dose Modifications. There are no dose reductions for pembrolizumab. − Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent an immunologic etiology. These adverse events may occur shortly after the first dose or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening AEs as per Table 9. • AE37 dose modifications − A reduction in the dose of AE37 may be required depending upon the local reaction to multiple doses (see Table 7). AE37 is given as split dose intradermal injections at two sites on the upper thigh 5 cm apart. If there is a large local reaction (>100 mm) such that the reaction at the two sites begins to merge, the subsequent dose of AE37 is reduced by one half (i.e., dose level – 1). See Table 7 and Table 8. − Vaccine-related toxicities requiring a ≥ 2 week delay in starting Cycle 2 or subsequent cycles will result in a dose level reduction for subsequent AE37 vaccinations. See Section 7.1.4, Table 7 and Table 8. 69 Table 7. AE37 vaccine local reaction assessment Local skin reaction at vaccination sites Grade 1 Grade 2 Grade 3 Grade 4 Mild erythema Non-confluent erythema, mild tenderness at site Confluent erythema, ulceration and/or severe pain at site Severe ulceration, necrosis; urgent intervention necessary Table 8. Dose levels for AE37 vaccine AE37 Vaccine Dose Xxxxx 0 Xxxxxxxx Xxxx Xxxx Xxxxx −0 Xxxx Xxxxx −2 Dose Level −3 Dose Level − 4 1000 mcg 500 mcg 250 mcg 125 mcg Discontinue
Dose Modifications. In order to maintain dose-intensity and cumulative dose-delivery, reasonable efforts should be made to minimize dose reductions and treatment delays. Any subject whose treatment is delayed should be evaluated on a weekly basis until adequate hematologic and non-hematologic parameters have been met. Toxicities may require the dose reduction of one or more of the study required medications. The investigator should carefully assess all treatment-associated toxicities and, whenever possible, determine if the toxicities can reasonably be attributed to a single agent or a causal relationship with one of the agents can reasonably be ruled out. If appropriate, dose reductions should not affect the dose of other products. For example, if the dose of cetuximab is reduced, cisplatin or carboplatin, 5-FU, and IP should be administered per protocol. • Toxicity grades are defined using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 • Any subject who requires a dose reduction due to drug-related toxicity will continue to receive the reduced dose for the remainder of study treatment • Dose escalations are not allowed It is imperative that sequencing of chemotherapy and IP be maintained throughout the study. Specifically, platinum and 5-FU should be administered on the same day, if possible. If short delays are required that separate the administration of platinum and 5-FU, all attempts should be made to dose these agents on the same day in subsequent cycles. Due to the immunosuppressive effects associated with the dosing period of 5-FU, all attempts should be made to avoid co-administration of IP until 48 hours after completion of 5-FU administration. In addition, the timing of imaging studies should not be affected by dose reductions or delays. Subjects should remain on study (i.e., continue receiving treatment with other agents and undergo all protocol-related assessments) until independently-confirmed disease progression. Thereafter, subjects should be followed for long-term survival per protocol.
Dose Modifications. It is anticipated that most of the treatment related toxicity on this trial will be caused by carboplatin/etoposide/atezolizumab. Myelosuppression, predominantly neutropenia, will occur frequently; common non-hematologic toxicities include fatigue, nausea, vomiting, and mucositis. In contrast, LB-100 is anticipated to be well tolerated; few toxicities observed in phase I overlapped the known toxicity profile of carboplatin, etoposide and atezolizumab. The following general dose modification rules will, therefore, be used for patients on the LB-100 treatment arm: If the initiation of a cycle is delayed due to carboplatin/etoposide/atezolizumab toxicity, the LB-100 will also be delayed to begin concurrently with the carboplatin/etoposide/atezolizumab. If atezolizumab is held then LB-100 should be held as well, as it is a potential immunomodulator If toxicity is typical of carboplatin/etoposide/atezolizumab and requires dose reductions, the dose of LB-100 should not be reduced. If the toxicity is attributed specifically to one or two agents (carboplatin, etoposide, atezolizumab), the attributed agents will be dose reduced; otherwise, the doses of all 3 drugs should be reduced. Patients who require a treatment delay of more than 28 days due to toxicity will be discontinued from the study. An exception is given for tapering of steroids. If a patient must be tapered off steroids used to treat adverse events, atezolizumab may be withheld until steroids are discontinued or reduced to prednisone dose (or dose equivalent) ≤ 10 mg/day.
Dose Modifications. Each dose modification or treatment delay must be documented, including the respective reason. The reason for dose modification should be directly related to a selinexor-associated AE, and not due to disease symptom/sign or to other medications. For all Grade ≥3 hematological or non-hematological AEs that are NOT selinexor related, after consultation with the Medical Monitor and at the discretion of the Investigator, selinexor dosing may be maintained. Selinexor should be discontinued for all selinexor-related life-threatening (Grade 4) AEs. Table 4 summarizes the selinexor dose levels; Table 5 describes supportive care and dose adjustment guidelines. Deviations from the guidelines are permitted after discussion between the Sponsor and the treating physician. Table 4: Selinexor Dose Modification Steps for Adverse Reactions Recommended Starting Dosage First Reduction 20 mg Days 1, 3 and 5 of each week (60 mg total per week) 20 mg Days 1 and 3 weekly (40 mg total per week) Table 5: Selinexor Dosage Modification for Adverse Reactions Adverse Reactiona Occurrence Action Hematologic Adverse Reactions Thrombocytopenia Platelet count 25,000 to less than 50,000/mcL Any • Reduce selinexor by 1 dose level (see Table 4). Platelet count 25,000 to less than 50,000/mcL with concurrent G3 bleeding Any • Interrupt selinexor and provide appropriate supportive care. • Restart selinexor after bleeding has resolved at 1 dose level lower (see Table 4). Platelet count less than 25,000/mcL Any • Interrupt selinexor and provide appropriate supportive care. • Monitor until platelet count returns to at least 50,000/mcL. • Restart selinexor at 1 dose level lower (see Table 4). Neutropenia Absolute neutrophil count of 0.5 to 1.0 x 109/L with fever Any • Interrupt selinexor and provide provide appropriate supportive care. • Monitor until neutrophil counts return to 1.0 x 109/L or higher. • Restart selinexor at 1 dose level lower (see Table 4). Absolute neutrophil count less than 0.5 x 109/L Any • Interrupt selinexor and provide appropriate supportive care. • Monitor until neutrophil counts return to 1.0 x 109/L or higher. • Restart selinexor at 1 dose level lower (see Table 4). Anemia Hemoglobin less than 8.0 g/dL Any • Reduce selinexor by 1 dose level (see Table 4). • Administer blood transfusions and/or other treatments per clinical guidelines. Life-threatening consequences Any • Interrupt selinexor and administer appropriate care with blood transfusions and/or other treatments pe...
