E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage IV or unresectable stage III, BRAFV600E/K mutation positive melanoma, naïve for BRAF/MEK, PD-1/PD-L1 or CTLA-4 targeting therapy |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare efficacy of upfront short-term vemurafenib + cobimetinib followed by ipilimumab + nivolumab (Arm A) versus standard ipilimumab + nivolumab treatment (Arm B) in patients with stage IV or unresectable stage III, BRAFV600E/K mutation positive melanoma, naïve for BRAF/MEK, PD-1/PD-L1 or CTLA-4 targeting therapy |
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E.2.2 | Secondary objectives of the trial |
• To describe duration of response and overall survival induced by vemurafenib + cobimetinib followed by the combination of ipilimumab + nivolumab (Arm A) as compared to ipilimumab + nivolumab t (Arm B)
• To describe toxicity observed in the two study arms
• To describe the rate of ongoing responses upon response-driven flat dose (240mg, q2w) nivolumab maintenance
• To describe the rate of response after re-induction in case of progression after initial response-driven treatment break
• To evaluate the changes in systemic immune competence |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to participate in this study, a subject must meet all of the following criteria:
• Adults 18 years and older
• World Health Organization (WHO) Performance Status 0-2
• Histologically or cytologically confirmed Stage IV, or unresectable stage III, BRAF V600E/K mutated melanoma
• Measurable disease according to RECIST 1.1
• Signed and dated informed consent form
• No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
• No prior BRAFi and/ or MEKi therapy
• No immunosuppressive medications
• Screening laboratory values must meet the following criteria and should be obtained within 10 days prior to randomization:
o WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.0mmol/L
o Creatinine ≤ 2x ULN
o AST, ALT ≤ 2.5 x ULN (≤5 x ULN for patients with liver metastases)
o Bilirubin ≤2 X ULN
o LDH > ULN, < 3xULN
• No symptomatic brain metastases (asysmptomatic brain metastases, accidentally found during screening can be included)
• No leptomeningeal metastases
• No active autoimmune disease requiring systemic treatment in the past 3 months or a documented history of autoimmune disease, or history of syndrome that required systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or immunosuppressive medications. (Subjects with vitiligo or resolved childhood asthma/atopy are excluded from this rule (and will not be excluded from this study). Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the study.)
• No evidence of interstitial lung disease or active, non-infectious pneumonitis
• No active infection requiring therapy
• No known additional malignancy that is progressing or requires active treatment
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days + the time required for nivolumab to undergo five half-lives) after the last dose of study medication
• WOBCP must have a negative serum or urine pregnancy test within 96 hours prior to the start of study treatment and must not be breast feeding
• Men must agree to the use of male contraception during the study treatment period and for at least 31 weeks after the last dose of study drug.
• Currently not participating in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
• No underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events
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E.4 | Principal exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Compare the best overall response rate (BORR) according to RECIST 1.1 of both arms |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 18 from start of treatment |
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E.5.2 | Secondary end point(s) |
• Progression-free survival (PFS) according to RECIST 1.1
• Overall survival (OS)
• Percentage of grade 3/4 toxicities according to CTCv4.03
• Percentage of ongoing response, percentage of patients requiring re-induction, response percentage upon re-induction
• Changes in tumor-specific T cell responses |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression and response related end-points will be assessed by CT every 6 weeks during treatment. Survival will be assessed every 12 weeks after the end of treatment. Safety will be assessed at each visit. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have either stopped protocol treatment and an evaluation of the disease has been performed
2. The trial is mature for the analysis of the primary end-point as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |