E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with metastatic melanoma, stage IIIC or IV (American Joint Committee on Cancer 2010) with hardly resectable/unresectable limited metastasis positive for the BRAF V600 mutation, which are expected to become resectable (R0) due to tumor shrinkage under vemurafenib + cobi-metinib. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with metastatic melanoma with hardly resectable/unresectable limited metastasis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025671 |
E.1.2 | Term | Malignant melanoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025670 |
E.1.2 | Term | Malignant melanoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Percent of patients who actually become resectable and are resected |
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E.2.2 | Secondary objectives of the trial |
Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment. Overall survival time after resection, in the group who actually underwent complete resection. Rate of objective responses. Tolerability. Overall survival and progression free survival time in the total study population. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Detection of biomarkers for response to vemurafenib + cobimetinib by analysis of baseline metastatic tumor tissues/ blood samples and comparing metastatic tu-mor tissues pretreatment and post treatment. Differences in gene expression, oncogenic muta-tion/copy number alteration profiles, and oncogenic signaling pathway status in baseline metastatic tumor-tissues/ blood samples and metastatic tumor tissues before/after neoadjuvant study treatment (at time of resection).
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E.3 | Principal inclusion criteria |
1. Adult patients, ≥ 18 years of age 2. Willing and able to give informed consent 3. Metastatic melanoma, stage IIIC or IV (American Joint Committee on Cancer 2010) 4. ECOG 0-1 5. MAP-kinase pathway inhibitor treatment-naïve 6. Positive for BRAF V600 mutation, preferentially to be shown from metastatic tumor tissue 7. Decision of eligibility for neoadjuvant combined vemurafenib and cobimetinib treatment by interdisci-plinary tumor board. Patient with limited numbers of metastases and few organ systems involved should be selected, making surgical resection after neoad-juvant treatment probable. 8. Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST V1.1) criteria 9. Adequate hematologic and organ function as defined by: • ANC ≥ 1.5 × 109/L • Platelets ≥ 100 × 109/L • Hemoglobin ≥ 9 g/dL • Albumin ≥ 2.5 g/dL • Bilirubin ≤ 1.5 × the upper limit of normal (ULN) • AST, ALT, and alkaline phosphatase ≤ 3 × ULN, except patients with documented liver metasta-ses: AST and/or ALT ≤ 5 × ULN • Patients with documented liver or bone metasta-ses: alkaline phosphatase ≤ 5 × ULN • Serum creatinine ≤ 1.5 × ULN 10. For fertile men: effective contraception during treat-ment and for 6 months after completion in such a manner that the risk of pregnancy is minimized 11. For women of childbearing potential, negative preg-nancy test performed within 28 days prior study en-rolment, preferably as close to the first dose as pos-sible, and agrees to use adequate contraception from pregnancy test onwards, through the dosing period, and for at least 6 months after the last dose of investigational product as: • complete abstinence from sexual intercourse • oral contraceptive, either combined or progesto-gen alone • injectable progestogen • implants of levonorgestrel • estrogenic vaginal ring • percutaneous contraceptive patches • intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year • male partner sterilization (vasectomy with docu-mentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject • double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
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E.4 | Principal exclusion criteria |
1. Candidates for direct surgery: patients with single site easily resectable metastasis 2. Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment 3. Active central nervous system metastases ex-cept metastases after complete resection or ste-reotactic irradiation and stable status for at least 3 months 4. History of carcinomatous meningitis 5. Severe cardiovascular disease within 6 months prior to study drug administration 6. History or evidence of cardiovascular risk includ-ing any of the following • LVEF < 50% or < LLN, whichever is lower • a QTc interval ≥ 450 ms • evidence of clinically significant uncontrolled arrhythmias 7. History or evidence of retinal vein occlusion 8. Previous malignancy within 5 years prior to study, except for basal or squamous cell carci-noma of the skin, melanoma in-situ, or carcino-ma in-situ of the cervix 9. Psychological, familial, sociological, or geograph-ical conditions that do not permit compliance with the protocol 10. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study 11. Legal incapacity or limited legal capacity 12. Subjects housed in an institution on official or le-gal orders 13. Participation in another clinical study with exper-imental therapy within the 30 days before start of treatment 14. Pregnancy or lactation period 15. Concomitant use of study therapy and drugs with a potential for QT prolongation (see database www.qtdrugs.org) 16. Known immediate or delayed hypersensitivity re-action or idiosyncrasy to cobimetinib and/or vemurafenib and/or to any of its excipients 17. Patients with diseases that affect liver function, such as viral hepatitis 18. Patients receiving medications known to increase the risk of peripheral edema
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the percentage of patients becoming operable after the combined treatment within 18 weeks. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after the combined treatment within 18 weeks |
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E.5.2 | Secondary end point(s) |
Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment. Overall survival time after resection, in the group who actually underwent complete resection Rate of objective responses Tolerability Overall survival and progression free survival time in the total study population
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression free survival time after resection, in the group who actually underwent complete resection, progression free survival rates at 6 and 12 months after start of treatment. Overall survival time after resection, in the group who actually underwent complete resection: day of death or end of study Rate of objective responses: every 6 weeks Tolerability: during the whole study Overall survival and progression free survival time in the total study population: study enrolement until the day of progression/death |
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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 | No |
E.8.1.2 | Open | No |
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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |