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. MedDRA version: 17.1 Level: PT Classification code 10025671 Term: Malignant melanoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 1
Conditions
Interventions
Trade Name: Zelboraf
Product Name: Vemurafenib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VEMURAFENIB
CAS Number: 918504-65-1
Other descriptive name: VEMURAFENIB
Concentration unit:
Sponsors
University Hospital Tübingen
Eligibility
Sex/Gender
All
Inclusion criteria
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) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 55 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 55 ;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) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 55 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 55 ;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) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 55 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 55
Exclusion criteria
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 ;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 ;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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Percent of patients who actually become resectable and are resected ;Secondary Objective: 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.;Primary end point(s): The primary endpoint is the percentage of patients becoming operable after the combined treatment within 18 weeks. ;Timepoint(s) of evaluation of this end point: after the combined treatment within 18 weeks;Main Objective: Percent of patients who actually become resectable and are resected ;Secondary Objective: 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.;Primary end point(s): The primary endpoint is the percentage of patients becoming operable after the combined treatment within 18 weeks. ;Timepoint(s) of evaluation of this end point: after the combined treatment within 18 weeks;Main Objective: Percent of patients who actually become resectable and are resected ;Secondary Objective: 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.;Primary end point( | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 ;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;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 ;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;Secondary end poin | — |
Countries
Austria
Contacts
Public ContactDepartment of Dermatology;Department of Dermatology;Department of Dermatology ;;
University Hospital Tübingen;University Hospital Tübingen;University Hospital Tübingen
Outcome results
None listed