eoadjuvant treatment with the combination of vemurafenib and cobimetinib (GDC-0973) in limited metastasis of malignant melanoma (AJCC stage IIIC/IV) and integrated biomarker study: a single armed phase II EADO trial
- Conditions
- 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: 17.1Level: PTClassification code 10025671Term: Malignant melanoma stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 17.1Level: PTClassification code 10025670Term: Malignant melanoma stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]
- Registration Number
- EUCTR2013-001546-34-AT
- Lead Sponsor
- niversity Hospital Tübingen
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 110
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
;
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
;
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
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
;
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
;
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method