Patients with brain metastasis (BM) from BRAFV600-mutated cutaneous melanoma. Patients will be enrolled into three cohorts: A. Neurologically asymptomatic patients who have not received prior local treatment (cohort A)
Conditions
Interventions
Trade Name: Zelboraf
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: vemurafenib
CAS Number: 918504-65-1
Current Sponsor co
Sponsors
Centre Eugène Marquis
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Men and women = 18 years of age. 2. Histologically confirmed metastatic cutaneous melanoma, mucous melanoma, or melanoma of unknown primary origin (stage IV). 3. Documented BRAFV600 mutation determined in a hospital center specializing in the molecular genetics of cancer that is certified by the French national cancer institute (INCa). 4. Presence of BM for which surgical resection is not a reasonable treatment option but that may be amenable to treatment with targeted therapy, to be decided in the onco-dermatology and/or neuro-oncology multidisciplinary team meeting (MDTM). 5. At least one measurable BM in at least one dimension between 5 and 40 mm on magnetic resonance imaging (MRI) with gadolinium (modified RECIST 1.1) 6. Patients having previously received a maximum of two systemic therapies during the metastatic phase, except BRAF, MEK or ERK inhibitors or tyrosine kinase pan-inhibitors (TKIs); prior ipilimumab therapy is allowed if patients have documented cerebral progression 4 weeks after the last injection of treatment and if MRI confirms progression at least 4 weeks later. A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed. 7. Patients who have received prior whole brain radiotherapy or radiosurgery and/or surgery for BM. In this case, they can be enrolled only after at least 4 weeks have elapsed since this treatment has ended, and MRI at inclusion must demonstrate a significant progression of at least one lesion according to RECIST 1.1 criteria. 8. Patients with symptomatic or asymptomatic BM. 9. Eastern Cooperative Oncology Group (ECOG) performance status = 2. 10. Patients must have recovered from all the side effects (grade = 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events, NCI-CTCAE, version 4.03) of their most recent systemic or local treatment (except alopecia). 11. Signed and dated informed consent before carrying out any procedures that are specific to the trial and are not procedures (examinations) conducted as part of normal patient care. 12. Patients willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other trial procedures. 13. Negative serum pregnancy test within 10 days of the first dose of the study treatment for women of childbearing age. Women of non-childbearing potential may be included if they are surgically sterile or postmenopausal for = 1 year. 14. Fertile men and women must use an effective method of contraception during treatment and for at least 3 months after the last administration of the study treatment. Effective methods of contraception are defined as those that have a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as injectable implants combined with oral contraception or intra-uterine devices, or as total abstinence in cases where the lifestyle of the patient ensures compliance. 15. Adequate hematologic, renal and hepatic function within 14 days of the administration of treatment: Hematologic Leucocytes > 2.0 x 109/L
Exclusion criteria
Exclusion criteria: 1. Uveal melanoma. Patients with mucous melanoma or melanoma of unknown primary origin are eligible if BRAFV600 mutation is confirmed. 2. Symptomatic or diffuse leptomeningeal involvement. 3. Symptoms of uncontrolled intracranial pressure. Increasing corticosteroid dose during the 7 days prior to the first dose of the study treatment is an exclusion criterion. Patients receiving corticosteroids and patients presenting intermittent seizures may be enrolled if the dose of corticosteroids and anti-epileptic treatments has been stable for at least 2 weeks before inclusion. 4. Indication for urgent neurosurgery or radiotherapy. 5. Prior malignancy active within the previous 3 years except for locally curable cancers that have been treated to complete remission or untreated stage I chronic lymphoid leukemia. 6. Known human immunodeficiency virus (HIV) infection. 7. Prior treatment with BRAF, MEK, or ERK inhibitors or pan-TKIs. 8. Concurrent administration of any anticancer therapies other than those administered in this study. 9. Treatment with any cytotoxic and/or investigational drug or targeted therapy within 4 weeks of the first dose of the study treatment, or ipilimumab, anti-PD-1 or anti-PD-L1 immunotherapy within 8 weeks of the study treatment and/or radiation therapy within 2 weeks of the study treatment. 10. Pregnant or breastfeeding women. 11. Refractory nausea and vomiting, intestinal malabsorption, or significant bowel resection that would preclude adequate absorption or cause an inability to swallow tablets. 12. Ulcerative colitis, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticula or other gastrointestinal condition increasing the risk of perforation. 13. Any of the following within the 6 months prior to the first dose of study treatment: - myocardial infarction, - severe/unstable angina, - symptomatic congestive heart failure (New York Heart Association grade =2), - cerebrovascular accident or transient ischemic attack, - pulmonary embolism, - grade > 2 hypertension not controlled by medications. 14. History or presence of clinically significant ventricular or atrial arrhythmia = grade 2 (NCI-CTCAE Version 4.03). 15. Corrected QT (cQT) interval = 450 ms and left ventricular ejection fraction (LVEF) below the lower limit of normal (LLN) or 21 mm Hg, - Serum cholesterol = Grade 2 (= 7.75 mmol/L), - Hypertriglyceridemia = Grade 2 (= 3.42 mmol/L), - Hyperglycemia (fasting) = Grade 2 (= 8.9 mmol/L). 17. Serious or uncontrolled medical disorders that, in the opinion of the investigator,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Evaluate the efficacy of cobimetinib + vemurafenib combination treatment in BRAFV600-mutated melanoma patients with asymptomatic, previously untreated Brain Metastasis (cohort A). ; Secondary Objective: Evaluate the efficacy of cobimetinib + vemurafenib combination treatment in BRAFV600-mutated melanoma patients with asymptomatic BM that has received prior local treatment (cohort B). Evaluate the efficacy of cobimetinib + vemurafenib combination treatment in BRAFV600-mutated melanoma patients with symptomatic BM (cohort C). Evaluate the safety of the cobimetinib + vemurafenib combination overall for the three cohorts (A, B, and C). Pharmacokinetic (PK) study: to estimate penetration of vemurafenib and cobimetinib across the blood-brain barrier. Kinetic study of BRAF mutation rate as predictive biomarker of the response. Pharmacogenetic study: identification of genetic variants predictive of clinical response. ;Primary end point(s): Complete or partial intracranial response rate in cohort A based on the evaluation of each patient's best tumor response by the centralized review committee according to modified RECIST 1.1 criteria.;Timepoint(s) of evaluation of this end point: Day 1 of C2, Day1 of C3 then every 2 cycles | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1- Complete or partial intracranial response rates in cohorts B and C based on the evaluation of each patient's best tumor response by the centralized review committee according to modified RECIST 1.1 criteria. 2- Intracranial duration of response (DR) and PFS of cohorts A, B and C. 3- The overall response rate, overall DR and overall PFS of cohorts A, B and C. 4- Overall survival (OS) in cohorts A, B and C. 5- The frequency of adverse events (AEs) by organ system and seriousness. ; Timepoint(s) of evaluation of this end point: 1- Day 1 of C2, Day1 of C3 then every 2 cycles 2- Day 1 of C2, Day1 of C3 then every 2 cycles 3- Day 1 of C2, Day1 of C3 then every 2 cycles 4- At every planned visit during study treatment. Every 8 weeks for non-progressive patients. Every 3 months for progressive patients. 5- At every planned visit, from treatment initiation until 30 days after treatment stop. | — |
Countries
France
Contacts
Public ContactMartine Gestin
Centre Eugène Marquis
Outcome results
None listed