Clinical Trial Finder

Inclusion criteria.

• - Signed informed consent.

• - Female and male patients ≥ 18 years of age.

• - Histologically confirmed metastatic melanoma (stage IV, per AJCC staging), carrying BRAF V600-mutation.

• - Performed SRS 14 ±7 days before baseline using a harmonized protocol in patients with at least one measurable intracranial target lesion for which the following criteria are met: - Previously untreated (Lesions in previously irradiated area should not be selected) - Largest diameter of ≥ 0.5 but ≤ 4 cm as determined by contrast-enhanced MRI and.

• - ≤ 10 brain metastases.

• - ECOG performance status 0 - 2.

• - Life expectancy ≥ 12 weeks.

• - Adequate bone marrow function as indicated by the following: - ANC ≥ 1500/µL, - Platelets ≥ 100,000/µL and.

• - Hemoglobin ≥ 9 g/dL.

• - Adequate renal function, as indicated by creatinine ≤ 1.5 x ULN.

• - Adequate liver function, as indicated by bilirubin < 1.5 x ULN and AST and ALT < 3 x ULN (documented liver metastases: AST and ALT < 5 x ULN) - Adequate coagulation within 28 days prior to baseline visit.

• - Patients without therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN.

• - Patients receiving therapeutic anticoagulation: stable anticoagulation regimen and stable INR.

• - Able to swallow pills.

• - Symptomatic brain metastases requiring immediate local interventions such as neurosurgery or radiosurgery.

• - Leptomeningeal disease (also synchronous with brain metastases) - Prior therapy with BRAF or MEK inhibitors within 12 weeks prior to baseline visit (prior therapies for metastatic melanoma including chemo-, cytokine-, immuno-, biological and vaccine-therapy will be al-lowed) 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 whole brain irradiation (Patients with prior local therapy of brain metas-tases are eligible) - Patients receiving therapeutic steroids are not stable on corticoster-oids 2 weeks before SRS.

• - Active and uncontrolled infection.

• - Known HIV infection or active HBV or HCV infection.

• - Active HBV infection (chronic and acute), defined as having a posi-tive hepatitis B surface antigen (HBsAg) test at screening (past or resolved HBV infection, defined as negative HBsAg test and a posi-tive total hepatitis B core antibody test at screening, are eligible) - Active HCV infection, defined as positive HCV antibody test and positive HCV RNA test at screening.

• - Intracranial radiation therapy within 14 days prior to SRS.

• - Extracranial radiation therapy within the last 14 days prior to baseline visit.

• - Treatment with strong CYP3A4/5 inhibitors (e.g. ketoconazole) and inducers (e.g. phenytoin, carbamazepine).

• - Unresolved toxicity of National Cancer Institute Common Terminology Crite-ria for Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia.

• - Conditions that will interfere significantly with the absorption of drugs (e.g. Colitis ulcerosa) - Inability to undergo MRI secondary to: - Metal, - Claustrophobia, or.

• - Gadolinium contrast allergy.

• - Previous malignancies active within the last 3 years, with the exception of locally curable cancers that have been treated to complete remis-sion or untreated stage I chronic lymphoid leukemia.

• - Unwillingness or inability to comply with study and follow-up procedures.

• - Known hypersensitivity to any of the excipients of cobimetinib and vemuraf-enib.

• - The following foods/supplements are prohibited at least 7 days prior to initia-tion of and during study treatment: - St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer) - Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor) - Patient is included in another interventional trial.

• - Use of any investigational or non-registered product within 4 weeks prior to baseline visit.

• - Woman of childbearing age with the exception they meet at least one of the following criteria: - Post-menopausal, - Sterilization, - Consistently & correct application of contraceptives (Pearl Index < 1%), - sexual abstinence, or.

• - vasectomy of the partner.

• - Pregnant or lactating women.

• - History, risk factor or retinal pathology that increases the risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology that is considered a risk factor for RVO or CSR, or a history of retinal detachment, central serous chorioretinopathy or reti-nal vein thrombosis.

• - Uncontrolled glaucoma with intraocular pressures > 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).

• - History of clinically significant cardiac dysfunction including: - Myocardial infarction, - Severe/unstable angina pectoris, - Symptomatic congestive heart failure (NYHA stage ≥ 2), - cerebrovascular accident or transient ischemic attack within the previous 6 months, - History of congenital long QT syndrome or mean QTcF > 450 msec or uncorrectable electrolyte abnormalities, - Hypertension > Grade 2 not controlled by medications.

• - Left ventricular ejection fraction (LVEF) < 50%, or.

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