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
Exclusion criteria
- 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 treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1
(PD-L1) is allowed.
- 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). (anticonvulsant levetiracetam is allowed; patient should be
stable on levetiracetam for 2 weeks)
- 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. The risk factors for RVO
are listed below:
- 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
- Uncontrolled arrhythmias
