An open-label phase II multicenter study of vemurafenib (Zelboraf®) plus cobimetinib (Cotellic®) after radiosurgery in patients with active BRAF-V600-mutant melanoma brain metastases
- Conditions
- patients with active BRAF-V600-mutant melanoma brain metastasesMedDRA version: 20.0Level: LLTClassification code 10027481Term: Metastatic melanomaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2017-000768-13-DE
- Lead Sponsor
- Technische Universität Dresden
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 32
• 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:
o Previously untreated (Lesions in previously irradiated area should not be selected)
o Largest diameter of = 0.5 but = 4 cm as determined by contrast-enhanced MRI
o = 10 brain metastases
• ECOG performance status 0 - 2
• Life expectancy = 12 weeks
• Adequate bone marrow function as indicated by the following:
o ANC = 1500/µL
o Platelets = 100,000/µL
o 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)
• INR in normal range
• Able to swallow pills
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 24
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 8
• 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 allowed). 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 metastases are eligible)
• Patients receiving therapeutic steroids are not stable on corticosteroids 2 weeks before SRS
• Active and uncontrolled infection
• Known HIV infection, or active HBV or HCV infection
o Active HBV infection (chronic and acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening (past or resolved HBV infection, defined as negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible)
o 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 Criteria 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:
o Metal
o Claustrophobia
o Gadolinium contrast allergy
• Previous malignancies active within the last 3 years, with the exception of locally curable cancers that have been treated to complete remission 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 vemurafinib
• The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
o St. John’s wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
o 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
• 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 retinal vein thrombosis. The risk factors for RVO are listed below:
oUncontrolled glaucoma with intraocular pressures > 21 mm Hg,
oSerum cholesterol = Grade 2 (= 7.75 mmol/L),
oHypertriglyceridemia = Grade 2 (= 3.42 mmol/L),
Hyperglycemia (fasting) = Grade 2 (= 8.9 mmol/L).
• History of clinically significant cardiac dysfunction including:
o Myocardia
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To investigate the Best overall response rate (BORR) in the brain by combination of vemurafenib plus cobimetinib after radiosurgery in patients with melanoma brain metastases;Secondary Objective: • Extracranial BORR<br>• BORR calculated for the whole body tumor sites<br>• Intracranial duration of response<br>• Extracranial duration of response<br>• Progression-free survival (PFS)<br>• Overall survival (OS)<br>• Safety<br>• Radiomics features predictive of long-term local control of brain metastases<br>• Radiomics features predicting treatment-related toxicity, e.g. radionecrosis, hemorrhage, edema. ;Primary end point(s): Best overall response rate in the brain within two years, defined as the rate of patients with complete response (CR) or partial response (PR);Timepoint(s) of evaluation of this end point: within 2 years of therapy with vemurafenib and cobimetinib, every 6 weeks
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • Extracranial BORR<br>• BORR calculated for the whole body tumor sites<br>• Intracranial duration and kind of response<br>• Extracranial duration and kind of response<br>• Progression-free survival<br>• Overall survival<br>Safety:<br>• Total adverse events<br>• Serious adverse events<br>• = Grade 3 adverse events<br>• Adverse events of special interest<br>• Adverse events leading to treatment discontinuation<br>Further Variables: <br>• Radiomics features predictive of long-term local control of brain metastases<br>• Radiomics features predicting treatment-related toxicity, e.g. radionecrosis, hemorrhage, edema.;Timepoint(s) of evaluation of this end point: within 2 years of therapy with vemurafenib and cobimetinib, every 3 months