patients with active BRAF-V600-mutant melanoma brain metastases MedDRA version: 20.0 Level: LLT Classification code 10027481 Term: Metastatic melanoma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Zelboraf
Product Name: Zelboraf
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Vemurafenib
CAS Number: 918504-65-1
Other descriptive name: VEMURAFENIB
Concentration unit: mg
Sponsors
Technische Universität Dresden
Eligibility
Sex/Gender
All
Inclusion criteria
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: 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 =65 years) yes F.1.3.1 Number of subjects for this age range 8
Exclusion criteria
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 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: o Uncontrolled glaucoma with intraocular pressures > 21 mm Hg, o Serum cholesterol = Grade 2 (= 7.75 mmol/L), o Hypertriglyceridemia = Grade 2 (= 3.42 mmol/L), Hyperglycemia (fasting) = Grade 2 (= 8.9 mmol/L). • History of clinically significant cardiac dysfunction including: o Myocardia
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 • BORR calculated for the whole body tumor sites • Intracranial duration of response • Extracranial duration of response • Progression-free survival (PFS) • Overall survival (OS) • Safety • Radiomics features predictive of long-term local control of brain metastases • 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
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Extracranial BORR • BORR calculated for the whole body tumor sites • Intracranial duration and kind of response • Extracranial duration and kind of response • Progression-free survival • Overall survival Safety: • Total adverse events • Serious adverse events • = Grade 3 adverse events • Adverse events of special interest • Adverse events leading to treatment discontinuation Further Variables: • Radiomics features predictive of long-term local control of brain metastases • 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 | — |
Countries
Germany
Contacts
Public ContactKKS Dresden / Julia Kalinka
Technische Universität Dresden
Outcome results
None listed