Status:
TERMINATED
Vemurafenib Plus Cobimetinib After Radiosurgery in Patients With BRAF-mutant Melanoma Brain Metastases
Lead Sponsor:
Technische Universität Dresden
Conditions:
Malignant Melanoma Stage IV
BRAF V600 Mutation
Eligibility:
All Genders
18+ years
Phase:
PHASE2
Brief Summary
This is a phase II, open label, non-randomised study of vemurafenib and cobimetinib after radiosurgery in adult patients with BRAFV600-mutant melanoma brain metastases. All patients will receive vemur...
Eligibility Criteria
Inclusion
- 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
Exclusion
Key Trial Info
Start Date :
July 1 2018
Trial Type :
INTERVENTIONAL
Allocation :
ACTUAL
End Date :
February 10 2023
Estimated Enrollment :
20 Patients enrolled
Trial Details
Trial ID
NCT03430947
Start Date
July 1 2018
End Date
February 10 2023
Last Update
September 14 2023
Active Locations (3)
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1
Technische Universität Dresden
Dresden, Germany, 01307
2
Ruprecht-Karls-University of Heidelberg, Faculty of Medicine
Heidelberg, Germany, 69120
3
Eberhard Karls University of Tübingen, University Medical Center
Tübingen, Germany, 72076