Clinical Trials /

Vemurafenib Plus Cobimetinib After Radiosurgery in Patients With BRAF-mutant Melanoma Brain Metastases

NCT03430947

Description:

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 vemurafenib 960 mg twice a day on days 1 - 28 combined with cobimetinib 60 mg once a day on days 1 - 21 of each 28-day treatment cycle until disease progression, drug toxicity or death. The primary objective of this study is to determine the best overall response rate (BORR) in the brain. The extracranial BORR, intra- and extracranial duration of response, progression-free survival and overall survival, adverse events, quality of life and radiomics features predicting long-term local control of brain metastases and treatment-related toxicity will also be examined.

Related Conditions:
  • Melanoma
  • Metastatic Malignant Neoplasm in the Brain
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vemurafenib Plus Cobimetinib After Radiosurgery in Patients With BRAF-mutant Melanoma Brain Metastases
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: TUD-CoBRIM-67
  • SECONDARY ID: 2017-000768-13
  • NCT ID: NCT03430947

Conditions

  • Malignant Melanoma Stage IV
  • BRAF V600 Mutation
  • Brain Metastases

Interventions

DrugSynonymsArms
VemurafenibTreatment
CobimetinibTreatment

Purpose

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 vemurafenib 960 mg twice a day on days 1 - 28 combined with cobimetinib 60 mg once a day on days 1 - 21 of each 28-day treatment cycle until disease progression, drug toxicity or death. The primary objective of this study is to determine the best overall response rate (BORR) in the brain. The extracranial BORR, intra- and extracranial duration of response, progression-free survival and overall survival, adverse events, quality of life and radiomics features predicting long-term local control of brain metastases and treatment-related toxicity will also be examined.

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalall patients will be treated with Vemurafenib + Cobimetinib
  • Vemurafenib
  • Cobimetinib

Eligibility 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:

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response rate in the brain
Time Frame:2 years
Safety Issue:
Description:rate of patients with complete response or partial response (intracranial)

Secondary Outcome Measures

Measure:Extracranial best overall response rate
Time Frame:2 years
Safety Issue:
Description:rate of patients with complete response or partial response (extracranial)
Measure:Best overall response rate calculated for the whole body tumor sites
Time Frame:2 years
Safety Issue:
Description:rate of patients with complete response or partial response
Measure:Intracranial duration of response
Time Frame:2 years
Safety Issue:
Description:time from best overall response in the brain to first documentation of intracranial progression
Measure:Extracranial duration of response
Time Frame:2 years
Safety Issue:
Description:time from best extracranial overall response to first documentation of extracranial progression
Measure:Progression-free survival
Time Frame:2 years
Safety Issue:
Description:time from first dose of study treatment until progression
Measure:Overall survival
Time Frame:2 years
Safety Issue:
Description:time from first dose of study treatment until death due to any cause
Measure:Incidence of adverse events
Time Frame:2 years
Safety Issue:
Description:Adverse events by type, frequency and severity using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; number of patients who withdraw from the study due to intolerable adverse events.
Measure:Radiomics for long-term control of brain metastases
Time Frame:every 6 weeks up to 2 years
Safety Issue:
Description:Radiomics features predictive of long-term local control of brain metastases using Magnetic Resonance Imaging
Measure:Radiomics for intracranial Treatment-related toxicity
Time Frame:every 6 weeks up to 2 years
Safety Issue:
Description:Radiomics features predicting treatment-related toxicity (e.g. radionecrosis, hemorrhage, edema) using Magnetic Resonance Imaging

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Technische Universität Dresden

Trial Keywords

  • Stereotactic radiosurgery
  • BRAF inhibitor
  • MEK inhibitor
  • Vemurafenib
  • Cobimetinib

Last Updated

April 9, 2021