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:

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 within the last 14 days 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 cm 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, AST or ALT ≤ 3 x ULN
             (documented liver metastases: AST and/or ALT ≤ 5 x ULN)

          -  Adequate coagulation within 28 days prior to baseline visit

               -  Patients not receiving 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 (prior therapies for metastatic melanoma
             including chemo-, cytokine-, immuno-, biological and vaccine-therapy will be allowed)

          -  Prior whole brain irradiation (Patients with prior local therapy of brain metastases
             are eligible)

          -  Requirement of more than 8 mg dexamethasone daily; patient should be stable on
             steroids for 2 weeks

          -  Active and uncontrolled infection including HBV, HCV und HIV

               -  positive HIV test at screening

               -  Active hepatitis B virus (HBV) infection (chronic and acute), defined as having a
                  positive hepatitis B surface antigen (HBsAg) test at screening.

               -  Active hepatitis C virus (HCV) infection, defined as having a positive HCV
                  antibody test and positive HCV RNA test at screening

          -  Prior intra- or extracranial radiation therapy within the last 14 days prior to SRS

          -  Treatment with strong CYP3A4/5 inhibitors (e.g. ketoconazole) and inducers (e.g.
             phenytoin, carbamazepine). The anticonvulsant levetiracetam is allowed but patient
             should have been 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:

               -  Metal

               -  Claustrophobia or

               -  Gadolinium contrast allergy

          -  Concomitant malignancies or previous malignancies within the last 5 years, with the
             exception of adequately treated basal or squamous cell carcinoma of the skin or
             carcinoma in situ of the cervix.

          -  Unwillingness or inability to comply with study and follow-up procedures

          -  Known hypersensitivity to any of the excipients of cobimetinib and vemurafenib

          -  The following foods/supplements are prohibited at least 7 days prior to initiation 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 trial (non-interventional studies are allowed)

          -  Use of any investigational or non-registered product within the 30 days before patient
             registration

          -  Woman of childbearing age with the exception they meet at least one of the following
             criteria:

               -  Post-menopausal (no menses for 12 months w.o. an alternative medical cause or FSH
                  greater than 40 U/ml for 6 months)

               -  Sterilization (hysterectomy, bilateral salpingectomy, bilateral tubal occlusion
                  or bilateral oophorectomy)

               -  Consistently and correct application of contraceptives with a failure less than 1
                  % per year (defined as highly effective birth control method)

          -  Pregnant or lactating women

          -  Positive serum pregnancy test within 7 days prior to baseline visit. Women of
             non-childbearing potential may be included without serum pregnancy test if they are
             either surgically sterile or have been postmenopausal for ≥ 1 year.

          -  History of or evidence of retinal pathology on ophthalmologic examination that is
             considered a risk factor for

               -  Neurosensory retinal detachment,

               -  Retinal Vein Occlusion (RVO), or

               -  Neovascular macular degeneration

          -  Patients should be excluded if they have the following current conditions:

               -  Uncontrolled glaucoma with intra-ocular pressures > 21 mmHg,

               -  Serum cholesterol ≥ Grade 2,

               -  Hypertriglyceridemia ≥ Grade 2, or

               -  Hyperglycemia (fasting) ≥ Grade 2

          -  History of clinically significant cardiac dysfunction, including the following:

               -  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,

               -  Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension
                  controlled with anti Hypertensives to ≤ Grade 1 are eligible),

               -  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:Best overall response rate in the brain defined as the rate of patients with complete response or partial response

Secondary Outcome Measures

Measure:Extracranial best overall response rate
Time Frame:2 years
Safety Issue:
Description:
Measure:Best overall response rate calculated for the whole body tumor sites
Time Frame:2 years
Safety Issue:
Description:
Measure:Intracranial duration of response
Time Frame:2 years
Safety Issue:
Description:
Measure:Extracranial duration of response
Time Frame:2 years
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:2 years
Safety Issue:
Description:
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:Recruiting
Lead Sponsor:Technische Universität Dresden

Trial Keywords

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

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