Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases

• Status: Terminated
• Trial end date: 2016-03-01
• Target enrollment: 0
• Participant gender: All

Summary

The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Melissa Burgess, MD
• Collaborator: Genentech, Inc.
• Treatments: Vemurafenib

Criteria

Inclusion Criteria:

• Signed informed consent

• Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600-mutation

• Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved laboratory

• At least one measurable intracranial target lesion for which all of the following criteria are met:

1. previously untreated or progressive according to RECIST 1.1 (equal to or greater than 20% increase in longest diameter on baseline scan) after previous local therapy (SRS and/or craniotomy)

2. immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (SRS and/or craniotomy)

3. largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced MRI

• Prior therapies for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy will be allowed but prior BRAF or MEK not allowed

• ECOG PS 0-2

• Life expectancy >12 weeks

• Age 18 years or older

• Adequate bone marrow function as indicated by the following:

1. ANC > 1500/µL

2. Platelets ≥ 100,000/µL

3. Hemoglobin > 9 g/dL

• Adequate renal function, as indicated by creatinine =/< 1.5 x the upper limit of normal (ULN)

• Adequate liver function, as indicated by bilirubin =/< 1.5 x ULN

• AST or ALT < 3 x ULN (patients with documented liver metastases: AST and/or ALT =/< 5 x ULN)

• Able to swallow pills

• Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. 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

• Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

Exclusion Criteria:

• Active infection

• Prior therapy with BRAFi and/or MEKi

• Leptomeningeal disease

• Symptomatic brain metastases requiring immediate local interventions such as craniotomy or SRS

• Increasing corticosteroid dose in 7 days prior to administration of first dose of study drug. Symptomatic patients that have stable or decreasing corticosteroid use in the past 7 days will be allowed

• Current use of therapeutic warfarin

• 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

• Inability to undergo MRI secondary to metal, claustrophobia, Gadolinium Contrast allergy

• Pregnant, lactating, or breast feeding women

• Prior radiation therapy within the last 14 days

• 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

• The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:

1. St. John's wort or hyperforin

2. Grapefruit juice

• 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

• Uncontrolled glaucoma with intra-ocular pressures > 21mmHg

• Serum cholesterol ≥ Grade 2

• Hypertriglyceridemia ≥ Grade 2

• Hyperglycemia (fasting) ≥ Grade 2

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

1. Current unstable angina

2. Current symptomatic congestive heart failure of NYHA class 2 or higher

3. History of congenital long QT syndrome or mean QTcF > 450 msec at baseline or uncorrectable electrolyte abnormalities

4. Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible)

5. Left ventricular ejection fraction (LVEF) below 50%

6. Uncontrolled Arrhythmias

7. Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months