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

NCT ID: NCT02230306

Last Updated: 2017-10-12

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-28
• Study Completion Date: 2016-03-31

Brief 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.

Conditions

Active Melanoma Brain Metastases

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cobimetinib in Combination with Vemurafenib

Vemurafenib (960 mg twice a day) will be taken on Days 1 - 28 of each 28-day treatment cycle. The first dose of vemurafenib should be taken in the morning, and the second dose should be taken in the evening. Vemurafenib can be taken with or without a meal and should be taken with a glass of water.

Cobimetinib (60 mg once a day) will be taken on Days 1 - 21 of each 28-day treatment cycle. The cobimetinib tablet should be taken at approximately the same time each day in the morning with the vemurafenib dose, but no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal and should never be chewed, cut, or crushed and should be taken with a glass of water.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

60mg once a day; will be taken on days 1-21 of each 28 day treatment cycle; will be taken in combination with Vemurafenib;

Vemurafenib

Intervention Type: DRUG

960mg twice a day; 28 day treatment cycle; will be taken in combination with Cobimetinib;

Interventions

Cobimetinib

60mg once a day; will be taken on days 1-21 of each 28 day treatment cycle; will be taken in combination with Vemurafenib;

Intervention Type: DRUG

Vemurafenib

960mg twice a day; 28 day treatment cycle; will be taken in combination with Cobimetinib;

Intervention Type: DRUG

Other Intervention Names

Zelboraf

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

Melissa Burgess, MD

OTHER

Sponsor Role: lead

Responsible Party

Melissa Burgess, MD

Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Melissa Burgess, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Richard Carvajal, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Anna Pavlick, MD

Role: PRINCIPAL_INVESTIGATOR

NYU Clinical Cancer Center

Mohammed Milhem, MD

Role: PRINCIPAL_INVESTIGATOR

Univ of Iowa

Ravi Amaravadi, MD

Role: PRINCIPAL_INVESTIGATOR

Univ of Pennsylvania

Harriet Kluger, MD

Role: PRINCIPAL_INVESTIGATOR

Yale New Haven Hospital

Locations

Harriet Kluger

New Haven, Connecticut, United States

Mohammed Milhem, MD

Iowa City, Iowa, United States

Anna Pavlick, MD

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Ravi Amaravadi, MD

Philadelphia, Pennsylvania, United States

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Countries

United States

Other Identifiers

ML29155

Identifier Type: OTHER

Identifier Source: secondary_id

13-123

Identifier Type: -

Identifier Source: org_study_id