The Effects of Vemurafenib + Cobimetinib on Immunity in Patients With Melanoma

NCT ID: NCT01813214

Last Updated: 2019-02-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-31
• Study Completion Date: 2016-12-31

Brief Summary

This study is for patients with malignant melanoma which has spread beyond the local area and cannot be surgically removed, and who have melanoma tumors that are accessible for repeat biopsies. This research study is a way of gaining new knowledge about treatment options for metastatic melanoma. This research study is evaluating the effects of the drugs vemurafenib and cobimetinib on the immune system.

Vemurafenib has been approved by the FDA for treatment of patients with advanced melanoma that harbors a B-RAF mutation. Vemurafenib works by blocking a protein called B-RAF. Researchers have found that a large number of melanomas have mutations (changes) in the BRAF gene. Genes are specific parts of your DNA that contain information on hereditary characteristics such as hair color and eye color. The BRAF gene codes for a protein called B-RAF, which is involved in sending signals in cells that can lead to cell growth. Research has determined that mutations in the BRAF gene at the V600 position cause a change in the B-RAF protein that can drive the growth and spread of melanoma cells.

Cobimetinib (GDC-0973, XL518) is a potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS/RAF pathway.

The purpose of this research study is to determine how vemurafenib and cobitmetinib may alter the immune system's reaction to melanoma, in order to learn how best to combine immune therapies with vemurafenib in the future.

Detailed Description

This is multicenter study of vemurafenib and cobimetinib in patients with biopsy-accessible advanced metastatic melanoma.

The trial will consist of a screening period, a treatment phase, and one post-study follow-up visit occurring about 30 days after the last dose of drug. Day 1 of the study will be defined as the first day a subject receives vemurafenib and/or cobitmetinib. During the treatment phase, all study assessments will be conducted on Day 1 (± 3 days) of each cycle, with the exception of computed tomography (CT) and/or magnetic resonance imaging (MRI), which should occur every 6 weeks (+/- 7 days).

All subjects will have biopsies performed of safely accessible tumors before starting treatment and at 1, 2, and 4 weeks later (days 8, 15, 29). In addition, any patient with accessible tumor at the time of progression will have a tumor biopsy performed at that time.

Mixed-effects models will be used to study the change in CD8 T cell counts per mm^2 of tissue, changes in expression of immunoinhibitory proteins (B7-H1/PD-L1, IDO, arginase), and changes in endothelial homing receptor ligands and tumor associated chemokines at pre-treatment at pre-treatment and at weeks 1, 2, and 4 after therapy. Subjects will be treated as random effects to account for individual variability. Potential covariates are age, gender, and ECOG performance status.

60 ml of blood for lymphocytes will be drawn on days 1, 8, 15, and 29.

Conditions

Melanoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Vemurafenib Monotherapy

Vemurafenib 960 mg po BID until unacceptable toxicity or progression of disease

Group Type: EXPERIMENTAL

Vemurafenib

Intervention Type: DRUG

Vemurafenib + Cobimetinib Combination Therapy

Vemurafenib 960 mg po BID until unacceptable toxicity or progression of disease

Cobimetinib will be given 60mg QD for 21 days on, then 7 days off, in a 28-day treatment cycle.

Group Type: EXPERIMENTAL

Vemurafenib

Intervention Type: DRUG

Cobimetinib

Intervention Type: DRUG

Interventions

Vemurafenib

Intervention Type: DRUG

Cobimetinib

Intervention Type: DRUG

Other Intervention Names

Zelboraf; R05185426 (PLX4032); RO5514041

Eligibility Criteria

Inclusion Criteria

• Patients must have discontinued cytotoxic therapy agents at least 4 weeks and cytokine and immunoregulatory antibody based immunotherapy at least 6 weeks prior to entering the study and have recovered from adverse events due to those agents.
• Patients must be completed radiation therapy at least 4 week previously
• Patients must have an ECOG performance status of 0, 1 or 2.
• Patients must have the following baseline laboratory values:

1. White Blood Count > 3,000/mm3

2. Absolute Granulocyte Count > 1,500/mm3

3. Platelet Count > 100,000/mm3

4. Hemoglobin > 9 g/dL

5. Serum creatinine < 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) > 40ml/min (CrCl= Wt (kg) x (140-age)*/72 x Cr. level, *female x 0.85)

6. AST and ALT < 3 x ULN (< 5 x ULN for patients with documented liver metastases)

7. Alkaline Phosphatase ≤ 2 x ULN (≤ 5x ULN for patients with known liver involvement and ≤ 7x ULN for patients with known bone involvement)

8. INR < 1.5 and aPTT within 1.1 x ULN. Patients on warfarin therapy are not eligible due to the requirement for multiple biopsies.

9. Total Bilirubin < 1.5 x ULN

• Patients must not receive any other investigational agents during the period on study or the four weeks prior to entry.
• Patients will be evaluated with a head CT or MRI within 4 weeks of enrollment. Patients must have no clinical evidence of active brain metastasis. Patients with a history of brain metastases must have had them treated greater than 4 weeks previously with the CNS lesions confirmed to be stable or regressing on imaging since the time of the last CNS treatment. Patients must have no residual neurologic symptoms while taking either no steroids or a stable dose of steroids for the 2 weeks prior to enrollment. Patients are allowed to be on a stable dose of anti-seizure meds.
• Patients who have had brain metastases will be eligible only if all of the following are true:

• the total number of brain metastases ever is ≤ 3
• all are less than or equal to 2 cm
• they have been resected surgically or have been treated with gamma-knife or stereotactic radiosurgery
• the patient has not taken any steroids or has not increased the dose of steroids ≤ 14 days prior to registration.
• Patients must not have another cancer diagnosis with a few exceptions- the following diagnoses will be allowed:

1. squamous cell cancer of the skin without known metastasis. Note, patients with suspected cuSCCs should have them excised prior to study registration.

2. basal cell cancer of the skin without known metastasis

3. carcinoma in situ of the breast (DCIS or LCIS)

4. carcinoma in situ of the cervix

5. any cancer without distant metastasis that has been treated successfully, without evidence of recurrence or metastasis for over 3 years

• Patients must not have a serious intercurrent illness including, but not limited to:

• Ongoing or active infection requiring parental antibiotics on Day 1
• History of congenital long QT syndrome or mean corrected QTc interval > 450 msec at baseline
• Clinically significant cardiovascular disease:

Myocardial infarction within 6 months Unstable angina New York Heart Association grade II or greater congestive heart failure (see Appendix E) Serious cardiac arrhythmia requiring medication Uncontrolled hypertension ≥ Grade 2 (patients with a history of hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible) Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or below 50%

• Serious, non-healing wound, active ulcer, or untreated bone fracture
• Psychiatric illness/social situations that would limit compliance with study requirements.

• Participants must not be known to be HIV positive (testing is not required)
• Participants must be Hepatitis C negative < 6 months prior to screening
• Participants must not have a history of malabsorption or other condition that would interfere with absorption of vemurafenib or cobimetinib
• Patients must be able to comply with study and follow-up procedures.
• Patients must not have following foods/supplements at least 7 days prior to initiation of and during study treatment: St. John's wort or hyperforin (potent cytochrome P450 CYP34A enzyme inducer) or Grapefruit juice (potent cytochrome P450 CYP34A enzyme inhibitor).
• Patients must not have significant ocular issues including history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, RVO, or neovascular macular degeneration.

The risk factors for RVO are listed below. Patients should be excluded if they have the following conditions:

1. Uncontrolled glaucoma with intra-ocular pressures > 21mmHg

2. Serum cholesterol ≥ Grade 2

3. Hypertriglyceridemia ≥ Grade 2

4. Hyperglycemia (fasting) ≥ Grade 2

• Patients must have the ability to understand and the willingness to sign a written informed consent document.

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

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

Melanoma Research Alliance

OTHER

Sponsor Role: collaborator

Georgetown University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael B Atkins, MD

Role: PRINCIPAL_INVESTIGATOR

Georgetown Lombardi Comprehensive Cancer Center

Locations

Georgetown Lombardi Comprehsnive Cancer Center

Washington D.C., District of Columbia, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

University of Virginia Health System

Charlottesville, Virginia, United States

Countries

United States

Other Identifiers

MLN28305

Identifier Type: -

Identifier Source: org_study_id