Clinical trial NCT01813214
Conditions: Melanoma
Keywords: melanoma vemurafenib cobitmetinib
Sponsor: Georgetown University
Start date: 2013-03-01; Completion date: 2016-12-01
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Vemurafenib 960 mg po BID until unacceptable toxicity or progression of disease arm 2: 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.
Interventions: intervention 1: Vemurafenib intervention 2: Cobimetinib
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents: