Melanoma Clinical Trial
Official title:
Randomized Phase II Trial of Vemurafenib (PLX4032/RG7204)/Cobimetinib (GDC-0973) With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma
This phase 2 clinical trial randomizes patients with BRAF mutant melanoma to either (1) standard of care (SOC) - BRAF inhibitor vemurafenib in combination with MEK inhibitor cobimetinib; or, (2) SOC plus bevacizumab, an anti-VEGF antibody that suppresses new blood vessel formation and can stimulate the immune system. Previous clinical studies in melanoma have shown that bevacizumab may improve clinical benefit (progression free survival) if combined with ipilimumab or abraxane. Preclinical studies suggest that VEGF increase plays a role in resistance to BRAF inhibitors. This randomized study will ask whether the addition of bevacizumab to targeted therapy SOC in BRAF mutant melanoma can improve response rates and clinical benefit. Patients may have received no therapy for advanced disease or up to 2 prior therapies, excluding BRAF and MEK inhibitors.
In this study, the drugs being used are vemurafenib, cobimetinib, and bevacizumab.
Vemurafenib has been approved by the FDA for treatment of patients with advanced melanoma
that harbors a BRAF mutation. However, vemurafenib in combination with cobimetinib has not
been approved by the FDA for the treatment of cancer. Bevacizumab has been approved by the
FDA for use in combination with first line chemotherapies for treatment of patients with
colorectal, breast and lung cancer. Bevacizumab has not been approved for use in patients
with metastatic melanoma.
Vemurafenib and cobimetinib attack different proteins that cause cancer cells to grow.
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. 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.
Vemurafenib works by preventing these altered B-RAF proteins from working, and thereby may
block the growth and spread of cancer cells in patients with melanoma. Cobimetinib works by
blocking a protein called MEK. MEK has been known to promote growth in cancer that carries
either a mutation in the BRAF or KRAS genes. The vemurafenib/cobimetinib combination has been
used in prior clinical studies. Information from those other research studies suggests that
these drugs can shrink melanoma tumors in the majority of patients and slow tumor growth as
compared to standard chemotherapy. Another drug to block the BRAF and MEK proteins was
recently approved by the FDA in the treatment of patients with B-RAFV600 mutant melanoma. The
researchers want to see if using vemurafenib and cobimetinib together will work in a similar
way to treat malignant melanoma.
Bevacizumab is a humanized monoclonal antibody (a type of protein that is normally made by
the immune system to help defend the body from infection and cancer) produced by using
recombinant DNA technology. Bevacizumab is an antibody directed against vascular endothelial
growth factor or VEGF. VEGF is a potent, specific growth factor with a well-defined role in
normal and abnormal blood vessel formation. It is present in a wide variety of normal
tissues, but is produced in excess by most solid cancers (tumors). In the setting of cancer,
VEGF promotes the growth of blood vessels that bring nutrients to tumor cells. Its expression
by the tumor has been associated with worse outcome in patients with a number of tumors types
including melanoma. In laboratory experiments, bevacizumab inhibits the growth of several
different types of human cancer cells by blocking the effects of VEGF.
The purpose of this research study is to determine the effectiveness of using the study drugs
vemurafenib, cobimetinib, and bevacizumab together relative to vemurafenib and cobimetinib
alone. This study will investigate whether using both study drugs lengthens the amount of
time before participants' melanoma worsens, increases the number of people whose melanoma
responds to treatment and what the side effects are of using the drugs together rather than
separately.
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