Trial of Vemurafenib With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma

• Overall survival [ Time Frame: Time between randomization and death due to any cause (overall survival rates also to be assessed at 12 and 18 months) ] [ Designated as safety issue: No ]
• Response rates and response durations [ Time Frame: From time of randomization to time of disease progression (restaging for tumor response to occur every 6 wks until wk 48, then every 12 wks thereafter) ] [ Designated as safety issue: No ]
• Serious adverse events associated with the addition of bevacizumab [ Time Frame: While on study, patients assessed for safety/ toxicity every 3 or 6 weeks (depending on the specific toxicity) until wk 48, then every 12 wks thereafter ] [ Designated as safety issue: Yes ]
• Effects of the addition of bevacizumab on tumor perfusion and immune function [ Time Frame: Upon completion of the protocol (3 years) ] [ Designated as safety issue: No ]
• Correlate blood markers of B-RAFV600 mutation with treatment efficacy [ Time Frame: Upon completion of the protocol (3 years) ] [ Designated as safety issue: No ]

In this study, the drugs being used are vemurafenib and bevacizumab. 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. Information from prior research studies suggests that this drug can shrink melanoma tumors in the majority of patients, delay tumor growth and prolong overall survival relative to standard chemotherapy. As a consequence, vemurafenib received FDA approval in August 2011 for the treatment of patients with B-RAFV600 mutant 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) directed against vascular endothelial growth factor (VEGF). VEGF is a potent growth factor with a well-defined role in normal and abnormal blood vessel formation. In the cancer setting, 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 tumor types including melanoma. In laboratory experiments, bevacizumab inhibits the growth of several different types of human cancer cells by blocking the effects of VEGF. 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; however, bevacizumab has not been approved for use in patients with metastatic melanoma.

The purpose of this research study is to determine the effectiveness of using vemurafenib and bevacizumab together relative to vemurafenib alone. This study will investigate whether using both study drugs lengthens the amount of time before a patient's melanoma worsens, increases the number of people whose melanoma responds to treatment and what side effects are associated with the use of both drugs together rather than separately.

• Melanoma
• Metastatic Melanoma

• Drug: Vemurafenib
  Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients until disease progression, intolerable toxicity, patient request for discontinuation, or study termination by the sponsor.
  Other Name: Zelboraf
• Drug: Bevacizumab
  Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks.
  Other Name: Avastin

• Active Comparator: Vemurafenib alone
  Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/ progression every 6 weeks until week 48, then every 12 weeks, thereafter. Patients will be followed until disease progression.
  Intervention: Drug: Vemurafenib
• Experimental: Combination Vemurafenib and Bevacizumab
  Patients will receive vemurafenib at a dose of 960 mg, orally, 2X a day. Bevacizumab will be administered at a dose of 15mg/kg, intravenously, every 3 weeks. Patients will be assessed for toxicity every 3 or 6 weeks (depending on the specific toxicity) and be restaged for tumor response/ progression every 6 weeks until week 48, then every 12 weeks, thereafter. Patients will be followed until disease progression.
  Interventions:

  • Drug: Vemurafenib
  • Drug: Bevacizumab

Inclusion Criteria:

• Metastatic or unresectable stage IIIc & clearly progressive melanoma
• Melanoma must be documented to contain a BRAFV600 mutation
• Measurable disease
• No more than 2 prior systemic treatment regimens for distant metastatic disease. The following prior therapy is permitted in either the adjuvant or metastatic setting: immunotherapy consisting of interferon, interleukin-2, GM-CSF, ipilimumab, anti-PD1 or other experimental agent; and cytotoxic chemotherapy consisting of dacarbazine, temozolomide, carboplatin +/- paclitaxel
• ECOG performance status of 0, 1, or 2

Exclusion Criteria:

• Pregnant or nursing mothers
• Treatment with a prior VEGF pathway, BRAF, or MEK inhibitor(s)
• Receipt of any other investigational agents during the period on study or the four weeks prior to entry
• Clinical evidence of active brain metastasis
• Concurrent uncontrolled malignancies that require therapy or other intervention
• Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study
• Core biopsy, skin cancer resection, or other minor surgical procedure within 7 days prior to Day 1 of the protocol
• Serious intercurrent illness
• HIV-positive patients receiving combination anti-retroviral therapy