Trial of Vemurafenib With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma - Full Text View

Sponsor:	Melanoma Research Foundation Breakthrough Consortium
Collaborator:	Genentech
Information provided by (Responsible Party):	Melanoma Research Foundation Breakthrough Consortium
ClinicalTrials.gov Identifier:	NCT01495988

Purpose

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.

Condition	Intervention	Phase
Melanoma Metastatic Melanoma	Drug: Vemurafenib Drug: Bevacizumab	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Randomized Phase II Trial of Vemurafenib (PLX4032/RG7204) With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma

Resource links provided by NLM:

MedlinePlus related topics: Cancer Melanoma

Drug Information available for: Bevacizumab Vemurafenib

U.S. FDA Resources

Further study details as provided by Melanoma Research Foundation Breakthrough Consortium:

Primary Outcome Measures:

Median progression free survival [ Time Frame: Time between randomization and disease progression (~6-11 months) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	180
Study Start Date:	June 2012
Estimated Study Completion Date:	March 2015
Estimated Primary Completion Date:	September 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.	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
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.	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

Arms

Assigned Interventions

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.

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

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.

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

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01495988

Contacts

Contact: Michael B Atkins, MD	617-632-9250	matkins@bidmc.harvard.edu
Contact: F. Stephen Hodi, MD	617-632-5053	stephen_hodi@dfci.harvard.edu

Locations

United States, Massachusetts
Beth Israel Deaconess Medical Center (BIDMC)	Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Michael B Atkins, MD 617-632-9250 matkins@bidmc.harvard.edu
Dana-Farber Cancer Institute	Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: F. Stephen Hodi, MD 617-632-5053 stephen_hodi@dfci.harvard.edu

Sponsors and Collaborators

Melanoma Research Foundation Breakthrough Consortium

Genentech

Investigators

Principal Investigator:	Michael B Atkins, MD	Beth Israel Deaconess Medical Center
Principal Investigator:	F. Stephen Hodi, MD	Dana-Farber Cancer Institute

More Information

No publications provided

Responsible Party:	Melanoma Research Foundation Breakthrough Consortium
ClinicalTrials.gov Identifier:	NCT01495988 History of Changes
Other Study ID Numbers:	ML27894
Study First Received:	December 9, 2011
Last Updated:	April 18, 2012
Health Authority:	United States: Institutional Review Board

Keywords provided by Melanoma Research Foundation Breakthrough Consortium:

Metastatic melanoma
BRAF-mutant
Stage IV melanoma
Vemurafenib
Bevacizumab

Additional relevant MeSH terms:

Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Bevacizumab

Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 23, 2012