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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Melanoma Research Foundation Breakthrough Consortium
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Melanoma Research Foundation Breakthrough Consortium
ClinicalTrials.gov Identifier:
NCT01495988
First received: December 9, 2011
Last updated: October 13, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Melanoma
Metastatic Melanoma
Drug: Vemurafenib
Drug: Bevacizumab
Drug: Cobimetinib
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)/Cobimetinib (GDC-0973) With or Without Bevacizumab in Patients With Stage IV BRAFV600 Mutant Melanoma

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: Time between phase Ib enrollment and phase II enrollment ] [ Designated as safety issue: No ]
    To establish the maximum tolerated dose (MTD) of bevacizumab in combination with vemurafenib and cobimetinib.

  • Median progression-free survival [ Time Frame: Time between randomization and disease progression (~10-15 months) ] [ Designated as safety issue: No ]
    To compare median progression-free survival (PFS) of patients with stage IV, BRAFV600E or BRAFV600K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.


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 ]
    Compare overall survival (OS) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.

  • Response rates [ Time Frame: From time of randomization to time of disease progression (restaging for tumor response to occur every 8 wks until wk 48, then every 12 wks thereafter) ] [ Designated as safety issue: No ]
    Compare response rate (RR) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.

  • Toxicity and safety profile [ Time Frame: While on study, patients will be assessed for toxicity every 4 weeks. ] [ Designated as safety issue: Yes ]
    Describe the toxicity and safety profile of treatment with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab in patients with stage IV, BRAFV600E/K melanoma.

  • Effects of the addition of bevacizumab on tumor angiogenesis, resistance mechanisms and immune function [ Time Frame: Upon completion of the protocol (3 years) ] [ Designated as safety issue: No ]
    Perform a variety of correlative studies aimed at understanding the effects of vemurafenib/cobimetinib, and bevacizumab administration relative to vemurafenib/cobimetinib on tumor angiogenesis, resistance mechanisms and immune function.

  • Correlate blood markers of B-RAFV600 mutation with treatment efficacy [ Time Frame: Upon completion of the protocol (3 years) ] [ Designated as safety issue: No ]
    Assess the effectiveness of blood reverse transcription polymerase chain reaction (RT-PCR) assay for BRAFV600 as a surrogate biomarker for tumor response and resistance in patients receiving vemurafenib/cobimetinib +/- bevacizumab.


Estimated Enrollment: 162
Study Start Date: August 2013
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Vemurafenib/Cobimetinib
Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients. Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 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: Cobimetinib
Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle.
Other Name: GDC-0973
Experimental: Vemurafenib/Cobimetinib + Bevacizumab
Vemurafenib will be given at a dose of 960 mg, orally, 2X a day to all patients. Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle. Bevacizumab will be administered at the MTD (determined by phase Ib safety lead-in), intravenously, every 2 weeks. Patients will be assessed for toxicity every 4 weeks and be restaged for tumor response/progression every 8 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
Drug: Cobimetinib
Cobimetinib will be given at a dose of 60mg, orally, 1X a day to all patients for 21 days, then 7 days off, in a 28 day treatment cycle.
Other Name: GDC-0973

Detailed Description:

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.

  Eligibility

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

Inclusion Criteria:

  1. Patients must have histological or cytological confirmed melanoma that is metastatic or unresectable stage IIIc and clearly progressive.
  2. Patients must have melanoma that is documented to contain a BRAFV600E or BRAFV600K mutation by a FDA-approved test.
  3. Age >= 18 years.
  4. Women must not be pregnant due to the fact that the effects of vemurafenib, cobimetinib, and/or bevacizumab on the developing human fetus are unknown. For this reason and because antiangiogenic agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence; defined in Appendix G) prior to study entry and for the duration of study participation. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately.
  5. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  6. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with bevacizumab, cobimetinib, and vemurafenib, female participants who are breastfeeding must agree to discontinue nursing prior to Day 1 of the study.
  7. Patients must have measurable disease as defined in Section 10.1 (cutaneous lesions measuring at least 1 cm will be considered measurable). Baseline CT or MRI scans of measurable disease sites must be performed within 4 weeks of study entry.
  8. Patients must have discontinued immunotherapy or other systemic therapy including investigational agents at least 4 weeks prior to entering the study and have recovered from adverse events due to those agents. Patients must agree to not receive any other investigational agents during study participation.
  9. Patients must have an ECOG performance status of 0, 1, or 2.
  10. Patients must have the following baseline laboratory values:

    1. White Blood Count > 3,000/mm3
    2. Absolute Neutrophil Count > 1,500/mm3
    3. Platelet Count > 100,000/mm3
    4. 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)
    5. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN for patients with documented liver metastases)
    6. Alkaline Phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement and =< 7 x ULN for patients with known bone involvement)
    7. International Normalized Ratio (INR) < 1.5 and aPTT within 1.1 x ULN
    8. Total Bilirubin < 1.5 x ULN
    9. UPC ratio < 1.0 at screening or 24 hours urine protein < 1 gm (Appendix D)
  11. Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Patients may not have received more than 2 prior systemic treatment regimens for distant metastatic disease. The following prior therapy is permitted in either the adjuvant or metastatic disease setting, provided treatment is discontinued at least 4 weeks prior to initiating study treatment:

    1. Immunotherapy, such as interferon, interleukin-2, GM-CSF, ipilimumab, anti-PD1 or other experimental agent.
    2. Cytotoxic chemotherapy, such as dacarbazine, temozolomide, carboplatin +/-paclitaxel.
  2. Patients may not have had radiation therapy within the last 4 weeks prior to initiation of study treatment.
  3. Patients who have had prior VEGF pathway inhibitor, BRAF or MEK inhibitor therapy are ineligible.
  4. Patients must have no clinical evidence of active brain metastasis. Patients with a history of brain metastases must meet all of the following criteria:

    1. Have completed treatment greater than 4 weeks prior to enrollment.
    2. Have CNS lesions that are confirmed to be stable or regressing on imaging since the time of the last CNS treatment including the pre-treatment CT or MRI scan for this trial.
    3. Patients must have no residual neurologic symptoms while taking no steroids, a stable or decreasing dose of steroids, or a stable dose of anti-seizure medication for the 2 weeks prior to enrollment.
  5. Patients must not have other concurrent uncontrolled malignancies, defined as a malignancy that currently requires therapy or other intervention. Patients with suspected cuSCCs should have them excised prior to study registration. Surgical resection should not be performed within 7 days of starting protocol therapy.
  6. Patients may not have had a major surgical procedure, open biopsy (excluding skin cancer resection, cutaneous/subcutaneous melanoma metastasis resection or biopsy or vascular access device insertion), or significant traumatic injury within 28 days prior to Day 1, or have an anticipated need for major surgical procedure or a planned elective surgical procedure during the course of the study.
  7. Patients may not have had a core biopsy, skin cancer resection, or other minor surgical procedure, including placement of a vascular access device, within 7 days prior to Day 1 of the protocol.
  8. Patients must not have a serious intercurrent illness including, but not limited to:

    1. Ongoing or active infection requiring parental antibiotics on Day 1
    2. A history of malabsorption or other condition that would interfere with absorption of vemurafenib or cobimetinib.
    3. History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
    4. History of congenital long QT syndrome or mean corrected QTc interval > 450 msec at baseline
    5. Clinically significant cardiovascular disease, defined as any of the following conditions:

    i. Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) ii. Prior history of hypertensive crisis or hypertensive encephalopathy iii. Myocardial infarction within 6 months iv. Unstable angina v. New York heart association grade II or greater congestive heart failure (Appendix C) vi. Serious cardiac arrhythmia requiring medication vii. LVEF < 50% or below institutional limit of normal f) History of stroke of TIAs within 6 months prior to Day 1 g) Grade II or greater peripheral vascular disease within 1 year prior to study entry or other significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 h) Serious, non-healing wound, active ulcer, or untreated bone fracture i) History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 j) Known hypersensitivity to any component of bevacizumab k) Known CNS disease, except for stable or regressing brain metastases. l) Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) m) Psychiatric illness/social situations that would limit compliance with study requirements.

    n) Significant ocular issues including history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (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 >21mm Hg
    2. Serum cholesterol >= Grade 2
    3. Hypertriglyceridemia >= Grade 2
    4. Hyperglycemia (fasting) >= Grade 2
  9. Patients must not have the following foods/ supplements at least 7 days prior to initiation of and during study treatment:

    1. St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
    2. Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
  10. Because patients with immune deficiency are at increased risk of lethal infections when treated with bone marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with bevacizumab, vemurafenib and cobimetinib.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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, California
The Angeles Clinic Not yet recruiting
Los Angeles, California, United States, 90025
Contact: Saba Mukarram    310-231-2181    smukarram@theangelesclinic.org   
Principal Investigator: Omid Hamid, MD         
United States, Colorado
University of Colorado Cancer Center Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Rene Gonzalez, MD       rene.gonzalez@ucdenver.edu   
Principal Investigator: Rene Gonzalez, MD         
United States, District of Columbia
Georgetown Lombardi Comprehensive Cancer Center Recruiting
Washington, District of Columbia, United States, 20007
Contact: Luciana Laguinge    202-687-1134    lml7@georgetown.edu   
Principal Investigator: Michael B Atkins, MD         
Sub-Investigator: Kellie Parks, PA         
Washington Cancer Institute at MedStar Washington Hospital Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Kate Burdekin    202-877-9374    kate.a.burdekin@medstar.net   
Principal Investigator: Sekwon Jang, MD         
Sub-Investigator: David J Perry, MD         
United States, Maryland
Harry and Jeannette Weinberg Cancer Institute at Franklin Square Recruiting
Baltimore, Maryland, United States, 21237
Contact: Jean Flack, RN    443-777-7364    jean.flack@medstar.net   
Principal Investigator: Pallavi Kumar, MD         
United States, Massachusetts
Beth Israel Deaconess Medical Center (BIDMC) Recruiting
Boston, Massachusetts, United States, 02215
Contact: Mekailah Simpson    617-632-9260      
Principal Investigator: David McDermott, MD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Lauren Ostman    617-632-5906    Lauren_Ostman@dfci.harvard.edu   
Principal Investigator: F S Hodi, MD         
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Courtney Coughlin       ccoughlin3@partners.org   
Principal Investigator: Donald Lawrence, MD         
United States, New York
NYU Clinical Cancer Center Recruiting
New York, New York, United States, 10016
Contact: Ethel Yepes    212-263-4402    Ethel.Yepes@nyumc.org   
Principal Investigator: Anna C Pavlick, DO         
NYU Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Caroline Sorlie, RN    212-731-5682    caroline.sorlie@nyumc.org   
Principal Investigator: Anna C Pavlick, DO         
United States, Ohio
OSU Comprehensive Cancer Center Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Kari Kendra, MD    614-366-0372    Kari.Kendra@osumc.edu   
Principal Investigator: Kari Kendra, MD         
United States, Pennsylvania
University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Carrie Muniz       munizca@upmc.edu   
Sub-Investigator: John Kirkwood, MD         
Principal Investigator: Hussein Tawbi, MD         
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Marjorie Wallace    615-322-5092    marjorie.wallace@vanderbilt.edu   
Principal Investigator: Jeffrey Sosman, MD         
United States, Washington
Seattle Cancer Care Alliance Recruiting
Seattle, Washington, United States, 98109
Contact: Vivian Nguyen    206-288-7614    vnguyen@seattlecca.org   
Principal Investigator: John Thompson, MD         
University of Washington Medical Center Recruiting
Seattle, Washington, United States, 98195
Contact: Linda Mendelson    206-667-5767    lmendels@fhcrc.org   
Principal Investigator: Kim Margolin, MD         
Sponsors and Collaborators
Melanoma Research Foundation Breakthrough Consortium
Genentech, Inc.
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, GEN-01
Study First Received: December 9, 2011
Last Updated: October 13, 2014
Health Authority: United States: Institutional Review Board
United States: Data and Safety Monitoring Board
United States: Food and Drug Administration

Keywords provided by Melanoma Research Foundation Breakthrough Consortium:
Metastatic melanoma
BRAF-mutant
Stage IV melanoma
Vemurafenib
Bevacizumab
Cobimetinib

Additional relevant MeSH terms:
Melanoma
Nevi and Melanomas
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014