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

NCT01495988 | Terminated Phase 2 Results DMC

• 2 other identifiers: ML27894GEN-01
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 14

Brief Summary

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.

Conditions

Melanoma; Metastatic Melanoma

Keywords

Metastatic melanoma; BRAF-mutant; Stage IV melanoma; Vemurafenib; Bevacizumab; Cobimetinib

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose

  To establish the maximum tolerated dose (MTD) of bevacizumab in combination with vemurafenib and cobimetinib.

  Until MTD determined (up to 6 months)

• Median Progression-free Survival

  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.

  Time between randomization and disease progression (~10-15 months)

Secondary Outcomes (5)

• Overall Survival

  Time between randomization and death due to any cause (overall survival rates also to be assessed at 12 and 18 months)

• Response Rates

  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)

• Toxicity and Safety Profile

  Until study completion

• Effects of the Addition of Bevacizumab on Tumor Angiogenesis, Resistance Mechanisms and Immune Function

  Upon completion of the protocol (3 years)

• Correlate Blood Markers of B-RAFV600 Mutation With Treatment Efficacy

  Upon completion of the protocol (3 years)

Study Arms (4)

Vemurafenib/Cobimetinib

ACTIVE COMPARATOR

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; Drug: Cobimetinib

Vemurafenib/Cobimetinib + Bevacizumab

EXPERIMENTAL

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; Drug: Bevacizumab; Drug: Cobimetinib

Vemurafenib

ACTIVE COMPARATOR

Vemurafenib will be given at a dose of 960 mg p.o. BID 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 + Bevacizumab

EXPERIMENTAL

Vemurafenib will be given at a dose of 960 mg p.o. BID to all patients. Patients assigned to the combination arm will also receive bevacizumab 15 mg/kg every IV 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; Drug: Bevacizumab

Interventions

Vemurafenib DRUG

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.

Also known as: Zelboraf

Vemurafenib; Vemurafenib + Bevacizumab; Vemurafenib/Cobimetinib; Vemurafenib/Cobimetinib + Bevacizumab

Bevacizumab DRUG

Patients assigned to the combination arm will also receive bevacizumab at 15mg/kg, intravenously, every 3 weeks.

Also known as: Avastin

Vemurafenib + Bevacizumab; Vemurafenib/Cobimetinib + Bevacizumab

Cobimetinib DRUG

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.

Also known as: GDC-0973

Vemurafenib/Cobimetinib; Vemurafenib/Cobimetinib + Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histological or cytological confirmed melanoma that is metastatic or unresectable stage IIIc and clearly progressive.
• Patients must have melanoma that is documented to contain a BRAFV600E or BRAFV600K mutation by a FDA-approved test.
• Age \>= 18 years.
• 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.
• 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).
• 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.
• 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.
• 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.
• Patients must have an ECOG performance status of 0, 1, or 2.
• Patients must have the following baseline laboratory values:
• White Blood Count \> 3,000/mm3
• Absolute Neutrophil Count \> 1,500/mm3
• Platelet Count \> 100,000/mm3
• 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)
• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) \< 3 x ULN (\< 5 x ULN for patients with documented liver metastases)

You may not qualify if:

• 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:
• Immunotherapy, such as interferon, interleukin-2, GM-CSF, ipilimumab, anti-PD1 or other experimental agent.
• Cytotoxic chemotherapy, such as dacarbazine, temozolomide, carboplatin +/-paclitaxel.
• Patients may not have had radiation therapy within the last 4 weeks prior to initiation of study treatment.
• Patients who have had prior VEGF pathway inhibitor, BRAF or MEK inhibitor therapy are ineligible.
• Patients must have no clinical evidence of active brain metastasis. Patients with a history of brain metastases must meet all of the following criteria:
• Have completed treatment greater than 4 weeks prior to enrollment.
• 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.
• 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.
• 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.
• 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.
• 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.
• Patients must not have a serious intercurrent illness including, but not limited to:
• Ongoing or active infection requiring parental antibiotics on Day 1
• A history of malabsorption or other condition that would interfere with absorption of vemurafenib or cobimetinib.

Sponsors & Collaborators

• Melanoma Research Foundation Breakthrough Consortium: lead
• Genentech, Inc.: collaborator

Study Sites (14)

The Angeles Clinic

Los Angeles, California, 90025, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Georgetown Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20007, United States

Location

Washington Cancer Institute at MedStar Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

Location

Harry and Jeannette Weinberg Cancer Institute at Franklin Square

Baltimore, Maryland, 21237, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center (BIDMC)

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

NYU Clinical Cancer Center

New York, New York, 10016, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

OSU Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

University of Washington Medical Center

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

Vemurafenib; Bevacizumab; cobimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study was terminated prematurely on June 13, 2016. No further accrual to the study will occur.

Results Point of Contact

• Title: Damon Collie
• Organization: The Emmes Corporation

dcollie@emmes.com

301-251-1161

Study Officials

• Michael B Atkins, MD

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

• F. Stephen Hodi, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2011
• First Posted: December 21, 2011
• Study Start: August 1, 2013
• Primary Completion: January 1, 2016
• Study Completion: June 1, 2016
• Last Updated: October 24, 2017
• Results First Posted: June 23, 2017

Record last verified: 2017-09

Locations

US (14)