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MelanomaPhase 2NCT01495988

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

A Phase 2 study testing Vemurafenib, Bevacizumab and Cobimetinib in people with Melanoma and Metastatic Melanoma, run by Melanoma Research Foundation Breakthrough Consortium at 14 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Melanoma, Metastatic Melanoma
What is being tested?
Vemurafenib, Bevacizumab and Cobimetinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
14 sitesUnited States
Study dates
Aug 2013to Jun 2016
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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)
  • Alkaline Phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement and =< 7 x ULN for patients with known bone involvement)
  • International Normalized Ratio (INR) < 1.5 and aPTT within 1.1 x ULN
  • Total Bilirubin < 1.5 x ULN
  • UPC ratio < 1.0 at screening or 24 hours urine protein < 1 gm (Appendix D)
  • Patients must have the ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • 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:
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  • 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.
  • History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
  • History of congenital long QT syndrome or mean corrected QTc interval > 450 msec at baseline
  • Clinically significant cardiovascular disease, defined as any of the following conditions:
  • 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.
  • 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:
  • Uncontrolled glaucoma with intra-ocular pressures >21mm Hg
  • Serum cholesterol >= Grade 2
  • Hypertriglyceridemia >= Grade 2
  • Hyperglycemia (fasting) >= Grade 2
  • Patients must not have the following foods/ supplements at least 7 days prior to initiation of and during study treatment:
  • St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
  • Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
  • 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.

Trial locations and contacts

14 sites in 1 country.

14 sites in 1 country

United States14 sites

  • University of Colorado Cancer Center

    Aurora, Colorado, 80045

  • Harry and Jeannette Weinberg Cancer Institute at Franklin Square

    Baltimore, Maryland, 21237

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Beth Israel Deaconess Medical Center (BIDMC)

    Boston, Massachusetts, 02215

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • OSU Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • The Angeles Clinic

    Los Angeles, California, 90025

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • NYU Clinical Cancer Center

    New York, New York, 10016

  • Columbia University Medical Center

    New York, New York, 10032

  • University of Pittsburgh Medical Center

    Pittsburgh, Pennsylvania, 15232

  • University of Washington Medical Center

    Seattle, Washington, 98109

  • Georgetown Lombardi Comprehensive Cancer Center

    Washington D.C., District of Columbia, 20007

  • Washington Cancer Institute at MedStar Washington Hospital Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

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.

Read the 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.

Being tested
Vemurafenib, Bevacizumab, Cobimetinib
Keywords
Metastatic melanoma, BRAF-mutant, Stage IV melanoma, Vemurafenib, Bevacizumab, Cobimetinib
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VemurafenibDrug

    Also called Zelboraf

    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.

  • BevacizumabDrug

    Also called Avastin

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

  • CobimetinibDrug

    Also called GDC-0973

    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.

Study groups in NCT01495988
Study groupRoleWhat they receive
Vemurafenib/CobimetinibActive comparatorVemurafenib 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.
Receives: Drug: Vemurafenib; Drug: Cobimetinib
Vemurafenib/Cobimetinib + BevacizumabExperimentalVemurafenib 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.
Receives: Drug: Vemurafenib; Drug: Bevacizumab; Drug: Cobimetinib
VemurafenibActive comparatorVemurafenib 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.
Receives: Drug: Vemurafenib
Vemurafenib + BevacizumabExperimentalVemurafenib 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.
Receives: Drug: Vemurafenib; Drug: Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose

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

    Measured: Until MTD determined (up to 6 months)

  2. 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.

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

Secondary outcomes (5)

  1. Overall Survival

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

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

  2. Response Rates

    Compare response rate (RR) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.

    Measured: 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)

  3. Toxicity and Safety Profile

    Describe the toxicity and safety profile of treatment with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab in patients with stage IV, BRAFV600E/K melanoma.

    Measured: Until study completion

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

    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.

    Measured: Upon completion of the protocol (3 years)

  5. Correlate Blood Markers of B-RAFV600 Mutation With Treatment Efficacy

    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.

    Measured: Upon completion of the protocol (3 years)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Dec 2011 (estimated)
  2. Study startAug 2013
  3. Primary completionJan 2016
  4. Study completionJun 2016

Why it stopped: Slow accrual; toxicity; change in priorities

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01495988
Sponsor's protocol ID
ML27894
Other IDs
GEN-01
Status last verified
Sep 2017
First submitted
9 Dec 2011
Last updated
24 Oct 2017
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vemurafenib, Bevacizumab and Cobimetinib in people with Melanoma and Metastatic Melanoma, run by Melanoma Research Foundation Breakthrough Consortium at 14 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 24 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (time frame: Until MTD determined (up to 6 months)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01495988.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Oct 2017.

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