Clinical Trials /

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

NCT01495988

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ML27894
  • SECONDARY ID: GEN-01
  • NCT ID: NCT01495988

Conditions

  • Melanoma
  • Metastatic Melanoma

Interventions

DrugSynonymsArms
VemurafenibZelborafVemurafenib
BevacizumabAvastinVemurafenib + Bevacizumab
CobimetinibGDC-0973Vemurafenib/Cobimetinib

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Vemurafenib
  • 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.
  • Vemurafenib
  • Bevacizumab
  • 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.
  • 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.
  • Vemurafenib
  • Bevacizumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:Until MTD determined (up to 6 months)
Safety Issue:
Description:To establish the maximum tolerated dose (MTD) of bevacizumab in combination with vemurafenib and cobimetinib.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:Compare overall survival (OS) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.
Measure: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)
Safety Issue:
Description:Compare response rate (RR) of patients with stage IV, BRAFV600E/K melanoma treated with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab.
Measure:Toxicity and Safety Profile
Time Frame:Until study completion
Safety Issue:
Description:Describe the toxicity and safety profile of treatment with vemurafenib/cobimetinib versus vemurafenib/cobimetinib and bevacizumab in patients with stage IV, BRAFV600E/K melanoma.
Measure:Effects of the Addition of Bevacizumab on Tumor Angiogenesis, Resistance Mechanisms and Immune Function
Time Frame:Upon completion of the protocol (3 years)
Safety Issue:
Description: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.
Measure:Correlate Blood Markers of B-RAFV600 Mutation With Treatment Efficacy
Time Frame:Upon completion of the protocol (3 years)
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Melanoma Research Foundation Breakthrough Consortium

Trial Keywords

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

Last Updated

October 24, 2017