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

Trial of Vemurafenib/<span class="go-doc-concept go-doc-intervention">Cobimetinib</span> With or Without <span class="go-doc-concept go-doc-intervention">Bevacizumab</span> in Patients With Stage IV BRAFV600 <span class="go-doc-concept go-doc-keyword">Mutant</span> <span class="go-doc-concept go-doc-disease">Melanoma</span>

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

    NCT ID: NCT01495988

    ORG ID: ML27894

    NCI ID: GEN-01

    Trial Conditions

    Melanoma

    Metastatic Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Vemurafenib Zelboraf Vemurafenib/Cobimetinib, Vemurafenib/Cobimetinib + Bevacizumab
    Bevacizumab Avastin Vemurafenib/Cobimetinib + Bevacizumab
    Cobimetinib GDC-0973 Vemurafenib/Cobimetinib, Vemurafenib/Cobimetinib + Bevacizumab

    Trial 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

    Name Type Description Interventions
    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. Vemurafenib, 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. Vemurafenib, Bevacizumab, Cobimetinib

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose

    Median progression-free survival

    Secondary Outcome Measures

    Overall survival

    Response rates

    Toxicity and safety profile

    Effects of the addition of bevacizumab on tumor angiogenesis, resistance mechanisms and immune function

    Correlate blood markers of B-RAFV600 mutation with treatment efficacy

    Trial Keywords

    Metastatic melanoma

    BRAF-mutant

    Stage IV melanoma

    Vemurafenib

    Bevacizumab

    Cobimetinib