Clinical Trials /

Vemurafenib With Sorafenib Tosylate or Crizotinib in Treating Patients With Advanced Malignancies With BRAF Mutations

NCT01531361

Description:

This phase I clinical trial studies vemurafenib with sorafenib tosylate or crizotinib in treating patients with advanced malignancies with BRAF mutations. Sorafenib tosylate and crizotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Sorafenib tosylate may also stop the growth of advanced malignancies by blocking blood flow to tumors. Drugs used in chemotherapy, such as vemurafenib, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vemurafenib together with sorafenib tosylate or crizotinib may kill more cancer cells.

Related Conditions:
  • Cancer
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Sorafenib</span> or <span class="go-doc-concept go-doc-intervention">Crizotinib</span> and Vemurafenib in Advanced Cancer

Title

  • Brief Title: Sorafenib or Crizotinib and Vemurafenib in Advanced Cancer
  • Official Title: A Phase I Trial of Sorafenib (CRAF, BRAF, KIT, RET, VEGFR, PDGFR Inhibitor) or Crizotinib (MET, ALK, ROS1 Inhibitor) in Combination With Vemurafenib (BRAF Inhibitor) in Patients With Advanced Malignancies
  • Clinical Trial IDs

    NCT ID: NCT01531361

    ORG ID: 2011-1183

    NCI ID: NCI-2012-00217

    Trial Conditions

    Advanced Cancers

    Trial Interventions

    Drug Synonyms Arms
    Vemurafenib PLX4032, R05185426 Vemurafenib + Sorafenib, Vemurafenib + Crizotinib
    Sorafenib Nexavar, Bay 43-9006 Vemurafenib + Sorafenib
    Crizotinib PF-02341066, Xalkori Vemurafenib + Crizotinib

    Trial Purpose

    The goal of this clinical research study is to find the highest tolerable dose of the
    combination of ZelborafTM (vemurafenib) with Nexavar (sorafenib) or Xalkori (crizotinib)
    that can be given to patients with advanced cancer. The safety of these drugs will also be
    studied.

    Vemurafenib is designed to block a protein called BRAFV600E inside the cancer cells, which
    is involved in cancer cell growth.

    Sorafenib is designed to block the function of important proteins in and outside of cancer
    cells. These proteins are involved in cancer cells growth and new blood vessel development.

    Crizotinib is designed to block certain abnormal genes found in cancer cells. This may
    cause the cancer cells to die.

    Detailed Description

    Study Groups:

    Dose escalation:

    If you are found to be eligible to take part in this study, your doctor will decide if you
    will receive vemurafenib either with sorafenib or crizotinib. Once it is decided which
    combination you will receive, you will be assigned to a dose level based on when you join
    the study.

    Up to 6 dose levels of vemurafenib with sorafenib will be tested. Up to 5 dose levels of
    vemurafenib with crizotinib will be tested. Up to 6 participants will be enrolled at each
    dose level. The first group of participants will receive the lowest dose level. Each new
    group will receive a higher dose than the group before it, if no intolerable side effects
    were seen. This will continue until the highest tolerable dose of vemurafenib either with
    sorafenib or crizotinib is found.

    Dose expansion:

    Once the highest tolerable dose of vemurafenib either with sorafenib or crizotinib is found,
    up to 14 more participants may be enrolled. This will be to further study the safety of the
    combination of drugs at that dose and the level of effectiveness of the study drugs in a
    certain tumor group.

    Study Drug Administration:

    Each study cycle is 28 days.

    You will take vemurafenib by mouth 2 times a day at the same time every day either with or
    without food, swallowed whole with a glass of water. Tablets should not be chewed or
    crushed. If you miss a dose, you can take it up to 4 hours before the next dose. You cannot
    take both doses at the same time.

    You will take sorafenib by mouth at the same time every day without food (at least 1 hour
    before or 2 hours after a meal). Depending on which dose level you are enrolled in, you will
    take sorafenib by mouth either 1 or 2 times a day. The doctor will discuss this with you.

    You will take crizotinib by mouth at the same time every day consistently either with or
    without food, swallowed whole with a glass of water. Depending on which dose level you are
    receiving, you will take crizotinib by mouth either 1 or 2 times a day. The doctor will
    discuss this with you.

    Study Visits:

    At every study visit, you will be asked if you have had any side effects.

    Around Days 1, 8, 15, and 22 of Cycle 1 and Day 1 of Cycles 2 and beyond:

    - Blood (about 2-4 tablespoons) will be drawn for mutation/genetic testing.
    Mutation/genetic testing looks at whether specific genes are changed (mutated) in the
    tumor.

    - Urine will be collected for mutation/genetic testing. You may collect your first urine
    of the morning, anytime during the day, or you may collect urine for 24 hours. You
    will be given containers to collect the urine and will be told how to use them.

    If you collect your urine over 24 hours, the study staff will give you a large (3-liter)
    urine storage container and a small (7-ounce) plastic collection container. You will
    urinate into the small collection container and then pour the urine into the large urine
    storage container within 10 minutes after the collection. You should write down the time of
    the first and last collections in the large storage container and return it to the study
    staff at the end of the 24-hour period.

    If you collect your first urine of the morning, the study staff will give you 3 plastic
    collection cups and 3 small tubes filled with a preservative solution. To collect your
    first morning urine, you will fill the collection cup with urine up to the 100 mL
    (milliliter) line, add 1 of the small tubes of preservative to the cup within 10 minutes,
    and then mark on the container that this is your first morning urine. If possible, fill the
    other 2 collection cups, adding a tube of preservative to each as just described and mark
    them as part of your first morning urine. You will return the collection cups to the study
    staff at your next visit.

    If you collect your urine anytime it suits you, the study staff will give you 3 plastic
    collection cups and 3 small tubes filled with a preservative solution. To collect your
    urine, you will fill the collection cup with urine up to the 100 mL line, add 1 of the small
    tubes of preservative to the cup within 10 minutes, and then mark on the container that this
    is your first morning urine. If possible, fill the other 2 collection cups, adding a tube
    of preservative to each as just described and mark them so the study doctor will know the
    time when you collected your urine. You will return the collection cups to the study staff
    at your next visit. Your study doctor or staff will give you more details, if needed.

    Around Days 15-21 of Cycle 1:

    - Your medical history will be recorded, including any cancer symptoms.

    - You will have a physical exam, including measurement of your weight and vital signs.

    - You will be asked about any health problems you may have and any other drugs or herbal
    supplements you may be taking.

    - Your performance status will be recorded.

    - Blood (about 1 tablespoon) will be drawn for routine tests.

    Before starting Cycles 2 and beyond:

    - Your medical history will be recorded, including any cancer symptoms.

    - You will have a physical exam, including measurement of your weight and vital signs.

    - You will be asked about any health problems you may have and any other drugs or herbal
    supplements you may be taking.

    - Your performance status will be recorded.

    - Blood (about 1 tablespoon) will be drawn for routine tests.

    - If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
    pregnancy test.

    Every other cycle (every 8 weeks):

    - Blood (about 1 tablespoon) will be drawn to check your thyroid gland.

    - You will have a skin exam by a skin doctor to check for any lesions that might have
    skin cancer.

    - You will have an x-ray, CT scan, MRI, and/or PET/CT scan to check the status of the
    disease. Blood (about 1 tablespoon) will be drawn for tumor marker testing. After at
    least 6 months of taking the study drugs, you may have CT, MRI, and/or PET/CT scans and
    blood drawn every 3 cycles (every 12 weeks) if the study doctor thinks it is needed.

    If the study doctor has to change your dose of study drugs, blood (about 1 tablespoon) will
    be drawn to check for abnormal minerals.

    Anytime during the study if your study doctor thinks it is needed:

    - You will have an ECG to check your heart function.

    - Blood (about 1 tablespoon) will be collected for abnormal mineral and digestive enzyme
    testing.

    - If you are taking the blood thinner warfarin, blood (about 1 teaspoon) will be drawn to
    test how well your blood clots.

    Length of Dosing:

    You may continue taking the study drugs for as long as the doctor thinks it is in your best
    interest. You will no longer be able to take the study drugs if the disease gets worse, if
    intolerable side effects occur, or if you are unable to follow study directions.

    Follow-up:

    You will have a follow-up-visit within 30 days after your last dose of study drugs. The
    following tests and procedures will be performed:

    - You will be asked about any health problems you may have and if you have had any side
    effects.

    - If the disease has gotten worse, blood (about 2-4 tablespoons) will be drawn for
    mutation/genetic testing.

    - If the disease has gotten worse, urine will be collected for mutation/genetic testing.
    You may collect your first urine of the morning, anytime during the day, or you may
    collect urine for 24 hours.

    If your study doctor thinks it is needed, you may have follow-up for a longer period of
    time.

    You may have a skin exam within 6 months after your last dose of study drugs to check for
    any new lesions that may have skin cancer if the doctor thinks it is needed.

    This is an investigational study. Vemurafenib is FDA approved and commercially available to
    treat progressive melanoma with the BRAFV600E mutation. Sorafenib is FDA approved and
    commercially available to treat progressive hepatocellular carcinoma and renal cell
    carcinoma. Crizotinib is FDA approved and commercially available to treat locally advanced
    or metastatic non-small lung cancer. Giving the combination of vemurafenib either with
    sorafenib or crizotinib to patients with advanced cancer is investigational.

    Up to 183 patients will be enrolled in this study. All will be enrolled at MD Anderson.

    Trial Arms

    Name Type Description Interventions
    Vemurafenib + Sorafenib Experimental There will be two treatment arms, Vemurafenib and Sorafenib and Vemurafenib and Crizotinib. Patients assigned to treatment arms per physician discretion. Dose Escalation Group Starting dose of Vemurafenib: 240 mg by mouth twice a day for 28 day cycle. Dose Escalation Group Starting dose of Sorafenib: 200 mg by mouth twice a day for 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. Vemurafenib, Sorafenib
    Vemurafenib + Crizotinib Experimental There will be two treatment arms, Vemurafenib and Sorafenib and Vemurafenib and Crizotinib. Patients assigned to treatment arms per physician discretion. Dose Escalation Group Starting Dose of Vemurafenib: 240 mg by mouth twice a day for 28 day cycle. Dose Escalation Group Starting dose of Crizotinib 250 mg by mouth daily for a 28 day cycle. Dose Expansion Group Starting Dose: Maximum tolerated dose (MTD) from dose escalation group. Vemurafenib, Crizotinib

    Eligibility Criteria

    Inclusion Criteria:

    1. Patients with advanced or metastatic cancers and BRAF mutations that are refractory
    to standard therapy, relapsed after standard therapy, or who have no standard therapy
    available that improves survival by at least three months. Patients with BRAF
    mutation in cell free DNA (tested in CLIA lab) are also eligible.

    2. Patients must be >/= 3 weeks beyond treatment with a cytotoxic chemotherapy regimen,
    or therapeutic radiation, or major surgery. Patients may have received palliative
    localized radiation immediately before or during treatment provided that radiation is
    not delivered to the only site of disease being treated under this protocol. For
    biologic/targeted agents patients must be >/= 5 half-lives or >/= 3 weeks from the
    last dose (whichever comes first). Patients previously treated with vemurafenib
    monotherapy do not have to stop medication before they start on the protocol.

    3. ECOG performance status </= 2

    4. Patients must be >/= 18 years of age.

    5. Patients must have adequate organ and marrow function defined as: absolute neutrophil
    count (ANC) >/= 1,000/mL, platelets >/=75,000/mL; creatinine </= 2 X ULN; total
    bilirubin </= 2 X ULN (exceptions may apply to benign non-malignant indirect
    hyperbilirubinemia such as Gilbert syndrome); ALT (SGPT) and/or AST (SGOT) </= 5 X
    ULN Exception for patients with liver metastasis: total bilirubin </= 3 x ULN; ALT
    (SGPT) </= 8 X ULN.

    6. Dermatology evaluation with excision of any suspicious lesions prior to initiation of
    therapy.

    7. Women of childbearing potential and men must agree to use adequate contraception
    (hormonal or barrier method of birth control; abstinence) prior to study entry, for
    the duration of study participation, and for 30 days after the last dose.

    8. Women of childbearing potential must have a negative serum or urine pregnancy test
    within 2 weeks prior to initiation of therapy.

    9. Life expectancy >12 weeks in the opinion of the Investigator.

    10. Patients must be able to understand and be willing to sign a written informed consent
    document.

    11. Patient must be able to swallow pills.

    Exclusion Criteria:

    1. Uncontrolled intercurrent illness, including, but not limited to, uncontrolled
    infection, uncontrolled asthma, need for hemodialysis, need for ventilatory support.

    2. Syndrome of congenital QTc prolongation or QTc >500 msec.

    3. Patients with clinically significant cardiovascular disease: history of
    cerebrovascular accident (CVA) within 6 months, myocardial infarction or unstable
    angina within 6 months, or unstable angina pectoris.

    4. Pregnant or lactating women.

    5. History of hypersensitivity to vemurafenib.

    6. History of hypersensitivity to sorafenib for vemurafenib/sorafenib arm.

    7. History of hypersensitivity to crizotinib for vemurafenib/crizotinib arm.

    8. History of hypersensitivity to any component of the formulation.

    9. Patients unwilling or unable to sign informed consent document.

    10. Patients using any of the following medications: mesoridazine, dronedarone,
    thioridazine, ziprasidone, levomethadyl, and saquinavir for vemurafenib/sorafenib
    arm.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum Tolerated Dose (MTD) of Sorafenib or Crizotinib in Combination With Vemurafenib

    Secondary Outcome Measures

    Tumor Response

    Trial Keywords

    Advanced Cancers

    Advanced Malignancies

    Metastatic cancers

    Vemurafenib

    PLX4032

    R05185426

    Sorafenib

    Nexavar

    Bay 43-9006

    Crizotinib

    PF-02341066

    Xalkori

    Maximum tolerated dose

    MTD

    Dose limiting toxicity

    DLT