Sorafenib and Bevacizumab to Treat Ovarian, Fallopian and Peritoneal Cancer
Condition: Ovarian Neoplasm; Fallopian Tube Cancer; Primary Peritoneal Cancer
MeSH terms: Fallopian Tube Neoplasms; Peritoneal Neoplasms; Ovarian Neoplasms
Intervention: Bevacizumab; BAY 43-9006
Intervention description: bevacizumab 5 mg/kg intravenous (IV) every two weeks; BAY 43-9006 200 mg po (by mouth) twice daily 5 out of 7 days each week (Mon-Fri)
Intervention MeSH terms: Bevacizumab; Sorafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Sorafenib; Ovarian Cancer; Fallopian Cancer; Bevacizumab; Peritoneal Cancer; Fallopian Tube Cancer

Summary:

      Background:

        -  Sorafenib and bevacizumab are anti-cancer drugs that work by targeting the blood vessels
           that allow tumors to grow. Using the two drugs together may more effectively block the
           formation of blood vessels that feed tumors.

        -  Sorafenib and bevacizumab both are approved by the Food and Drug Administration for use
           in other cancers but have not ovarian cancer. In a preliminary trial of this drug
           combination, however, tumors in 6 of 14 patients with ovarian cancer shrank.

      Objectives:

        -  To determine the safety and activity of the combination of sorafenib and bevacizumab for
           treating patients with ovarian, fallopian and peritoneal cancer.

        -  To determine how sorafenib and bevacizumab may affect the cancer by measuring amounts of
           different proteins in small biopsy samples of tumor taken before starting treatment and
           after 6 weeks.

      Eligibility:

        -  Females 18 years of age and older with ovarian, fallopian, or peritoneal cancer whose
           disease has not responded to standard treatment or for which no standard treatment is
           available.

        -  Patients must have not been previously treated with bevacizumab or must have had their
           disease worsen while taking bevacizumab-based therapy.

      Design:

        -  Patients take 200 mg of sorafenib by mouth twice a day Monday through Friday each week
           and 5 mg/kg of bevacizumab through a vein every 2 weeks.

        -  Tumor biopsies and imaging scans (magnetic resonance imaging (MRI) and positron emission
           tomography (PET) are done before treatment, 3 days after beginning treatment, and 6
           weeks into therapy.

        -  Computed tomography (CT) or other imaging tests are done every 8 weeks to evaluate
           response to treatment.

        -  History, physical examinations, blood and urine tests are done periodically during
           treatment for health checks and research purposes.

        -  About 74 patients are to be enrolled in the trial.
    

Eligibility criteria:

        -  ELIGIBILITY CRITERIA:

        Histopathologically documented recurrent/refractory epithelial ovarian cancer, primary
        peritoneal cancer or fallopian tube cancer from a previous biopsy verified by the
        Laboratory of Pathology, National Cancer Institute (NCI).

        -Recurrent/refractory disease defined as progression within 6 months of upfront
        platinum-containing therapy or progression after subsequent therapy in previously relapsed
        patients.

        Disease amenable to percutaneous or skin biopsy as determined by an associate investigator
        and a member of the interventional team.

        Patient willingness to have biopsies performed.

        Measurable disease defined as tumor greater than or equal to 1 cm.

        Age greater than or equal to 18 years.

        Life expectancy of more than 3 months.

        Performance status of 0 to 1 according to the Eastern Cooperative Oncology Group (ECOG)
        criteria.

        Adequate organ function as defined below:

        Laboratory Test Required value

          -  Leukocytes greater than or equal to 3,000/ microliter

          -  Absolute neutrophil count greater than or equal to 1,200/ microliter

          -  Platelets greater than or equal to 100,000/ microliter

          -  Total bilirubin less than or equal to 1.5 times the institutional upper limits of
             normal

          -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and
             alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than or
             equal to 2.5 times the institutional upper limit of normal

          -  Creatinine less than or equal to 1.5 mg/dL

        OR

          -  Creatinine clearance greater than or equal to 45 mL/min/1.73 m^2 for patients with
             creatinine levels above institutional normal.

          -  Activated partial thromboplastin time (PTT) less than 1.5 times the institutional
             upper limits of normal

          -  Prothrombin Time (PT)/ International normalized ratio (INR) less than 1.5 times the
             institutional upper limits of normal

          -  Amylase and Lipase Less than institutional upper limits of normal

        Patients must have a urine protein/creatinine ratio (UPC) less than 1.0 for enrollment.

        No surgery, radiation therapy, chemotherapy, immunotherapy, biotherapy, or hormonal therapy
        (exception raloxifene for bone health) within four weeks (6 weeks for mitomycin C,
        carboplatin, or nitrosoureas);

        No metabolically active complimentary or alternative therapy for at least 1 week, defined
        as any ingested or administered chemical substances including herbal medications, but not
        including acupuncture, hypnosis, meditation, or other non-chemical treatments.

        No monoclonal antibody therapy for at least 6 weeks.

        Patients must have recovered from any acute toxicity related to prior therapy, including
        surgery. Toxicity should be less than or equal to grade 1 (as defined by Common Terminology
        Criteria for Adverse Events (CTCAE v3) or returned to baseline. Peripheral neuropathy less
        than or equal to grade 2 will be allowed as this patient population has universally been
        treated with platinum-based chemotherapy with residual neuropathy being a common
        occurrence.

        No other invasive malignancies within the past two years (with the exception of
        non-melanoma skin cancers, non-invasive bladder cancer, stage I endometrial cancer or
        cervical cancer synchronous to the ovarian cancer diagnosis and cured by surgical
        resection).

        Ability to understand and sign an informed consent form.

        Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin),
        Non-steroidal anti-inflammatory drugs (NSAIDs), and other maintenance medications prior to
        study entry will be allowed to continue their supportive therapies.

        Ability to tolerate orally administered medications.

        Contraception is not a consideration as these patients have all had surgical removal of
        their reproductive organs. Pregnant women are excluded from this study because BAY 43-9006
        and bevacizumab are agents with the potential for teratogenic or abortifacient effects.
        Because there is an unknown but potential risk for adverse events in nursing infants
        secondary to treatment of the mother with BAY 43-9006 and/or bevacizumab, breastfeeding
        should be discontinued if the mother is treated with BAY 43-9006 and/or bevacizumab.

        There is no limit on the number of prior regimens with which a patient has been treated.

        Patients who have been treated with bevacizumab previously are eligible for the trial if
        they have progressed while on bevacizumab-based therapy.

        -Disease progression on bevacizumab therapy will be defined as documented increase in
        disease based on imaging while the patient is receiving bevacizumab or within three months
        of their last dose of bevacizumab.

        Patients must be at least 6 weeks from their last dose of bevacizumab prior to being
        enrolled on study.

        Patients who have a healed fistula greater than 28 days prior to enrollment are eligible
        (refer to section 3.2.15 for patients who have had prior bevacizumab)

        EXCLUSION CRITERIA:

        Serious non-healing wounds (including wounds healing by secondary intention), acute or
        non-healing ulcers, or bone fractures within 3 months of enrollment.

        Moderate or massive hemoptysis or surgery within 28 days of enrollment.

        Ongoing treatment with any other investigational agents.

        Brain metastases

          -  Patients with central nervous system (CNS) metastases within the past 2 years are
             ineligible. Patients who have had CNS disease curatively treated and without
             recurrence for 2 years may be eligible. but any CNS disease that has not undergone
             curative therapy with radiation, gamma knife, and/or surgical therapy are ineligible.

          -  CNS imaging will not be mandated for all patients. However, if there is clinical
             suspicion of CNS involvement, a contrast computed tomography (CT) or magnetic
             resonance imaging (MRI) of the brain will be required.

          -  Patients with CNS metastases may not be on steroids for the purpose of CNS disease or
             edema control.

          -  Patients with CNS disease must be on an anti-seizure medication and that medication
             cannot be a CYPP4503A modulating agent.

        Thrombotic or embolic events within the past 6 months such as a cerebrovascular accident
        (including transient ischemic attacks), pulmonary embolism, unstable angina, or myocardial
        infarction. Fully treated deep vein thrombosis no longer requiring anticoagulation will be
        allowed.

        Uncontrolled intercurrent illness including, but not limited to, ongoing or active
        infection, symptomatic congestive heart failure (American Heart Association (AHA) Class II
        or worse), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
        situations that would limit compliance with study requirements.

        -Patients with evidence of active infection will become eligible for reconsideration 7 days
        after completing antibiotic therapy.

        Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral
        therapy are excluded from the study because of possible pharmacokinetic interactions with
        sorafenib, bevacizumab, and/or the combination.

        Hypertension defined as systolic blood pressure greater than 150 mmHg or diastolic pressure
        greater than 90 mmHg despite optimal medical management.

        Therapeutic anticoagulation with coumadin, heparins, or heparinoids.

        Evidence of a bleeding diathesis.

        History of high grade varices or arteriovenous malformations.

        Patients previously treated with sorafenib will not be eligible for this trial.

        Fistula or bowel obstruction or perforation in the 28 days prior to enrollment.

        Patients must not be taking the cytochrome p450 (CYP450) enzyme-inducing drugs phenytoin,
        carbamazepine, phenobarbital, St. John's wort, or rifampin.

        For patients who have been previously treated with bevacizumab, any severe toxicity
        associated with bevacizumab while the patient was being treated with the agent will make
        the patient ineligible for the trial. This includes bevacizumab-induced hypertensive
        crisis, arterial thromboembolic events (including cardiac ischemia or cerebrovascular
        ischemia or other arterial thrombosis), nephrotic syndrome, gastrointestinal perforation,
        serious hemorrhage, and fistulas (unless the fistula completely resolved while the patient
        was still on bevacizumab or it has been surgically corrected).