Bevacizumab to Treat Kaposi's Sarcoma in HIV-Positive and HIV-Negative Patients
Condition: Kaposi's Sarcoma; HIV Infections; HIV Seronegativity
MeSH terms: Sarcoma, Kaposi; Sarcoma
Intervention: Bevacizumab
Intervention description: 15 mg/kg day intravenously on day 1, day 8, then every 3 weeks.
Intervention MeSH terms: Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Angiogenesis; Cancer; HHV-8; KSHV; Skin; Kaposi Sarcoma; KS

Summary:

      This study will examine the safety and effectiveness of the experimental drug bevacizumab for
      treating both non-acquired immune deficiency syndrome (AIDS) and AIDS-associated Kaposi's
      sarcoma (KS). KS tumors depend on the formation of new blood vessels for their growth.
      Bevacizumab is an antibody to a protein called vascular endothelial growth factor (VEGF) that
      is produced by the body and is involved in blood vessel growth. Bevacizumab may block the
      action of VEGF, and thus help shrink KS lesions.

      Patients 18 years of age and older with Kaposi's sarcoma that is restricted to the skin and
      is not life threatening may be eligible for this study. Candidates will be screened with a
      medical history and physical examination, blood and urine tests, electrocardiogram (EKG),
      chest x-ray, and, if needed, imaging studies to evaluate internal tumors.

      Participants will receive bevacizumab intravenously (by vein) once a week for 2 weeks and
      then every 3 weeks at the National Institutes of Health (NIH) Clinical Center. The first
      infusion takes about 90 minutes, the second takes about 60 minutes, and subsequent infusions
      take about 30 minutes. Infusions may take longer, however, if the drug is better tolerated at
      a slower infusion rate. Patients will be evaluated with the following tests and procedures:

        -  Physical examination, assessment of drug side effects, measurement of KS lesions, and
           photographs of lesions once a week for the first 6 weeks of therapy, and then every 3
           weeks.

        -  cluster of differentiation 4 (CD4) cell counts and human immunodeficiency virus (HIV)
           viral load in HIV-positive patients every 12 weeks.

        -  Biopsies of lesions: upon entering the study, at week 12, and at the time of a response
           of the tumor to therapy or at the end of treatment, if treatment ends at week 18 or
           later.

        -  Additional biopsies, if requested. (Additional biopsies are not required.)

        -  Other procedures, such as computed tomography (CT) or magnetic resonance imaging (MRI)
           scans, if medically indicated.

      Patients may continue bevacizumab therapy indefinitely if they are benefiting from it, as
      long as they have no substantial toxicity or other conditions that would cause them to stop
      receiving it and the protocol remains open.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Age greater than or equal to 18 years.

        Kaposi's sarcoma pathologically confirmed by Center for Cancer Research (CCR) pathology.

        Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

        Life expectancy greater than 6 months.

        The following hematologic parameters:

          -  Hemoglobin greater than 9 g/dl;

          -  White blood cell (WBC) greater than 1000/mm^3;

          -  Absolute neutrophil count (ANC) greater than 750/mm^3;

          -  Platelets greater than 75,000/mm^3;

          -  Prothrombin time (PT) and partial thromboplastin time (PTT) less than or equal to 120%
             of control, unless patient has the presence of a lupus anticoagulant.

        The following hepatic parameters:

        Bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) unless the
        patient is receiving protease inhibitor therapy known to be associated with increased
        bilirubin:

        in this case total bilirubin less than or equal to 7.5 mg/dl and the direct fraction less
        than or equal to 0.7 mg/dl.

        -Examples of protease inhibitors known to increase bilirubin levels include indinavir,
        ritonavir, nelfinavir, and atazanavir.

        Aspartate aminotransferase (AST)/glutamic oxaloacetic transaminase (GOT) less than or equal
        to 2.5 times the upper limit of normal.

        Either Serum creatinine less than or equal to 1.5 mg/dL or measured creatinine clearance
        greater than or equal to 60 mL/min.

        Either Urine protein less than 1+ or measured 24 hour urine protein less than 500
        milligram.

        Blood pressure: systolic blood pressure (SBP) less than 160 mm/Hg; diastolic blood pressure
        (DBP) less than 95 mm/Hg.

        At least 5 assessable cutaneous lesions previously untreated by local therapy.

        Patients with human immunodeficiency virus (HIV) infection must be willing to comply with a
        regimen of highly active antiretroviral therapy and be on a regimen of highly active
        antiretroviral therapy (HAART) selected for best potential efficacy for at least 1 month
        with evidence of Kaposi sarcoma (KS) progression on the HAART regimen or be on a optimized
        regimen of HAART for 4 months or longer with no evidence of KS regression.

        Patients must be willing to use effective birth control.

        EXCLUSION CRITERIA:

        Symptomatic, extensive pulmonary involvement.

        Symptomatic visceral KS excluding the oral cavity.

        Inability to provide informed consent.

        Chemotherapy within 3 weeks.

        Prior therapy with SU5416.

        Supraphysiologic doses of corticosteroids within 3 weeks.

        Major surgical procedure (including periodontal) within 4 weeks.

        Surgical or other non-healing wounds unrelated to KS.

        Pregnancy.

        Breast feeding.

        Past or present history of malignant tumors other than KS unless: a) in a complete
        remission for greater than or equal to 1 year from the time a response was first
        documented; b) completely resected basal cell carcinoma; or c) in situ squamous cell
        carcinoma of the cervix or anus.

        Evidence of a severe or life-threatening infection within 2 weeks of entry onto the study.

        A condition that would require the patient to receive intravenous antibiotics on a day of
        bevacizumab infusion.

        Need for chronic daily aspirin greater than or equal to 325 mg/daily or nonsteroidal
        medication interfering with platelet function.

        Therapeutic anticoagulation with international normalized ratio (INR) greater than 1.5,
        unless the patient is on full dose warfarin. If a patient is on full-dose anticoagulants,
        the following criteria should be met for enrollment:

        The subject must have an in-range INR (usually between 2 and 3) on a stable dose of
        warfarin or on stable dose of low molecular weight (LMW) heparin;

        The subject must not have active bleeding or pathological conditions that carry high risk
        of bleeding (e.g. tumor involving major vessels).

        History of deep venous or arterial thrombosis.

        History of gastrointestinal bleeding.

        Clinically significant cardiovascular disease such as uncontrolled hypertension (with
        systolic BP greater than 160 mm/Hg or diastolic blood pressure greater than 95 mm/Hg),
        unstable angina, New York Heart Association grade II or greater congestive heart failure,
        cardiac arrhythmia requiring medication, clinically significant peripheral artery disease,
        grade II or greater peripheral vascular disease, myocardial infarction.

        Substantial central nervous system (CNS) disease including history of CNS bleeding, mass
        lesions in the brain, uncontrolled seizure disorder, recent history of cerebrovascular
        accident (CVA) (e.g. within the past 6 months), history of transient ischemic attack (TIA)
        within the past 6 months..

        Coagulopathy.

        Patients with unstable bone fractures that are not stress/weight bearing able.

        Patients with any other abnormality that would be scored as a grade 3 toxicity, except
        lymphopenia, direct manifestations of KS, direct manifestation of HIV, direct manifestation
        of HIV therapy, hyperbilirubinemia associated with protease inhibitors, asymptomatic
        hyperuricemia.

        Previous intravenous immunoglobulin (IVIG) or monoclonal antibody therapy within 30 days
        prior to enrollment.

        Known hypersensitivity to bevacizumab.

        Known hypersensitivity to Chinese hamster ovary cell products.

        Known hypersensitivity to other recombinant human or humanized antibodies.

        Previous bevacizumab.

        Any condition that, in the opinion of the Principal Investigator or Study Chairperson,
        would preclude the inclusion of a patient onto this research study.