Pilot Study of Liposomal Doxorubicin Combined With Bevacizumab Followed by Bevacizumab Monotherapy in Adults With Advanced Kaposi s Sarcoma
Condition: Sarcoma, Kaposi
MeSH terms: Sarcoma, Kaposi; Sarcoma
Intervention: Liposomal Doxorubicin; Bevacizumab
Intervention description: Induction phase dose: Intravenous (IV) bevacizumab 15 mg/kg once, followed 7 days later by liposomal doxorubicin mg/m^2 and bevacizumab every 3 weeks for six cycles.; Induction phase dose: Intravenous (IV) bevacizumab 15 mg/kg once, followed 7 days later by liposomal doxorubicin mg/m^2 and bevacizumab every 3 weeks for six cycles. Maintenance phase dose: IV bevacizumab every 3 weeks for 11 cycles.
Intervention MeSH terms: Bevacizumab; Doxorubicin; Liposomal doxorubicin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Kaposi's Sarcoma; HIV; Doxil; VEGF; Bevacizumab

Summary:

      Background:

        -  The drug liposomal doxorubicin is approved by the U.S. Food and Drug Administration
           (FDA) for the treatment of Kaposi's sarcoma (KS). A second drug, bevacizumab, is a
           biologic agent (such as antibodies, interleukins, and vaccines) that stops abnormal
           blood supply to tumors. Bevacizumab is approved by the FDA, in combination with other
           drugs, for the treatment of breast cancer, colon cancer, and lung cancer.

        -  Researchers are now studying the combination of liposomal doxorubicin with bevacizumab
           as a novel approach to the treatment of advanced KS. Researches will be measuring KS
           tumor responses to this combination to determine whether the drugs might have anti-KS
           activity.

      Objectives:

        -  To estimate the overall response rate (ORR) of six cycles of liposomal doxorubicin
           combined with bevacizumab in patients with advanced KS.

        -  To evaluate the safety of the regimen and to estimate the complete response rate after
           six cycles, the median number of cycles needed to obtain a partial response, and the
           12-month progression-free survival.

      Eligibility:

        -  Patients 18 years or older with relatively severe acquired immune deficiency syndrome
           (AIDS)-related KS or patients with KS unrelated to AIDS or human immunodeficiency virus
           (HIV) infection, whose KS that can be evaluated for potential response to therapy and
           meet a number of other criteria.

        -  Women who are pregnant or breastfeeding are not eligible.

        -  Other ineligibility criteria include surgery within 4 weeks, chemotherapy within 3
           weeks, heart disease, hemoptysis (coughing up blood), or gastrointestinal bleeding.

      Design:

        -  Researchers will conduct the following tests before the start of the study:

        -  Physical examination and a detailed medical history.

        -  A biopsy.

        -  Blood and urine tests.

        -  Treatment will include two phases, an induction phase and a maintenance phase:

        -  Induction phase dose: Intravenous (IV) bevacizumab 15 mg/kg once, followed 7 days later
           by liposomal doxorubicin mg/m2 and bevacizumab every 3 weeks for six cycles.

      Maintenance phase dose: IV bevacizumab every 3 weeks for 11 cycles.

        -  Monitoring will include a review of side effects, physical exam (including blood
           pressure), and blood and urine samples; following the induction phase, the patient will
           receive a multi gated acquisition scan and electrocardiography (EKG) to record
           electrical activity in the heart.

        -  Research tests include blood and saliva samples, additional biopsies (optional), and
           noninvasive imaging.

        -  Treatment is stopped if any of the following occur: completion of 1 year of therapy,
           progressive KS, patient preference, or unacceptable toxicity.

        -  Post-treatment evaluations include clinic visits every 3 months or as needed up to 2
           years, and blood and saliva samples (for research).
    

Eligibility criteria:

        -INCLUSION CRITERIA:

          1. Age greater than or equal to 18 years

          2. Kaposi s sarcoma pathologically confirmed by Center for Cancer Research (CCR)
             pathology

          3. Evaluable Kaposi's sarcoma (KS) involving the skin and/or viscera, including at least
             one of the following:

               -  KS of the skin with greater than or equal to 5 KS lesions that are evaluable by
                  non-invasive methods that have not been treated with local therapeutic modalities

               -  Pulmonary KS evaluable by computed tomography (CT) scan

               -  Gastrointestinal KS evaluable by direct visualization or fiberoptic
                  instrumentation

               -  Biopsy proven lymph node involvement measurable by CT scan

          4. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

          5. Life expectancy > 6 months

          6. At least one of the following indications for therapy:

               -  Pulmonary involvement

               -  Visceral involvement

               -  Pain

               -  Edema

               -  Substantial lymph node involvement

               -  Ulcerating lesions

               -  Decreased range of joint motion due to KS

               -  Multiple lesions not amenable to local therapy

               -  Significant psychological impact leading to social withdrawal

          7. Patients with human immunodeficiency virus (HIV) infection must be willing to comply
             with a regimen of highly active antiretroviral therapy (HAART).

          8. Patients may have received any number of prior therapies, including monotherapy with
             liposomal doxorubicin or bevacizumab

          9. Blood pressure

               -  Systolic blood pressure (SBP) < 150 mm/Hg

               -  Diastolic blood pressure (DBP) < 90 mm/Hg

               -  Patients receiving anti-hypertensive medicines must be on a stable regimen for at
                  least 1 month

         10. Ejection fraction (EF) > 50% by multigated acquisition scan (MUGA)

         11. The following hematologic parameters:

               -  Hemoglobin > 9 g/dl

               -  White blood cell (WBC) > 1000/mm(3)

               -  Absolute neutrophil count (ANC) > 750/mm(3)

               -  Platelets > 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

         12. The following hepatic parameters:

               -  Bilirubin less than or equal to 1.5 times upper limit of normal (ULN) unless the
                  patient is receiving protease inhibitor therapy (i.e. indinavir, ritonavir,
                  nelfinavir, and atazanavir) 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
                  is less than or equal to 0.7 mg/dl.

               -  Aspartate aminotransferase (AST)/glutamic oxaloacetic transaminase (GOT) less
                  than or equal to 2.5 times the upper limit of normal

         13. Either serum creatinine less than or equal to 1.5 mg/dL or measured creatinine
             clearance greater than or equal to 60 mL/min

         14. Either urine protein <1+ or measured 24 hour urine protein < 500 milligram

         15. Able to take aspirin 81mg daily.

         16. Study participant must use birth control measure prior to study entry (during
             screening), during study participation, and for 12 weeks after bevacizumab is
             discontinued.

         17. Inclusion of women and minorities: Both men and women and members of all races and
             ethnic groups are eligible for this trial.

        EXCLUSION CRITERIA:

          1. Inability to provide informed consent.

          2. KS therapy other than HAART within 3 weeks.

          3. History of cumulative doxorubicin or liposomal doxorubicin dose >430 mg/m(2).

          4. Supraphysiologic doses of corticosteroids within 3 weeks.

          5. Major surgical procedure (including periodontal) within 4 weeks.

          6. Surgical or other non-healing wounds, other than KS ulcers.

          7. Pregnancy (because of unknown potential for fetal malformation).

          8. Breast feeding (because of unknown potential for adverse infant developmental
             consequences).

          9. Has an uncontrolled illness including, but not limited to, ongoing or active infection
             requiring intravenous (IV) antibiotics, symptomatic congestive heart failure, unstable
             angina pectoris, cardiac arrhythmia, cirrhosis, or psychiatric illness/social
             situations that would limit adherence to study requirements.

         10. 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

         11. Severe or life-threatening infection within 2 weeks of entry onto the study.

         12. History of deep venous or arterial thrombotic disease (including but not limited to,
             acute myocardial infarction due to coronary thrombosis, ischemic stroke, and
             peripheral arterial disease), unless:

               -  Line-related thrombosis without embolus

               -  Occurring greater than or equal to 1 year prior to screening

         13. Known procoagulant disorder including prothrombin gene mutation 20210, antithrombin
             III deficiency, protein c deficiency, protein S deficiency and antiphospholipid
             syndrome but not including heterozygosity for the Factor V Leiden mutation or the
             presence of a lupus anticoagulant in the absence of other criteria for the
             antiphospholipid syndrome.

         14. Known bleeding diathesis.

         15. History of severe gastrointestinal bleeding within 6 months. Patients with
             gastrointestinal blood loss due to KS may be included.

         16. Hemoptysis within 4 weeks.

         17. 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).

         18. Proteinuria > 500 mg/24hrs.

         19. Patients with any other abnormality that would be scored as a grade 3 or greater
             toxicity, except:

               -  Lymphopenia

               -  Direct manifestations of KS

               -  Direct manifestation of HIV

               -  Direct manifestation of HIV therapy (i.e. Hyperbilirubinemia associated with
                  protease inhibitors)

               -  Asymptomatic hyperuricemia

               -  Hypophosphatemia

         20. Previous bevacizumab within 6 weeks prior to enrollment.

         21. Known hypersensitivity to bevacizumab, Chinese hamster ovary cell products, or other
             recombinant human or humanized antibodies.

         22. Any other condition, including the presence of laboratory abnormalities, which in the
             opinion of the Principal Investigator or Lead Associate Investigator, places the
             subject at unacceptable risk if there were to participate in the study or confounds
             the ability to interpret data from the study.