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Pilot Study of Liposomal Doxorubicin Combined With Bevacizumab Followed by Bevacizumab Monotherapy in Adults With Advanced Kaposi s Sarcoma

NCT00923936

Description:

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).

Related Conditions:
  • Kaposi Sarcoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Pilot Study of <span class="go-doc-concept go-doc-intervention">Liposomal Doxorubicin</span> Combined With <span class="go-doc-concept go-doc-intervention">Bevacizumab</span> Followed by <span class="go-doc-concept go-doc-intervention">Bevacizumab</span> Monotherapy in Adults With Advanced Kaposi s Sarcoma

Title

  • Brief Title: Pilot Study of Liposomal Doxorubicin Combined With Bevacizumab Followed by Bevacizumab Monotherapy in Adults With Advanced Kaposi s Sarcoma
  • Official Title: Pilot Study of Liposomal Doxorubicin Combined With Bevacizumab Followed by Bevacizumab Monotherapy in Adults With Advanced Kaposi s Sarcoma
  • Clinical Trial IDs

    NCT ID: NCT00923936

    NCT Alias ID: NCT00902239

    ORG ID: 090130

    NCI ID: 09-C-0130

    Trial Conditions

    Sarcoma, Kaposi

    Trial Interventions

    Drug Synonyms Arms
    Liposomal Doxorubicin 2, 1
    Bevacizumab 2, 1

    Trial Purpose

    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 AIDS-related KS or patients with KS
    unrelated to AIDS or 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).

    Detailed Description

    Background:

    - Standard treatment for advanced Kaposi s sarcoma (KS) is a liposomal anthracycline,
    plus antiretroviral therapy (HAART) in patients with HIV.

    - KS is not curable and relapses are common. Prolonged use of liposomal anthracyclines
    with cumulative dosing exceeding 550 mg/m(2) is frequently required.

    - KS is notable for pathogenic autocrine and paracrine VEGF signaling. The monoclonal
    antibody, bevacizumab is a rational agent for the treatment of KS.

    - Preliminary results from our phase II study of bevacizumab monotherapy, 03-C0110,
    suggest that bevacizumab has promising activity in the treatment of KS.

    - The combination of anti-angiogenic therapy with cytotoxic chemotherapy has been a
    successful strategy in KS as well as other solid tumors.

    - This pilot study will evaluate the activity and safety of liposomal doxorubicin
    combined with bevacizumab followed by bevacizumab maintenance in patients with advanced
    KS. A goal of this combination strategy is to develop a tolerable and highly active
    regimen that would limit the need for prolonged anthracycline use.

    Objectives:

    - The primary objective is to estimate the overall response rate (ORR) of six cycles of
    liposomal doxorubicin combined with bevacizumab in patients with advanced KS.

    - Secondary objectives include evaluation of the safety of the regimen, as well as
    estimation of the complete response rate after 6 cycles, the median number of cycles
    need to obtain a partial response, and 12-month progression-free survival.

    Eligibility:

    Inclusion criteria:

    - Age greater than or equal to 18

    - Biopsy proven KS

    - Indication for chemotherapy

    - Any HIV status

    - Normal MUGA

    - Able to tolerate aspirin 81 mg

    - SBP < 150, DBP < 90

    - Urine protein < 1+ or 500mg/24hrs

    Exclusion Criteria:

    - Surgery within 4 weeks

    - Thrombo-embolic disease

    - Chemotherapy within 3 weeks

    - Hemoptysis or severe gastrointestinal bleeding, unless caused by KS

    - Pregnancy or breast feeding

    Design:

    - This is an open label, single center pilot with 2 cohorts. Cohort 1: HIV negative, HIV
    infected with stable KS despite 1 year of HAART with HIV viremic control, or HIV
    infected with progressive KS despite 4 months of HAART with HIV viremic control.
    Cohort 2: All other patients with advanced AIDS-associated KS.

    - Subjects will receive bevacizumab 15 mg/kg and liposomal doxorubicin 20 mg/m(2) every 3
    weeks until complete response (CR) or a maximum of 6 cycles. Those with stable disease
    or better will continue on bevacizumab 15 mg/kg monotherapy every 3 weeks for 11
    cycles. HIV infected subjects will receive HAART.

    - ORR will be calculated with 80% CI for each cohort separately. If estimates in the two
    cohorts are similar (p> 0.30 by a Fisher s exact test), they may be combined to form
    a somewhat more precise estimate of ORR after 6 cycles of treatment.

    - A total of 10 evaluable patients will be accrued in each cohort.

    Trial Arms

    Name Type Description Interventions
    1 Active Comparator HIV Negative, HIV infected with Stable KS or HIV infected with progressive KS Liposomal Doxorubicin, Bevacizumab
    2 Active Comparator All other patients with advanced AIDS-associated KS Liposomal Doxorubicin, Bevacizumab

    Eligibility Criteria

    -INCLUSION CRITERIA:

    1. Age greater than or equal to 18 years

    2. Kaposi s sarcoma pathologically confirmed by CCR pathology

    3. Evaluable 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 CT scan

    - Gastrointestinal KS evaluable by direct visualization or fiberoptic
    instrumentation

    - Biopsy proven lymph node involvement measurable by CT scan

    4. 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 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

    - SBP < 150 mm/Hg

    - DBP < 90 mm/Hg

    - Patients receiving anti-hypertensive medicines must be on a stable regimen for
    at least 1 month

    10. EF > 50% by MUGA

    11. The following hematologic parameters:

    - Hemoglobin > 9 g/dl

    - WBC > 1000/mm(3)

    - ANC > 750/mm(3)

    - Platelets > 75,000/mm(3)

    - PT and 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 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.

    - AST/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 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 hembolus

    - 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 CNS disease including.

    - History of CNS bleeding.

    - Mass lesions in the brain.

    - Uncontrolled seizure disorder.

    - Recent history of 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Estimate the overall response rate (ORR) of six cycles of liposomal doxorubicin combined with bevacizumab in patients with advanced KS.

    Secondary Outcome Measures

    Evaluation of the safety of the regimen, as well as estimation of the complete response rate after 6 cycles, the median number of cycles need to obtain a partial response, and 12- month progression-free survival.

    Trial Keywords

    Kaposi's Sarcoma

    HIV

    Doxil

    VEGF

    Bevacizumab

    Kaposi Sarcoma