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
Study type: Interventional
Phase: Phase 2

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).
    

Detailed description: 
      Background:

        -  Standard treatment for advanced Kaposi's sarcoma (KS) is a liposomal anthracycline, plus
           antiretroviral therapy (HAART) in patients with human immunodeficiency virus (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 vascular endothelial growth factor
           (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 multigated acquisition scan (MUGA)

        -  Able to tolerate aspirin 81 mg

        -  systolic blood pressure (SBP) <150, diastolic blood pressure (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.
    

Intervention name(s): Liposomal Doxorubicin; Bevacizumab
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Doxil; Avastin
Intervention MeSH terms: Bevacizumab; Doxorubicin; Liposomal doxorubicin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Kaposi's Sarcoma; HIV; Doxil; VEGF; Bevacizumab