Clinical trial NCT00923936: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sarcoma, Kaposi
Keywords: Kaposi's Sarcoma
HIV
Doxil
VEGF
Bevacizumab
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2009-06-18
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Primary outcomes:
measure: Overall Response Rate (ORR) of Six Cycles of Liposomal Doxorubicin Combined With Bevacizumab in Patients With Advanced KS.
timeFrame: 6 cycles, an average of 18 weeks
Secondary outcomes:
measure: Complete Response Rate After 6 Cycles of Liposomal Doxorubicin Combined With Bevacizumab
timeFrame: 6 cycles, an average of 18 weeks
measure: Count of Participants With Serious and Non-serious Adverse Events
timeFrame: 7 years and 6 months and 21 days
measure: Median Number of Cycles Need to Obtain a Partial Response
timeFrame: 6 cycles, an average of 18 weeks
measure: Percentage of Participants With 12- Month Progression-free Survival (PFS)
timeFrame: 12 months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Robert Yarchoan, M.D.
role: PRINCIPAL_INVESTIGATOR
References: