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

Phase 2
18 Years
Open (Enrolling)
Sarcoma, Kaposi

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Trial Information

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


- 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.


- 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.


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 gastrointestinal bleeding, unless caused by KS

- Pregnancy or breast feeding


- 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.

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

- 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

- Pulmonary KS evaluable by CT scan

- Gastrointestinal KS evaluable by direct visualization or fiberoptic

- 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

-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

17. Inclusion of women and minorities: Both men and women and members of all races and
ethnic groups are eligible for this trial.


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

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 withouth 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 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

- 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 ther were to participate in the study or confounds
the ability to interpret data from the study.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Primary objective is to estaimate the overall response rate (ORR) of six cycles of liposomal doxorubicin combined with bevacizumab in patients with advanced KS.

Principal Investigator

Robert Yarchoan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

April 2009

Completion Date:

March 2014

Related Keywords:

  • Sarcoma, Kaposi
  • Kaposi's Sarcoma
  • HIV
  • Doxil
  • VEGF
  • Bevacizumab
  • Kaposi Sarcoma
  • Sarcoma, Kaposi
  • Sarcoma



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892