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Phase II Study of Intravenous Recombinant Humanized Anti-Vascular Endothelial Cell Growth Factor Antibody (Bevacizumab) in Classical (HIV-Negative) and in AIDS-Associated Kaposi's Sarcoma

Phase 2
18 Years
Not Enrolling
Kaposi's Sarcoma, HIV Infections, HIV Seronegativity

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Trial Information

Phase II Study of Intravenous Recombinant Humanized Anti-Vascular Endothelial Cell Growth Factor Antibody (Bevacizumab) in Classical (HIV-Negative) and in AIDS-Associated Kaposi's Sarcoma


This is a phase II study to determine the activity of bevacizumab, a putative antiangiogenic
agent, in Kaposi's sarcoma (KS). Bevacizumab is a humanized recombinant antibody to vascular
endothelial cell growth factor (VEGF), an important cytokine in the pathogenesis of KS.


To assess the antitumor effect of bevacizumab 15 mg/kg administered intravenously once every
three weeks in patients with human immunodeficiency virus (HIV)-associated Kaposi's sarcoma
(KS). Other objectives include assessment of the antitumor effect of bevacizumab 15 mg/kg
administered intravenously once every three weeks in patients with classical KS; assessment
of the toxicity profile of bevacizumab in HIV-infected and HIV-negative patients with KS;
exploration in a preliminary fashion effect of bevacizumab on KS progression free survival;
and study of a number of biochemical parameters, including stromal cell-derived factor-1
(SDF-1) expression in KS lesions; human herpes virus-8 (HHV-8) viral load in peripheral
blood mononuclear cells; serum vascular endothelial growth factor (VEGF) levels over the
course of treatment; and changes in viral interleukin 6 (IL-6) levels over the course of


Key eligibility parameters include HIV-associated or classical Kaposi's sarcoma, age greater
than or equal to 18 years, and life expectancy greater than 6 months. Patients with HIV
infection must have either KS progression on a regimen of highly active antiretroviral
therapy (HAART) for at least one month, or no KS regression while on an optimized regimen of
HAART for 4 months or longer.


Patients will be sequentially enrolled, administered a loading dose of 15 mg/kg bevacizumab
intravenously on day 1, and then administered 15 mg/kg bevacizumab intravenously every 3
weeks beginning one week after the loading dose. The drug will be temporarily discontinued
for toxicity, intercurrent major surgical procedures, or other factors that would pose a
safety concern. Patients will undergo a biopsy of a KS lesion at entry, on cycle 4, day 21,
and at the time of a formal response or when the patient stops treatment. Patients will
undergo a number of other tests as well, including blood tests and non-invasive imaging
studies of KS lesions.

Inclusion Criteria


Age greater than or equal to 18 years.

Kaposi's sarcoma pathologically confirmed by Center for Cancer Research (CCR) pathology.

Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

Life expectancy greater than 6 months.

The following hematologic parameters:

- Hemoglobin greater than 9 g/dl;

- White blood cell (WBC) greater than 1000/mm^3;

- Absolute neutrophil count (ANC) greater than 750/mm^3;

- Platelets greater than 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.

The following hepatic parameters:

Bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) unless the
patient is receiving protease inhibitor therapy known to be associated with increased

in this case total bilirubin less than or equal to 7.5 mg/dl and the direct fraction less
than or equal to 0.7 mg/dl.

-Examples of protease inhibitors known to increase bilirubin levels include indinavir,
ritonavir, nelfinavir, and atazanavir.

Aspartate aminotransferase (AST)/glutamic oxaloacetic transaminase (GOT) less than or
equal to 2.5 times the upper limit of normal.

Either Serum creatinine less than or equal to 1.5 mg/dL or measured creatinine clearance
greater than or equal to 60 mL/min.

Either Urine protein less than 1+ or measured 24 hour urine protein less than 500

Blood pressure: systolic blood pressure (SBP) less than 160 mm/Hg; diastolic blood
pressure (DBP) less than 95 mm/Hg.

At least 5 assessable cutaneous lesions previously untreated by local therapy.

Patients with human immunodeficiency virus (HIV) infection must be willing to comply with
a regimen of highly active antiretroviral therapy and be on a regimen of highly active
antiretroviral therapy (HAART) selected for best potential efficacy for at least 1 month
with evidence of Kaposi sarcoma (KS) progression on the HAART regimen or be on a optimized
regimen of HAART for 4 months or longer with no evidence of KS regression.

Patients must be willing to use effective birth control.


Symptomatic, extensive pulmonary involvement.

Symptomatic visceral KS excluding the oral cavity.

Inability to provide informed consent.

Chemotherapy within 3 weeks.

Prior therapy with SU5416.

Supraphysiologic doses of corticosteroids within 3 weeks.

Major surgical procedure (including periodontal) within 4 weeks.

Surgical or other non-healing wounds unrelated to KS.


Breast feeding.

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.

Evidence of a severe or life-threatening infection within 2 weeks of entry onto the study.

A condition that would require the patient to receive intravenous antibiotics on a day of
bevacizumab infusion.

Need for chronic daily aspirin greater than or equal to 325 mg/daily or nonsteroidal
medication interfering with platelet function.

Therapeutic anticoagulation with international normalized ratio (INR) greater than 1.5,
unless the patient is on full dose warfarin. If a patient is on full-dose anticoagulants,
the following criteria should be met for enrollment:

The subject must have an in-range INR (usually between 2 and 3) on a stable dose of
warfarin or on stable dose of low molecular weight (LMW) heparin;

The subject must not have active bleeding or pathological conditions that carry high risk
of bleeding (e.g. tumor involving major vessels).

History of deep venous or arterial thrombosis.

History of gastrointestinal bleeding.

Clinically significant cardiovascular disease such as uncontrolled hypertension (with
systolic BP greater than 160 mm/Hg or diastolic blood pressure greater than 95 mm/Hg),
unstable angina, New York Heart Association grade II or greater congestive heart failure,
cardiac arrhythmia requiring medication, clinically significant peripheral artery disease,
grade II or greater peripheral vascular disease, myocardial infarction.

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), history of transient ischemic attack (TIA)
within the past 6 months..


Patients with unstable bone fractures that are not stress/weight bearing able.

Patients with any other abnormality that would be scored as a grade 3 toxicity, except
lymphopenia, direct manifestations of KS, direct manifestation of HIV, direct
manifestation of HIV therapy, hyperbilirubinemia associated with protease inhibitors,
asymptomatic hyperuricemia.

Previous intravenous immunoglobulin (IVIG) or monoclonal antibody therapy within 30 days
prior to enrollment.

Known hypersensitivity to bevacizumab.

Known hypersensitivity to Chinese hamster ovary cell products.

Known hypersensitivity to other recombinant human or humanized antibodies.

Previous bevacizumab.

Any condition that, in the opinion of the Principal Investigator or Study Chairperson,
would preclude the inclusion of a patient onto this research study.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response Rate

Outcome Description:

Percentage of participants with a complete response (CR) + partial response (PR)per the Modified AIDS Clinical Trial Group Criteria (ACTG) for HIV-KS. PR is a 50% decrease in the number and/or size of previously existing lesions for 4 weeks; or complete flattening of at least 50% of all previously raised lesions lasting for at least 4 weeks; or a 50% decrease in the sum of the products of the largest perpendicular diameters of the marker lesions lasting for at least 4 weeks; CR is the absence of any detectable residual disease, including tumor associated edema, persisting for at least 4 weeks.

Outcome Time Frame:

36 months

Safety Issue:


Principal Investigator

Robert Yarchoan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

February 2003

Completion Date:

March 2010

Related Keywords:

  • Kaposi's Sarcoma
  • HIV Infections
  • HIV Seronegativity
  • Angiogenesis
  • Cancer
  • HHV-8
  • KSHV
  • Skin
  • Kaposi Sarcoma
  • KS
  • HIV Infections
  • Acquired Immunodeficiency Syndrome
  • Sarcoma, Kaposi
  • Sarcoma



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