Bevacizumab to Treat Kaposi's Sarcoma in HIV-Positive and HIV-Negative Patients

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 study will examine the safety and effectiveness of the experimental drug bevacizumab for treating both non-acquired immune deficiency syndrome (AIDS) and AIDS-associated Kaposi's sarcoma (KS). KS tumors depend on the formation of new blood vessels for their growth. Bevacizumab is an antibody to a protein called vascular endothelial growth factor (VEGF) that is produced by the body and is involved in blood vessel growth. Bevacizumab may block the action of VEGF, and thus help shrink KS lesions.

Patients 18 years of age and older with Kaposi's sarcoma that is restricted to the skin and is not life threatening may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood and urine tests, electrocardiogram (EKG), chest x-ray, and, if needed, imaging studies to evaluate internal tumors.

Participants will receive bevacizumab intravenously (by vein) once a week for 2 weeks and then every 3 weeks at the National Institutes of Health (NIH) Clinical Center. The first infusion takes about 90 minutes, the second takes about 60 minutes, and subsequent infusions take about 30 minutes. Infusions may take longer, however, if the drug is better tolerated at a slower infusion rate. Patients will be evaluated with the following tests and procedures:

• Physical examination, assessment of drug side effects, measurement of KS lesions, and photographs of lesions once a week for the first 6 weeks of therapy, and then every 3 weeks.
• cluster of differentiation 4 (CD4) cell counts and human immunodeficiency virus (HIV) viral load in HIV-positive patients every 12 weeks.
• Biopsies of lesions: upon entering the study, at week 12, and at the time of a response of the tumor to therapy or at the end of treatment, if treatment ends at week 18 or later.
• Additional biopsies, if requested. (Additional biopsies are not required.)
• Other procedures, such as computed tomography (CT) or magnetic resonance imaging (MRI) scans, if medically indicated.

Patients may continue bevacizumab therapy indefinitely if they are benefiting from it, as long as they have no substantial toxicity or other conditions that would cause them to stop receiving it and the protocol remains open.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Kaposi's Sarcoma; HIV Seronegativity
• Intervention / Treatment: Biological: Bevacizumab

Detailed Description

BACKGROUND:

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.

OBJECTIVES:

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 treatment.

ELIGIBILITY:

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.

DESIGN:

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.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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 bilirubin:

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 milligram.

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.

EXCLUSION CRITERIA:

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.

Pregnancy.

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..

Coagulopathy.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Pts with HIV-associated Kaposi's Sarcoma; 15 mg/kg bevacizumab intravenously on days 1 and 8 then every 3 weeks.	Biological: Bevacizumab; 15 mg/kg day intravenously on day 1, day 8, then every 3 weeks.; Other Names: Avastin
Experimental: Cohort 2: Pts with classic Kaposi's Sarcoma (HIV-uninfected); 15 mg/kg bevacizumab intravenously on days 1 and 8 then every 3 weeks.	Biological: Bevacizumab; 15 mg/kg day intravenously on day 1, day 8, then every 3 weeks.; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	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.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	Here are the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module.	70 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Robert Yarchoan, M.D., National Cancer Institute, National Institutes of Health

Publications and helpful links

General Publications

• Uldrick TS, Wyvill KM, Kumar P, O'Mahony D, Bernstein W, Aleman K, Polizzotto MN, Steinberg SM, Pittaluga S, Marshall V, Whitby D, Little RF, Yarchoan R. Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. J Clin Oncol. 2012 May 1;30(13):1476-83. doi: 10.1200/JCO.2011.39.6853. Epub 2012 Mar 19.
• Uldrick T, Wyvill K, Kumar P, Bernstein W, O'Mahony D, Polizzotto M, Aleman K, Steinberg S, Pittaluga S, Little R, and Yarchoan R. A Phase II Study Targeting Vascular Endothelial Growth Factor with the Humanized Monoclonal Antibody Bevacizumab in the Treatment of Patients with HIV-Associated Kaposi Sarcoma. 17th Conference on Retroviruses and Opportunistic Infections. Oral Presentation. February 17, 2010.

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2003
• Primary Completion (Actual): March 15, 2010
• Study Completion (Actual): March 15, 2010

Study Registration Dates

• First Submitted: February 21, 2003
• First Submitted That Met QC Criteria: February 20, 2003
• First Posted (Estimate): February 21, 2003

Study Record Updates

• Last Update Posted (Actual): September 6, 2017
• Last Update Submitted That Met QC Criteria: August 7, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Cancer; Skin; Angiogenesis; HHV-8; KS; KSHV; Kaposi Sarcoma
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; DNA Virus Infections; Herpesviridae Infections; Neoplasms, Vascular Tissue; Sarcoma; Sarcoma, Kaposi; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 030110; 03-C-0110

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No