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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Response Rate
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •Symptomatic, extensive pulmonary involvement.
- •Symptomatic visceral KS excluding the oral cavity.
- •Inability to provide informed consent.
- •Chemotherapy within 3 weeks.
- •Prior therapy with SU
- •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..
- •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.
研究组 & 干预措施
Cohort 2: Pts with classic Kaposi's Sarcoma (HIV-uninfected)
15 mg/kg bevacizumab intravenously on days 1 and 8 then every 3 weeks.
干预措施: Bevacizumab (Biological)
Cohort 1: Pts with HIV-associated Kaposi's Sarcoma
15 mg/kg bevacizumab intravenously on days 1 and 8 then every 3 weeks.
干预措施: Bevacizumab (Biological)
结局指标
主要结局
Response Rate
时间窗: 36 months
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.
次要结局
- Number of Participants With Adverse Events(70 months)
研究者
Robert Yarchoan
Principal Investigator
National Institutes of Health Clinical Center (CC)