NCT00601991撤回2 期
A Multi-Center Phase 2 Study of Vascular Endothelial Growth Factor (VEGF) Trap as a Single Agent in Acute Myeloid Leukemia
适应症
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 主要终点
- Response rate of aflibercept
研究概览
简要总结
RATIONALE: Aflibercept may stop the growth of cancer cells by blocking blood flow to the cancer.
PURPOSE: This phase II trial is studying how well aflibercept works in treating patients with advanced refractory, relapsed, or untreated acute myeloid leukemia.
详细描述
OBJECTIVES:
Primary
- To determine the response rate to aflibercept as a single agent in adult patients with advanced refractory, relapsed, or untreated acute myeloid leukemia (AML).
- To determine the 3-month progression-free survival following treatment with at least 4 courses of aflibercept in these patients.
Secondary
- To determine if there is any correlation between pre-treatment expression of VEGFR1 or VEGFR2 by marrow myeloblasts and disease response to aflibercept.
- To determine if bone marrow microvessel density (MVD) pre-treatment correlates with disease response to aflibercept, and if any decrease in MVD following treatment correlates with changes in bone marrow blast percentage (disease response).
- To assess changes in circulating endothelial cells (CEC) and circulating endothelial progenitor cells (EPC) as pharmacodynamic markers of aflibercept activity and possible correlates of disease response to aflibercept.
- To measure blood levels of free VEGF versus VEGF bound by aflibercept post-treatment to determine if the chosen dose of aflibercept is sufficient to bind all detectable soluble VEGF in these patients.
- To characterize the population pharmacokinetics of aflibercept with its associated interpatient variability and to explore for demographic and clinical covariates.
- To derive individual estimates of the duration over which VEGF-saturating aflibercept concentrations were systematically present and to examine their distribution across the population.
- To explore the potential relationship between the systemic-free and bound aflibercept levels and safety and efficacy data.
研究设计
- 研究类型
- Interventional
- 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
- •DISEASE CHARACTERISTICS:
- •Acute myeloid leukemia (AML), as defined by WHO criteria and documented by morphologic examination of bone marrow aspirate and biopsy, including the following stages:
- •AML that is refractory to at least one course of induction chemotherapy
- •AML that has relapsed following one or more histologically documented complete remissions
- •Patients relapsing following chemotherapy alone, following autologous hematopoietic stem cell transplant, or following allogeneic hematopoietic stem cell transplant
- •Patients with untreated AML if they are felt not to be eligible for standard induction chemotherapy because of age or comorbidity
- •No CNS disease
- •PATIENT CHARACTERISTICS:
- •Inclusion criteria:
- •ECOG performance status 0-2
- •Life expectancy ≥ 60 days
- •AST/ALT ≤ 2.5 times upper limit of normal (ULN)
- •Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
- •Urine protein:creatinine ratio < 1 OR 24-hour urine protein < 500 mg
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception prior to, during, and for at least 6 months after completion of study therapy
排除标准
- •Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
- •Serious or nonhealing wound, ulcer, or bone fracture
- •History of allergic reactions attributed to compounds of similar chemical or biological composition to other agents used in the study
- •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of treatment
- •Clinically significant cardiovascular disease within the past 6 months, including any of the following:
- •History of cerebrovascular accident
- •Myocardial infarction, coronary artery bypass graft, or unstable angina
- •New York Heart Association class III-IV congestive heart failure or serious cardiac arrhythmia requiring medication
- •Clinically significant peripheral vascular disease
- •Pulmonary embolism, deep venous thrombosis, or other thromboembolic event
- •Uncontrolled hypertension, defined as BP > 150/100 mm Hg, or systolic BP > 180 mm Hg if diastolic blood pressure is < 90 mm Hg, on at least 2 repeated determinations on separate days within the past 3 months
- •Evidence of bleeding diathesis or coagulopathy
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
- •Significant traumatic injury within 28 days prior to day 1 of therapy
- •PRIOR CONCURRENT THERAPY:
- •Recovered from all therapy
- •At least 4 weeks since prior chemotherapy and radiotherapy
- •At least 4 weeks since prior FDA approved agents for treatment of myelodysplastic syndromes and/or AML, including lenalidomide and arsenic trioxide
- •No prior anti-VEGF, anti-VEGFR, or antiangiogenic agents (e.g., bevacizumab)
- •More than 28 days since prior major surgical procedure or open biopsy
- •More than 2 days since prior bone marrow aspirate/biopsy or central venous catheter placement
- •No anticipation of need for major surgical procedure during the study course
- •Full-dose anticoagulation (e.g., warfarin) with PT/INR > 1.5 allowed provided that both of the following criteria are met:
- •In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant
- •No active bleeding or pathological condition that carries a high risk of bleeding (e.g., known varices)
- •Prior and concurrent hydroxyurea allowed for blast control
- •Hydroxyurea must be discontinued no more than 24 hrs after the first dose of aflibercept
- •No HIV-positive patients on combination antiretroviral therapy
- •No other concurrent investigational agents
结局指标
主要结局
Response rate of aflibercept
时间窗: day 14 of cycle 4 (14-day cycle)
As determined by the International Working Group: Complete response: bone marrow blast(BMB) percentage (%) \<=5% of nucleated cells and no detectable extramedullary disease; Partial response: BMB \>5% but decreased by at least 50% pre-treatment (pre-tx) value OR extramedullary disease still present; Stable disease: BMB \>5% and decreased or increased by \<50% of pre-tx value and no new extramedullary disease; Progressive disease: BMB \>=20% and an increase of at least 50% of pre-tx value and/or appearance of at least 50% in circulating blasts
次要结局
- Progression-free survival in patients who achieve either a complete or partial response OR stable disease(at 12 weeks)
- Bone marrow microvessel density determination at baseline, after courses 2 and 4 of treatment(at baseline, at day 29 and at day 57)
- Pharmacokinetics of free versus bound VEGF Trap(Before and after 1st infusion on day 1, before infusion on day 1 of each 14-day cycle, and 60 days after last dose)
研究者
Stephen Strickland
Assistant Professor of Medicine; Hematologist/Oncologist
Vanderbilt-Ingram Cancer Center
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