A Multi-Center Phase 2 Study of VEGF Trap as a Single Agent in Acute Myeloid Leukemia
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.
Biological: VEGF Trap
Procedure: Bone marrow biopsy
Procedure: bone marrow aspiration
|Study Design:||Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multi-Center Phase 2 Study of Vascular Endothelial Growth Factor (VEGF) Trap as a Single Agent in Acute Myeloid Leukemia|
- Response rate of aflibercept [ Time Frame: 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
- Bone marrow microvessel density determination at baseline, after courses 2 and 4 of treatment [ Time Frame: at baseline, at day 29 and at day 57 ]Density of microscopically small blood vessels in bone marrow biopsies
- Pharmacokinetics of free versus bound VEGF Trap [ Time Frame: Before and after 1st infusion on day 1, before infusion on day 1 of each 14-day cycle, and 60 days after last dose ]Blood levels of free VEGF Trap compared to bound VEGF trap to determine if the chosen level of VEGF Trap is sufficient to bind all detectable soluble VEGF in this group of patients
- Progression-free survival in patients who achieve either a complete or partial response OR stable disease [ Time Frame: at 12 weeks ]Patients who undergo a minimum of 4 cycles of treatment and who have either a complete or partial response to treatment or who have stable disease and who are free of progressive disease at 12 weeks
|Study Start Date:||March 2007|
|Study Completion Date:||October 2009|
|Estimated Primary Completion Date:||March 2009 (Final data collection date for primary outcome measure)|
Biological: VEGF Trap
- 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.
- 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.
OUTLINE: This is a multicenter study.
Patients receive aflibercept IV over 1 hour on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo bone marrow and blood sample collection periodically for pharmacokinetic/pharmacodynamic studies. Samples are analyzed for peak plasma-free aflibercept levels after the first infusion, trough plasma-free and bound aflibercept levels prior to each subsequent infusion and 60 days after the last infusion, and anti-aflibercept antibody via ELISA methods; circulating endothelial cells (CEC's) via ELISA and flow cytometry to determine if there is correlation between changes in circulating endothelial cells and changes in bone marrow blast percentage (i.e., disease response); myeloblast expression of VEGFR-1 and VRGFR-2 via immunohistochemistry (IHC); endothelial progenitor cells colony forming units (EPC-CFU's) to determine via in situ staining if changes in circulating endothelial progenitors following treatment with aflibercept correlates with disease response, and if there is a subpopulation of patients identified by pre-treatment circulating EPC-CFU's that may benefit from aflibercept; and bone marrow microvessel density (MVD) determination via immunohistochemistry.
After completion of study treatment, patients are followed for 60 days.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00601991
|Principal Investigator:||Stephen Strickland, MD||Vanderbilt-Ingram Cancer Center|