A Multi-Center Phase 2 Study of Vascular Endothelial Growth Factor (VEGF) Trap as a Single Agent in Acute Myeloid Leukemia
- 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
- 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.
Masking: Open Label, Primary Purpose: Treatment
Response rate of aflibercept
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
day 14 of cycle 4 (14-day cycle)
Stephen Strickland, MD
Vanderbilt-Ingram Cancer Center
United States: Food and Drug Administration
VICC HEM 0652