Phase 2 Study of the Anti-Angiogenesis Agent AG-013736 in Patients with Poor Prognosis Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

Background: AG-013736 is a potent and selective inhibitor of VEGF, PDGF and cKit receptor tyrosine kinases with broad preclinical activity in solid tumors and an AML model. To investigate the anti-leukemic effects of AG-013736 in patients with poor prognosis AML and MDS, we performed a multicenter Phase II Trial.

Methods: Eligible patients (pts) had poor prognosis AML (defined as age of pt ≥65 years, secondary AML, or unfavorable cytogenetics) or poor prognosis MDS (defined as ≥10% myeloblasts in marrow or blood). A 2-stage Simon design was employed with an “unimportant” response rate set at 10% and an “important” rate at 30%. The α and β rates were set at 0.1 with 1 response (complete or partial) in 11 pts in the first stage required before proceeding to the second stage. A successful trial required at least 5 responses in 25 pts. AG-013736 was dosed orally at 5 mg twice a day. Marrow and blood samples were taken for various markers of angiogenesis and microvessel density.

Results: 12 pts (8 AML; 4 MDS) were enrolled including 1 pt who replaced a patient who was withdrawn for lack of compliance after 1 dose. Average age was 77 (range 58–88) years; 7 men, 5 women; 10 white and 2 Asian. All pts were ECOG performance status 0 (5 pts) or 1 (7). 8 pts required blood and 9 platelet transfusions. 8 pts discontinued for lack of efficacy, 3 for non-compliance, and 1 for refusal to participate further. AG-013736-related Grade 3 and 4 adverse events (AEs) included hypertension or blood pressure (BP) elevation (4), mucosal inflammation (1), and deep vein thrombosis (1). Common (>10%) mild-moderate AEs included hoarseness (8 pts), diarrhea (5), BP increased or hypertension (4), proteinuria (3), and mucosal inflammation (2). 9 (75%) pts required at least 1 antihypertensive medication. There were no responses, and therefore enrollment was stopped at 12 patients. Patients received study drug for a median of 53 (range 1–190) days, and 2 pts, one with AML and one with MDS, had stable disease for 132 and 190 days, respectively. Treatment-related changes in biomarkers are being assessed.

Conclusion: AG-013736 was generally well tolerated in this small cohort of elderly pts, 2 of whom had stable disease of significant duration. The combination of AG-013736 with other targeted therapies or cytotoxic agents appears feasible and may be warranted in future studies in patients with poor prognosis AML/MDS.