Phase I/II Study of PR104, a Bioreductive Prodrug, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) Using Patient-Specific Adaptive Dose Selection

Abstract Abstract 1523 Background: The pre-prodrug PR104 is rapidly converted systemically to its alcohol metabolite PR-104A, a bioreductive prodrug that undergoes metabolic activation to DNA-crosslinking nitrogen mustard metabolites. This activation is catalysed by hypoxia-dependent reductases, and also by aldo-keto reductase 1C3 (AKR1C3) independently of hypoxia. Impressive in vivo activity in AML mouse models and evidence of hypoxia in leukemia infiltrated bone marrow (Benito et al, PLoS One, in press), AKR1C3 expression in AML blast cells (Birtwistle et al., Mutat Res 2009; 662: 67) and the observation of dose-limiting myelotoxicity in solid tumor phase 1 studies (Jameson et al., Cancer Chemother Pharmacol 2010; 65: 791) served as the rationale for this study. Methods: Patients (pts) with relapsed/refractory AML after 1 or 2 prior treatments received PR104 as a 1-hour intravenous infusion q 2 wks for up to 3 cycles with response and toxicity assessed by day 42. Pts who did not achieve a complete remission (CR) by day 42 were removed from the study. Patient-specific doses were assigned using an adaptive dose selection method (Thall et al., Biometrics 2008;64: 1126) based on age, 1 vs 2 prior treatments, and first CR duration of Results: To date, 25 pts, median age 57 yrs (range, 20–75) have received PR104. 68% had 2 prior treatments and 88% had a first CR duration of 1 year and became platelet transfusion independent at month 6. The second pt with a CRp was removed from study on day 43 and underwent allogeneic stem cell transplant. No responses were seen in the 8 patients given PR104 at doses Conclusions: PR104 administered at doses 3 to 4× the solid tumor MTD is well tolerated in pts with relapsed/refractory AML. Myelosuppression, primarily neutropenia and thrombocytopenia, can be prolonged at doses ≥3 gm/m2. Hypoxia appears to be a prevalent feature of the leukemic microenvironment. Evidence of activity at doses of 3 or 4 gm/m2 support continued evaluation of this regimen in AML and consideration for use in pts considered for stem cell transplant. Disclosures: Melink: Proacta: Employment, Equity Ownership. Gutheil: Proacta: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.