Safety and Efficacy Study of PD-616 Plus Cytarabine to Treat Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Protocol RT12-US-AML-a is a 2-part, Phase 1/2, multi-center, open-label, dose-escalation study of PD-616 in combination with low-dose cytarabine in patients with AML or high-risk MDS not eligible for standard therapy. Part 1 of this study (Phase 1 portion) employs a sequential group-dose escalation design to determine the DLT and MTD of PD-616 in combination with low-dose cytarabine (primary objective). The safety and PK profiles as well as the preliminary efficacy of PD-616 in combination with cytarabine also will be examined (secondary objectives). Approximately 21 patients are planned to be enrolled in Part 1. After provision of written informed consent, patients are to be evaluated for study eligibility during the Screening period which should be within 14 days before the first day of study drug administration (Cycle 1, Day 1 \[C1D1\]; Baseline). Patients who are determined to be eligible, based on Screening assessments, will be enrolled in the study on C1D1, which is the first day of study drug administration. Part 2 of this study (Phase 2 portion) will commence with approval of the Safety Review Committee (SRC) after identification of the MTD, or if the MTD is not established, the maximum feasible dose has been evaluated in Part 1. Twelve additional patients will be enrolled and treated with PD-616 at the MTD (or other biologically relevant dose) in combination with low-dose cytarabine according to the same schedule as in Part 1. The safety profile, PK, and efficacy of the study drug combination will be further investigated in Part 2 of this study. Each cycle of treatment consists of a treatment period (D1 through D12) and a rest period (D13 through D28). During the treatment period, patients are required to return to the study center on D1 through D5 and D8 through D12 for study drug to be administered and evaluations to be performed. During the rest period, patients are required to return to the study center at least once a week for study evaluations. In addition, patients are required to be evaluated for peripheral blasts by flow cytometry in the last week of each cycle (D22 to D28) and to receive bone marrow examination in the last week (D22 to D28) of C1. Patients with evidence of complete response (CR) in peripheral blood by flow cytometry are to have a repeat bone marrow examination performed to confirm CR. All patients are to attend the Study Drug Discontinuation Visit within 3 days after discontinuing study drug. Thereafter, patients will enter the post-study period and be followed monthly (±3 days), starting 30±3 days after last study drug administration, through 1 year post-C1D1. During the post-study period, patients who discontinue for reasons other than progressive disease (PD) also will have follow-up blood samples collected for evaluation of changes in the percentage of blasts every month until PD or receipt of alternative therapy, whichever occurs first, up to 1 year post-C1D1. During the post-study period, patients with evidence of CR in peripheral blood by flow cytometry are to have a repeat bone marrow examination performed to confirm CR.