A Phase 1 Study of ASP2215 in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia

Brief Summary

Detailed Description

This is a four-part trial. In Part 1, subjects will be enrolled to successive cohorts to determine the maximum tolerated dose (MTD). Dose escalation decision will be made based on DLTs that occur after the first dose of ASP2215 during remission induction. The treatment will consist of three distinct periods: remission induction, consolidation and maintenance. In Part 2, subjects will be enrolled into an expansion cohort. Subjects will receive ASP2215 at the MTD established in Part 1 or recommended expansion dose, and will also receive remission induction, consolidation and maintenance therapy. The DLT observation period during the expansion cohort will be from the start of dosing of ASP2215 during the first remission induction treatment until Day 21 of the first consolidation cycle or before the start of the second consolidation cycle, whichever is sooner; as well as from the start of maintenance treatment until Day 28 of the second maintenance cycle. If testing at a dose level must be stopped, then a lower dose may be tested for remaining subjects to be enrolled. In Part 3, two cohorts will be enrolled to evaluate an alternative anthracycline and ASP2215 schedule. During remission induction, ASP2215 dosing will begin at day 8 and continue for 14 days to day 21. Subjects will be hospitalized during remission induction therapy while receiving chemotherapy. In cohort 3A, some subjects will be enrolled to receive 7+3 regimen consisting of cytarabine and an alternative antracycline, daunorubicin. During remission induction subjects will receive a 7+3 induction regimen consisting of daunorubicin IV infusion on days 1 through 3 and cytarabine as a continuous infusion on days 1 through 7. In cohort 3B, some subjects will be enrolled to receive 7+3 regimen consisting of cytarabine and idarubicin at an alternative dosing schedule for ASP2215 during remission induction. During remission induction subjects will receive a 7+3 induction regimen consisting of idarubicin by IV infusion on days 1 through 3 and cytarabine as a continuous infusion on days 1 through 7. For Part 3, if day 21 bone marrow evaluation shows residual blasts and the bone marrow is not aplastic, a second induction cycle with the same regimen will be given starting at least 7 days after last dose of ASP2215 and no later than day 35 of the first induction cycle. Consolidation and Maintenance therapy follow the same schedule and dosage outlined in Part 1.The DLT observation period for dose escalation decisions will be from the start of ASP2215 administration during the first remission induction treatment until day 42 of the last remission induction treatment cycle or before the start of the first consolidation cycle, whichever is sooner. A subject that receives less than 80% of the intended dose of any of the study drugs during the remission induction period may be replaced. Part 3 may be expanded for additional subjects to ensure at least some subjects are FLT3 + in each of the Alternative Anthracycline and Schedule Cohorts. In Part 4, the effect of continuous ASP2215 exposure during consolidation will be evaluated. During remission induction, subjects will receive a 7+3 induction regimen consisting of daunorubicin on days 1 through 3 and cytarabine as a continuous infusion on days 1 through 7. ASP2215 will be given at the designated dose, once daily starting on day 8, and continued for 14 days until day 21. If day 21 bone marrow evaluation shows residual blasts and the bone marrow is not aplastic, a second induction cycle with the same regimen will be given starting at least 7 days after last dose of ASP2215 and no later than day 35 of the first induction cycle. Consolidation therapy will follow the same schedule and dosage outlined in Part 1 except for the ASP2215 schedule. ASP2215 will be given at the designated dose, once daily starting on day 1 up to day 56, which is the maximum number of days between each consolidation cycle. Subjects may participate in up to 3 consolidation cycles. Maintenance therapy and posttreatment will also follow the same schedule and dosage outlined in Part 1. The DLT observation period will be during the first consolidation cycle only. This will be from the start of ASP2215 administration (consolidation cycle 1 day 1) until consolidation cycle 1 day 56 or the next chemotherapy cycle, whichever is sooner.

Primary Outcomes

Secondary Outcomes

• Pharmacokinetics profile of ASP2215: AUC24, Cmax, Ctrough and tmax(Days 8, 11, 17, and 28 for remission induction and Days 1, 2, and 15 for consolidation)
• Pharmacokinetics of cytarabine: Css(Days 3 and 8)