The purpose of this study is to describe the dose limiting toxicities (DLT) and define the maximum tolerated dose (MTD) of ASP2215 when combined with cytarabine/idarubicin or daunorubicin remission induction in a 7+3 schedule. Safety and tolerability of ASP2215 will also be evaluated. This study will also characterize the pharmacokinetics (PK) of ASP2215 when given in combination with cytarabine/idarubicin or cytarabine/daunorubicin remission induction and high-dose cytarabine (HiDAC) consolidation therapy in newly diagnosed acute myeloid leukemia as well as evaluate the effect of ASP2215 on the PK of cytarabine.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Oral
lyophilized powder administered intravenously
solution administered intravenously
solution administered intravenously
Site US10003
Los Angeles, California, United States
Site US10013
New Haven, Connecticut, United States
Site US10004
Chicago, Illinois, United States
Site US10009
Westwood, Kansas, United States
Site US10001
Baltimore, Maryland, United States
Site US10002
New York, New York, United States
Site US10014
Cleveland, Ohio, United States
Site US10019
Oklahoma City, Oklahoma, United States
Site US10006
Philadelphia, Pennsylvania, United States
Site US10010
San Antonio, Texas, United States
Safety and tolerability assessed by development of dose limiting toxicities, adverse events, and define maximum tolerated dose (MTD)
Time frame: up to 2.5 years after start of the treatment
Pharmacokinetics profile of ASP2215: AUC24, Cmax, Ctrough and tmax
Area under the curve at 24 hours (AUC24), maximum concentration (Cmax), minimum concentration (Ctrough), and time after dosing when Cmax occurs (tmax)
Time frame: Days 8, 11, 17, and 28 for remission induction and Days 1, 2, and 15 for consolidation
Pharmacokinetics of cytarabine: Css
Steady state concentration (Css)
Time frame: Days 3 and 8
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