The objectives of this study are to determine the safety and tolerability of ASP2215 as well as the maximum tolerated dose (MTD) based on the onset of dose limiting toxicity (DLT) and/or determine the recommended dose (RD) of ASP2215 for the next phase in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML).
This study will be conducted to determine the safety, tolerability, PK, PD, and efficacy of single and repeated oral dosing of ASP2215 once daily in patients with relapsed or refractory AML. After the determination of the MTD and/or RD, an expansion cohort might be set to further investigate the safety and efficacy of ASP2215. This study will consist of a single-dose period (Cycle 0, 2 days) and a repeated-dose period (Cycle 1 and subsequent cycles, each cycle consisting of 28 days). The enrolled subjects will orally receive their assigned single dose in Cycle 0 (Day -2), followed by a 2-day observation period (dosing day inclusive). In Cycle 1 and subsequent cycles (one cycle is defined as 28 days), the subjects will receive oral ASP2215 once daily repeatedly until one of the discontinuation criteria is met. Another dosing regimen may be considered such as dosing twice daily based on the safety and PK data that will become available. In this study, the Bayesian-Continual Reassessment Method (hereinafter, Bayesian-CRM) will be used as a reference for dose-escalation procedures, and based on the onset of DLTs, the RD level of the subsequent cohort will be set higher or lower. DLTs will be assessed during Cycle 0 and Cycle 1 (30 days). ASP2215 may be escalated by one dose level if the subject meets the criteria at the end of each cycle after Cycle 1 and the investigator/sub-investigator judges escalation of ASP2215 is of clinical benefit. Dose reduction of ASP2215 will be considered if study drug-related toxicities are observed in a subject.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
oral
Site JP00002
Aichi, Japan
Site JP00003
Fukuoka, Japan
Site JP00001
Gunma, Japan
Site JP00004
Tokyo, Japan
Site JP00005
Tokyo, Japan
Safety and Tolerability assessed through adverse events to determine maximum tolerated dose
Time frame: Up to 17 months
Response Rate
Response Rate includes following parameters; CR rate, composite CR \[CR + CRp + CRi\] rate, overall response rate \[CRc + PR\], duration of response
Time frame: Up to 16 months
Pharmacokinetics of ASP2215 in plasma: AUCinf
Area under the concentration-time curve from the time of dosing extrapolated to time infinity
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUClast
Area under the concentration-time curve from the time of dosing to the last measurable concentration
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUC24
Area under the plasma concentration time curve from time 0 to 24 hours
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUC48
Area under the plasma concentration time curve from time 0 to 48 hours
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: Cmax
Maximum concentration
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: C24
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Concentration at 24 hours
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: CLF
Oral clearance
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Lambda z
Terminal first order elimination rate constant
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215: tmax
Time to attain Cmax
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: t1/2
Apparent terminal elimination half-life
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: Vz/F
Apparent volume of distribution during the terminal elimination phase after oral dosing
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in plasma: AUCtau
Area under the plasma concentration time curve during a dosing interval
Time frame: Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: PTR
Peak-trough ratio
Time frame: Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Rac(AUC)
Accumulation ratio calculated using the area under the concentration-time curve
Time frame: Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Rac(Cmax)
Accumulation ratio calculated using the maximum concentration
Time frame: Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Rac derived t1/2
t1/2 derived from accumulation index
Time frame: Cycle 1 Day 28
Pharmacokinetics of ASP2215 in plasma: Ctrough
Plasma trough concentration
Time frame: Cycle 1 Day 8, Day 15, Day 22, Day 28 and Day 29
Pharmacokinetics of ASP2215 in urine: Ae24
Amount of drug excreted in urine from time 0 to 24 hours
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: Ae48
Amount of drug excreted in urine from time 0 to 48 hours
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: Ae24%
Fraction of drug excreted into urine from time 0 to 24 hours as % of dose
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: Ae48%
Fraction of drug excreted into urine from time 0 to 48 hours as % of dose
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1
Pharmacokinetics of ASP2215 in urine: CLR
Renal clearance
Time frame: Cycle 0 Day -2 through Cycle 1 Day 1 and Cycle 1 Day 28
Pharmacokinetics of ASP2215 in urine: Aetau
Amount of drug excreted in urine during a dosing interval
Time frame: Cycle 1 Day 28
Pharmacokinetics of ASP2215 in urine: Aetau %
Fraction of drug excreted in urine during a dosing interval
Time frame: Cycle 1 Day 28