A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or Refractory Acute Myeloid Leukemia
ASP2215 hemifumarate is a new chemical entity (NCE) discovered by Astellas Pharma Inc. in collaboration with Kotobuki Pharmaceutical Co., Ltd. ASP2215 has an inhibitory effect on tyrosine kinases, mainly FLT3, Axl and ALK. ASP2215 demonstrated favorable efficacy in a non-clinical AML model, which means complete regression of tumors in the xenograft model mice transplanted with MV4-11, human AML cell line expressing FLT3-ITD, by repeated oral doses. In addition, ASP2215 inhibited the growth of cells expressing either wild type FLT3, FLT3-ITD, FLT3-D835Y, or FLT3-ITD-D835YThe primary objectives of this study are to:ï?· Assess the safety and tolerability, including determination of the maximum tolerated dose (MTD), of oral ASP2215 in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML) Determine the pharmacokinetic (PK) parameters of ASP2215
Inclusion:Subject is eligible for the study if all of the following apply:1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA Authorization for U.S. sites) must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).2. Subject is 18 years of age at the time of obtaining informed consent.3. Subject is defined as morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2008) and fulfills one of the following: Refractory to at least 1 cycle of induction chemotherapy, ï¿½ Relapsed after achieving remission with a prior therapy, 4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score less than or equal to 2.5. Subjectï¿½s interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), or at least 5 half-lives for prior experimental agents or noncytotoxic agents, including immunosuppressive therapy posthematopoietic stem cell transplantation (HSCT).6. Subject must meet the following criteria as indicated on the clinical laboratory tests*.ï¿½ Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ï¿½ 2.5 ï¿½institutional upper limit normal (ULN)ï¿½ Total serum bilirubin ï¿½ 1.5 ï¿½ institutional ULNï¿½ Serum creatinine ï¿½ 1.5 ï¿½ institutional ULN or an estimated glomerular filtration rate(eGFR) of greater than 50 ml/min as calculated by the Modification of Diet in Renal Disease(MDRD) equation.7. Subject is suitable for oral administration of study drug.8. Female subject must be either: Of non child bearing potential: post-menopausal (defined as at least 1 year without any menses) prior to Screening,or documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening) Or, if of childbearing potential, must have a negative urine pregnancy test at Screening*, and must use two forms of birth control** (at least one of which must be a barrier method) starting at Screening and throughout the study period and for 28 days after the final study drug administration.9. Female subject must not be breastfeeding at Screening or during the study period, and for 28 days after the final study drug administration.10. Female subject must not donate ova starting at Screening and throughout the study period, and for 28 days after the final study drug administration.11. Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control** (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 90 daysafter the final study drug administration.12. Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration.13. Subject agrees not to participate in another interventional study while on treatment.
ASP2215 will be administered once daily in the following dose levels. However, not all dose levels will enroll, as described in the Study Design Overview.Cohort 1 will comprise the initial dose escalation cohort with up to 10 dose levels (Table 1). This cohort will be run at approximately 5 centers which will only participate in the dose expansion cohort (Cohort 2) if the enrollment in the dose escalation cohort (Cohort 1) is on a pause (i.e. dose level being tested at the time is fully enrolled and the one higher dose level has not yet been opened. Subjects will be treated daily in 28 day cycles (with the exception of Cycle 1 where subjects will receive 29 doses). The DLT observation period is 30 days starting with the first dose taken on Day -2, and including the first 28 day treatment cycle. Subjects in Cycle 1 will have PK sampling performed prior to start of the first cycle and after receiving a single dose of the study drug on Day -2.This study will follow an accelerated titration design. Dose levels are set at around 50% increments. One subject will be treated at the starting dose level of 20 mg. If no DLT is identified, the next subject will be enrolled at double the dose level, i.e. dose level 3 (40 mg see Table 1). This dose escalationapproach will continue wherein only odd numbered dose levels (1, 3, 5) are tested until the first instance of a DLT or second instance (observed in two subjects at any of these dose levels) of a grade 2 AE judged by the investigator to be related (e.g., possibly, probably, or definitely) to study drug (except for hematologic toxicities) occur.When a DLT or second instance (observed in two subjects) of grade 2 AE related to study drug is observed in a subject, the dose escalation schedule will stop the double-dose level method and follow the next consecutive dose level in Table 1utilizing the modified 3+3 design. Modified 3+3 design testing each consecutive dose level may also be followed if recommended by dose escalationcommittee based on the review of pharmacokinetics data. After dose level 5 (80 mg), each subsequent dose level (6-10) will be tested using the 3+3 design. In this phase, 3 subjects will be treated at each dose level. If no DLTs are observed, the subsequent subjects will be treated at the next dose level. If one DLT is observed in a dose level, 3 more subjects will be enrolled at that dose level.If the 3 additional subjects do not experience a DLT, the next dose level will be initiated. If 2 or more DLTs occur in a dose level the next lower dose level will be declared the maximum tolerated dose (MTD).
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