ASP2215 in Japanese Patients with Relapsed or Refractory Acute Myeloid Leukemia: Preliminary Results from a Phase 1 Open-Label, Dose-Escalation Study
Authors: Naoe Tomoki , Sakura Toru , Kobayashi Yukio , Usuki Kensuke , Miyamoto Toshihiro , Iida Hiroatsu , Morita Satoshi , Bahceci Erkut , Kaneko Masahito , Yamada Shunsuke , Takeshita Shigeru , Miyawaki Shuichi 
Published: October 2019

Abstract
Background: FMS-like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML) are strongly associated with poor prognosis and leukocytosis. Approximately 15-35% of AML patients have internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence and 5-10% have a missense mutation of D835 within the tyrosine kinase domain. ASP2215 potently inhibits FLT3 with established preclinical activity against both ITD and D835 mutations. Preliminary results from a Phase 1/2, first-in-human study suggest ASP2215 is generally well tolerated and associated with antileukemic activity in FLT3 mutation-positive (FLT3+) subjects with relapsed or refractory AML (R/R AML). The safety and antileukemic activity of ASP2215 is currently being evaluated in an ongoing, Phase 1 study in Japanese subjects with relapsed or refractory (R/R) AML.
Methods: This open-label, dose-escalation study, conducted in adult Japanese subjects (≥18 years) with R/R AML, consisted of a single- and a repeated-dose periods. ASP2215 (20-300 mg) was orally administered to subjects as a single dose (Cycle 0) and then once daily (Cycle 1 and subsequent cycles, each cycle was 28 days) until one of the discontinuation criteria were met. Dose escalation proceeded in a step-wise manner, based on the onset of dose-limiting toxicity (DLT) during Cycles 0 and 1, with the next dose level determined sequentially using the Bayesian Continual Reassessment Method (CRM). The study design allowed that at least one subject would receive the 20 mg dose and at least three subjects would receive higher doses (40-300 mg) of ASP2215. Primary endpoints included ASP2215 tolerability and determination of maximum tolerated dose (MTD, defined as the dose where posterior mean DLT incidence is ~33% when calculated using Bayesian CRM). Secondary endpoints included clinical response (based on Cheson's criteria) and pharmacokinetic profile.
Results: As of June 24, 2015, 18 subjects with a median age of 71.5 years (range: 60-81 years) and 94% with ECOG 0-1 have received ASP2215 at dosages of 20 mg (n=1), 40 mg (n=4), 80 mg (n=4), 120 mg (n=4), and 200 mg (n=5). Three subjects were FLT3-ITD mutation positive, eight were FLT3-ITD negative, and the FLT3-ITD status for the other seven was unknown; FLT3 point mutation status for the majority (94%) of these subjects is not yet available. Only one DLT (tumor lysis syndrome), experienced at the 120 mg dose, has been reported suggesting MTD has not yet been reached. Abnormal hepatic function (n=5) and stomatitis (n=3) were the only treatment-related AEs occurring in ≥3 subjects. Grade ≥3 AEs were thrombocytopenia (n=2), febrile neutropenia (n=1), device-related infection (n=1), tumor lysis syndrome (n=1) and pneumonia (n=1). Five serious AEs deemed to be possibly or probably treatment related by the investigators (febrile neutropenia, edema, pneumonia, device-related infection, subdural hematoma) occurred in three subjects. ASP2215 plasma concentrations increased with doses from 20 mg to 200 mg with median time to maximal concentration of 2-6 hr. A total of 13 subjects had evaluable bone marrow to assess antileukemic activity; six of whom achieved at least partial response (Table).
Conclusions: These preliminary findings in Japanese patients with R/R AML suggest ASP2215 is a well-tolerated FLT3 inhibitor with dose dependent increase in PK and has shown antileukemic activity in Japanese patients. ASP2215 tolerability, PK profile, and antileukemic activity are consistent with the ongoing dose-escalation/dose-expansion study being conducted in the US and Europe. Based on the positive findings, randomized Phase 3 trials have been planned.
Table 1. Best Clinical Response by ASP2215 Dose and FLT3 Mutation Status Dose (mg) FLT3-ITD mutation status Best response Assessment day with first report of best response 20 Unknown CRi Day 28 40 Negative NR Day 29 Negative PR Day 29 Negative NR Day 29 80 Negative CR Day 28 Negative NR Day 11 Positive PR Day 28 Unknown NR Day 30 120 Negative NR Day 29 Positive CRi Day 57 200 Negative CRp Day 39 Positive NR Day 21 Unknown NR Day 27 CR, Complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; NR, no response; PR, partial response.

Disclosures
Naoe: Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Pfizer Inc.: Research Funding; Toyama Chemical CO., LTD.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Celgene K.K.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. Off Label Use: ASP2215 is an investigational product for the treatment of AML. Sakura:Astellas: Other: Principal Investigator of the clinical research; study fee. Kobayashi:Gilead Sciences: Research Funding. Usuki:Kyowa Hakko Kirin: Other: personal fees, Research Funding; Shire: Research Funding; Takeda Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Research Funding; Shionogi: Other: personal fees; SymBio Pharmaceutical: Other: personal fees, Research Funding; Eisai: Research Funding; Otsuka Pharmaceutical: Research Funding; MSD: Other: personal fees, Research Funding; Sanofi: Other: personal fees, Research Funding; Novartis: Other: personal fees, Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Taiho Pharmaceutical: Other: personal fees, Research Funding; Fuji Film RI Pharma: Other: personal fees; Chugai Pharmaceutical: Other: personal fees; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other; Astellas: Research Funding. Iida:Astellas: Other: Principal Investigator of the clinical research; study fee. Morita:Astellas: Honoraria, Other: Personal fees. Bahceci:Astellas Pharma Global Development: Employment. Kaneko:Astellas Pharma, Inc.: Employment. Yamada:Astellas Pharma, Inc.: Employment. Takeshita:Astellas Pharma, Inc.: Employment. Miyawaki:Astellas Pharma Inc.: Consultancy, Other: personal fees; Ohtsuka Pharma Co, LTD.: Other: Safety Data Committee.