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1069 Final Results of the Chrysalis Trial: A First-in-Human Phase 1/2 Dose-

Escalation, Dose-Expansion Study of Gilteritinib (ASP2215) in Patients with


Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)
Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: FLT3 and IDH Targeted Therapies in
AML

Monday, December 5, 2016: 4:30 PM


San Diego Ballroom AB (Marriott Marquis San Diego Marina)

Alexander E. Perl, MD1 , Jessica K. Altman, MD2 , Jorge E. Cortes, MD3 , Catherine C. Smith, MD4 , Mark Litzow, MD5 , Maria
R. Baer, MD6 , David F. Claxton, MD7 , Harry P. Erba, MD, PhD8 , Stanley C. Gill, PhD9*, Stuart L. Goldberg, MD10, Joseph G.
Jurcic, MD11, Richard A. Larson, MD12, Charles Liu, PhD13*, Ellen K. Ritchie, MD14, Gary J. Schiller, MD15, Alexander I.
Spira, MD, PhD16, Stephen A. Strickland 17, Raoul Tibes, MD, PhD18, Celalettin Ustun, MD19, Eunice S. Wang, MD20,
Robert K. Stuart, MD21, Christoph Rllig, MD22*, Andreas Neubauer, MD23, Giovanni Martinelli24, Erkut Bahceci,
MD25 and Mark J. Levis, MD, PhD26
1 University of Pennsylvania-Abramson Comprehensive Cancer Center, Philadelphia, PA
2 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
3 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4 University of California at San Francisco, San Francisco, CA
5 Mayo Clinic, Rochester, MN
6 Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD
7 Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA
8 University of Alabama at Birmingham, Birmingham, AL
9 Formerly with Astellas Pharma US, Inc., Northbrook, IL
10Division of Leukemia, The John Theurer Cancer Center, Hackensack, NJ
11Columbia University Medical Center, New York, NY
12University of Chicago Comprehensive Cancer Center, Chicago, IL
13Astellas Pharma US, Inc., Northbrook, IL
14Weill Cornell Medical College, New York, NY
15University of California Los Angeles Medical Center, Los Angeles, CA
16Virginia Cancer Specialists, Fairfax, VA
17Vanderbilt University Medical Center, Nashville, TN
18Mayo Clinic Arizona, Phoenix, AZ
19Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis,

Minnesota, USA, Minneapolis, MN


20Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
21Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
22Medizinische Klinik und Poliklinik I, Universittsklinikum Carl Gustav Carus, Dresden, Germany
23Department of Hematology and Oncology, University Hospital Giessen and Marburg, Marburg, Germany
24Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
25Astellas Pharma Global Development, Northbrook, IL
26Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD

Background: Gilteritinib (ASP2215) is a novel, highly selective, potent oral FLT3/AXL inhibitor with preclinical activity
against FLT3-ITD activating and FLT3-D835 resistance mutations. The objectives of this phase 1/2 study were to assess
gilteritinib safety/tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles after single- and multiple-day
dosing, and antileukemic effects in patients with R/R AML.

Methods: This open-label study (NCT02014558) enrolled patients (18 yr) into 1 of 7 dose-escalation cohorts (20450
mg once daily [QD]) or concomitant dose-expansion cohorts. While confirmed FLT3 mutation was not an inclusion
criterion, each expanded dose level enrolled 10 patients with FLT3 mutations (FLT3 mut+ ); 120 and 200 mg dose levels
were further expanded with 40 FLT3 mut+ patients. The choice to expand these dose cohorts was based upon FLT3
inhibition in correlative assays and clinical activity seen during dose escalation. Safety and tolerability were primary
endpoints; blood samples were drawn from patients in the dose-escalation cohorts to evaluate gilteritinib PK parameters
and PD effects. Antileukemic response rates (eg, complete remission [CR], CR with incomplete platelet recovery [CRp], CR
with incomplete hematological recovery [CRi], overall response rate [ORR]) were secondary endpoints.

Results: Patients (N=252; 129M:123F, median age 62 yr [range: 2190]) enrolled between October 2013 and August
2015 received 1 dose of gilteritinib. The study population was heavily pretreated: 70% (n=177) had 2 prior AML
therapies, 29% (n=73) had a prior stem cell transplant, and 25% (n=63) had prior TKI treatment with sorafenib most
commonly used. Across the study, 194 patients had a locally confirmed FLT3 mutation (ITD, n=159; D835, n=13; ITD-
D835, n=16; other, n=6). For all enrolled patients, progressive disease (n=75), lack of efficacy (n=44), adverse events
(n=34), and death (n=29) were the most common reasons for treatment discontinuation. Seven deaths were considered
possibly/probably related to treatment: pulmonary embolism, respiratory failure, hemoptysis, intracranial bleed,
ventricular fibrillation, septic shock, and neutropenia (all n=1). Maximum tolerated dose was determined to be 300 mg
when 2 of 3 patients in the 450 mg cohort experienced diarrhea and/or hepatic transaminase elevation as dose-limiting
toxicities. Diarrhea (16%) and fatigue (15%) were the most commonly reported treatment-related adverse events of any
grade. Less than 5% of patients (11/252) had a maximum post-baseline QTcF interval >500 msec. Gilteritinib
concentrations were generally dose proportional and showed both a long-elimination half-life (45159 h) and
substantial accumulation (3.210 fold) by day 15. An exposure-related increase in the inhibition of FLT3
phosphorylation with increasing doses of gilteritinib was also observed. Gilteritinib showed strong antileukemic activity
in FLT3 mut+ patients (ORR=49%); response was observed less frequently in patients with wild-type FLT3 (ORR=12%).
While CR, CRi, and CRp occurred at all doses, responses were enriched among FLT3 mut+ patients with gilteritinib steady-
state trough concentrations 100 ng/mL, which correlated with potent FLT3 inhibition in PD assays and corresponded to
doses 80 mg. The ORR in 169 FLT3 mut+ patients receiving 80 mg was 52% (Table); median overall survival in this
patient population was ~31 wk (range: 1.761; Figure) and median duration of response was 20 wk (range: 1.155).
Clinical responses occurred in FLT3 mut+ patients with -ITD, -D835, and both mutations (ORR: 55%, 17%, and 62%,
respectively) as well as in FLT3 mut+ patients with or without prior TKI treatment (ORR: 42% vs 56%, respectively).

Conclusions: This PD-driven, first-in-human study shows that gilteritinib was well tolerated and generated frequent,
prolonged, clinically important responses in FLT3 mut+ patients with R/R AML. Antileukemic responses were enriched in
FLT3 mut+ patients treated at doses that consistently and potently inhibited FLT3 phosphorylation. The survival of these
patients appears better than expected for this patient population when treated with standard therapy. Our data suggest
that FLT3 inhibition may improve survival in patients with FLT3 mut+ R/R AML; as such, phase 3 testing of oral gilteritinib
120 mg QD in patients with FLT3 mut+ R/R AML after first-line therapy is underway (NCT02421939).
Disclosures: Perl: Astellas US Pharma Inc.: Consultancy, Membership on an entity's Board of Directors or advisory
committees; Daichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Asana
Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog
Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium
Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Altman: CSL
Limited: Other: Was funding to the institution for clinical trial, Research Funding; BioLineRx: Other: Was funding to the
institution for clinical trial, Research Funding; Pfizer: Other: Was funding to the institution for clinical trial, Research
Funding; Agios: Other: Was funding to the institution for clinical trial, Research Funding; Astellas: Other: Was funding
to the institution for clinical trial, Research Funding; Genentech: Other: Was funding to the institution for clinical trial,
Research Funding; Celgene: Other: Was funding to the institution for clinical trial, Research Funding; Seattle
Genetics: Other: advisory board; Epizyme: Other: Was funding to the institution for clinical trial, Research
Funding; MethylGene: Other: Was funding to the institution for clinical trial, Research Funding; Boehringer
Ingelheim: Other: Was funding to the institution for clinical trial, Research Funding; Syros: Other: advisory
board; Ariad: Other: advisory board; Cyclacel: Other: Was funding to the institution for clinical trial, Research
Funding; Spectrum: Other: advisory board; BMS: Membership on an entity's Board of Directors or advisory committees,
Research Funding; Janssen: Other: advisory board. Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy,
Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research
Funding. Smith: Astellas: Research Funding. Erba: Jannsen: Consultancy, Research Funding; Millennium
Pharmaceuticals, Inc.: Research Funding; Agios: Research Funding; Juno: Research Funding; Incyte: Consultancy, DSMB,
Speakers Bureau; Daiichi Sankyo: Consultancy; Ariad: Consultancy; Amgen: Consultancy, Research
Funding; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Seattle Genetics: Consultancy, Research
Funding; Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research
Funding; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy. Gill: Astellas: Employment. Goldberg: Bristol
Myers Squibb, Novartis: Speakers Bureau; Novartis: Consultancy; COTA
Inc: Employment; Pfizer: Honoraria; Neostem: Equity Ownership. Jurcic: Astellas: Research
Funding. Larson: Astellas: Consultancy, Research Funding; Bristol-Myers
Squibb: Consultancy. Liu: Astellas: Employment. Ritchie: Celgene: Consultancy, Other: Travel, Accomodations,
Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel,
Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy,
Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research
Funding. Schiller: Incyte Corporation: Research Funding. Strickland: Celator: Research Funding; Cyclacel: Research
Funding; Karyopharm Therapeutica: Research Funding; GlaxoSmithKline: Research
Funding; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Ambit: Consultancy; Alexion
Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; CTI Biopharma: Consultancy; Daiichi
Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research
Funding; Sanofi: Research Funding. Wang: Incyte: Speakers Bureau; Immunogen: Research
Funding. Stuart: Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research
Funding; Agios: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research
Funding; Astellas: Research Funding. Martinelli: Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers
Bureau; BMS: Speakers Bureau; Roche: Consultancy, Speakers
Bureau; MSD: Consultancy; Genentech: Consultancy; Novartis: Speakers Bureau; Celgene: Consultancy, Speakers
Bureau; Amgen: Consultancy, Speakers Bureau. Bahceci: Astellas: Employment. Levis: Millennium: Consultancy,
Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy,
Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

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in AML
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