Results of a Phase 1/2a dose–escalation study of FF-10501-01, an IMPDH inhibitor, in patients with acute myeloid leukemia or myelodysplastic syndromes

Abstract

FF-10501-01 potently inhibits inosine-5-monophosphate dehydrogenase (IMPDH), inducing anti-proliferative and pro-apoptotic effects in acute myeloid leukemia (AML) human cell lines resistant to hypomethylating agents. In this Phase 1/2a study, Phase 1 enrolled 38 patients with relapsed/refractory AML (n = 28) or myelodysplastic syndromes (MDS/CMML, n = 10) to receive FF-10501 oral doses 50–500 mg/m² BID for 14 or 21 days out of each 28-day cycle. Fifteen additional patients with HMA-resistant MDS/CMML (Phase 2a) were treated at 400 mg/m² BID for 21 days. Most Phase 1 adverse events were disease-related and low-grade. 3 of 19 (16%) evaluable AML patients achieved partial remission (31, 7, and 5 months). 2 of 20 (10%) evaluable MDS/CMML patients (Phase 1 and 2a) attained marrow complete remission, one continuing treatment for 17 months. While FF-10501-01 demonstrated clinical activity and target inhibition in heavily pretreated patients with AML and MDS/CMML, increased mucositis events led to Phase 2a closure (ClinTrials.gov#NCT02193958).

Keywords:

• AML
• MDS
• CMML
• IMPDH inhibition
• Phase 1/2a

Acknowledgments

This work was supported by a grant from FUJIFILM Pharmaceuticals USA, Inc. and by the University of Texas MD Anderson Cancer Center Support Grant CA016672. We want to thank the patients who volunteered to participate in this trial as well as their families, caregivers and the clinical staffs of Department of Leukemia, The University of Texas MD Anderson Cancer Center and the Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic, for assisting in their care. In addition, we would like to acknowledge the contributions of Atsushi Takeo, Ryo Yamashita, Minako Matsusita, Kensuke Komatsu, and Motoki Saito who developed the XMP measurement method; Takuji Kanamoto and Chie Kurosaki who analyzed the PK/PD correlations; Timothy Madden, Ruth Ann Subach, Takeaki Suzuki and Catherine Wheeler for data and critical manuscript review and figure generation, as well as Kathleen Tiefenwerth, Susan Denton, Georgine Price, Whitney Smith, Christine Anderson and Anjum Zaki for their assistance with data management and study oversight.

Author contributions

GG-M, MAS, CD, NP, YA, KN, FR, EG, HK, AA, SM, AG, HC, and AN were responsible for acquisition of the data.

GG-M and MK were responsible for the development of the protocol.

MK and LB were the medical monitors responsible for study medical supervision and data review.

GM and MJ were responsible for analysis and interpretation of pharmacokinetic and pharmacodynamic data.

MM was responsible for biomarker development and XMP measurement method.

GG-M, MAS, HI, LB and MK were responsible for interpretation of the clinical data and for writing the manuscript.

Disclosure statement

GG-M received research funding from FUJIFILM Pharmaceuticals U.S.A., Inc. MAS has served on advisory boards for Takeda/Millennium and Celgene. CD has no competing financial interests. NP has served as consultant and received honoraria from Celgene, Stemline, Incyte, Novartis, MustangBio, Roche Diagnostics and LFB; has received research funding/clinical trials support from Stemline, Novartis, Abbvie, Samus, Cellectus, Plexxikon, Daiichi-Sankyo and Affymetrix; and has received grants/funding from Affymetrix and SagerStrong Foundation. YA has no competing financial interests. KN has no competing financial interests. FR has received honoraria from Astex Pharmaceuticals, Inc. EJ has research support and consulting fees from AbbVie, Amgen, Pfizer, and Takeda. RD has no competing financial interests. HK has institutional research funding to MD Anderson from Amgen, ARIAD, Astex, BristolMyers Squibb, Novartis, and Pfizer; has received honoraria from AbbVie, Actinium, Agios, Amgen, ImmunoGen, Orsinex, Pfizer, and Takeda and research support from AbbVie, Agios, Amgen, ARIAD, Astex, Bristol-Myers Squibb, Cyclacel, Daiichi-Sankyo, ImmunoGen, Jazz Pharmaceuticals, Novartis, and Pfizer. AA has served as consultant for and received honoraria from Pfizer, Glycomimetics and KiTE Pharmaceuticals, and has research support from Macrogenics, Abbvie, AmGen, Samumed, and Takeda. SM has served on advisory boards for Celgene/Acceleron and Novartis; received honoraria from Aplastic Anemia and MDS International Foundation, Celgene, Bristol Myers Squib, McGraw Hill Hematology Oncology Board Review, Partnership for Health Analytic Research, LLC (PHAR LLC); held consultancies with BioPharm, Celgene, and Novartis; and has research funding from Celgene and Novartis. AG has served on advisory boards for Celgene and Pfizer, and has research funding from Celgene, Incyte, Imago Biosciences, CTI Biopharma, Roche, and Sierra Oncology. HC has served as consultant for Agios, Celgene and Daiichi; has served on Speaker Bureaus for Agios, Celgene, Sanofi, Novartis, and Jazz; has served on Independent Review Committees (IRC) for Abbvie and Takeda; and has received research support for Investigator-Initiated Trials from Celgene and Syndax. AN has served on advisory board of Patient IP; has served as consultant and on speaker bureau for Karyopharma, Tolero, Novartis, Incyte, Daiichi Sankyo, and Abbvie, has served on Data Monitoring Committee for MEI; and has research support from Jazz Pharmaceutical. MK, LB, GM and MJ are consultants to FUJIFILM Pharmaceuticals USA, Inc. HI and MM are employees of FUJIFILM Corporation.