PMID- 30849661 OWN - NLM STAT- MEDLINE DCOM- 20191210 LR - 20211204 IS - 1873-5835 (Electronic) IS - 0145-2126 (Print) IS - 0145-2126 (Linking) VI - 79 DP - 2019 Apr TI - Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. PG - 38-44 LID - S0145-2126(19)30038-4 [pii] LID - 10.1016/j.leukres.2019.02.012 [doi] AB - Glasdegib is a potent and selective oral inhibitor of the Hedgehog pathway. We report data from the single-arm, lead-in cohort of an open-label phase 1b/2 trial of glasdegib in patients with primary/secondary myelofibrosis (MF) previously treated with at least one Janus kinase inhibitor (JAKi). Patients received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints included adverse events (AEs). Secondary endpoints included patients with spleen volume reduction (SVR) >/=35% at week 24, patients with >/=50% total symptom score (TSS) reduction, and pharmacokinetics. All 21 treated patients had one or more AE and five (23.8%) had serious AEs. Most common (>30%) AEs were dysgeusia (61.9%), muscle spasms (57.1%), alopecia (38.1%), fatigue (33.3%), and decreased appetite (33.3%). Although no patient had >/=35% SVR at week 24, one patient previously treated with ruxolitinib had an SVR of 32.9%. At week 12, two (9.5%) patients had >/=50% reduction in TSS from baseline and 40% had >/=20% reduction. One patient had an anaemia response. Following administration of glasdegib 100 mg once daily, the median time to peak plasma concentrations at steady-state generally occurred at 1 h post-dose. The safety profile of glasdegib monotherapy was manageable in patients with primary/secondary MF. Further study of glasdegib in combination with JAKi in a MF population may be warranted. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Gerds, Aaron T AU - Gerds AT AD - Leukemia and Myeloid Disorders Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: gerds@ccf.org. FAU - Tauchi, Tetsuzo AU - Tauchi T AD - Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Electronic address: tauchi@tokyomed.ac.jp. FAU - Ritchie, Ellen AU - Ritchie E AD - Weill Cornell Medical College of Cornell University, 1300 York Ave, New York, NY 10065, USA. Electronic address: ritchie@med.cornell.edu. FAU - Deininger, Michael AU - Deininger M AD - Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112, USA. Electronic address: michael.deininger@hci.utah.edu. FAU - Jamieson, Catriona AU - Jamieson C AD - Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Dr, La Jolla, CA 92093, USA. Electronic address: cjamieson@ucsd.edu. FAU - Mesa, Ruben AU - Mesa R AD - UT Health San Antonio Cancer Center, 7979 Wurzbach Rd, San Antonio, TX 78229, USA. Electronic address: mesar@uthscsa.edu. FAU - Heaney, Mark AU - Heaney M AD - Columbia University Medical Center, 630 West 168th St, New York, NY 10032, USA. Electronic address: mlh2192@cumc.columbia.edu. FAU - Komatsu, Norio AU - Komatsu N AD - Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: komatsun@juntendo.ac.jp. FAU - Minami, Hironobu AU - Minami H AD - Division of Medical Oncology /Hematology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Electronic address: hminami@med.kobe-u.ac.jp. FAU - Su, Yun AU - Su Y AD - Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: yun_su@msn.edu. FAU - Shaik, Naveed AU - Shaik N AD - Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121 USA. Electronic address: naveed.shaik@pfizer.com. FAU - Zhang, Xiaoxi AU - Zhang X AD - Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: xiaoxi.zhang@pfizer.com. FAU - DiRienzo, Christine AU - DiRienzo C AD - Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: christine.d.dirienzo@pfizer.com. FAU - Zeremski, Mirjana AU - Zeremski M AD - Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, United States. Electronic address: mirjana.zeremski@pfizer.com. FAU - Chan, Geoffrey AU - Chan G AD - Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: geoffrey.chan@pfizer.com. FAU - Talpaz, Moshe AU - Talpaz M AD - Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Dr, Ann Arbor, MI 48109, USA. Electronic address: mtalpaz@med.umich.edu. LA - eng GR - P30 CA054174/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20190228 PL - England TA - Leuk Res JT - Leukemia research JID - 7706787 RN - 0 (Benzimidazoles) RN - 0 (Nitriles) RN - 0 (Phenylurea Compounds) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - 82S8X8XX8H (ruxolitinib) RN - K673DMO5H9 (glasdegib) SB - IM EIN - Leuk Res. 2019 Jun;81:105. PMID: 31029462 MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Benzimidazoles/pharmacokinetics/*therapeutic use MH - Chemotherapy, Adjuvant MH - Female MH - Humans MH - Male MH - Middle Aged MH - Nitriles MH - Organ Size/drug effects MH - Phenylurea Compounds/pharmacokinetics/*therapeutic use MH - Primary Myelofibrosis/*drug therapy/metabolism/mortality/pathology MH - Pyrazoles/*therapeutic use MH - Pyrimidines MH - Spleen/drug effects/pathology MH - Treatment Outcome MH - Young Adult PMC - PMC8148985 MID - NIHMS1698052 OTO - NOTNLM OT - Glasdegib OT - Hedgehog inhibitor OT - Myelofibrosis OT - Smoothened inhibitor COIS- Declaration of interest ATG declares receiving consulting fees and research funding from Celgene, Incyte, and CTI Biopharma, consulting fees from Apexx Oncology, and research funding from Gilead, Genentech, Roche, Imago Biosciences, Pfizer, and Samus Therapeutics. TT declares receiving research funding from Pfizer. ER declares receiving consulting fees and research funding from Novartis, honoraria from Incyte and Pfizer, and speaker's bureau from Celgene. MD has no conflict of interests to disclose. CJ declares having equity ownership from Impact Biomedicines and Wintherix, receiving research funding from Celgene and Johnson & Johnson, and patents & royalties from Forty Seven Inc. RM declares receiving consulting fees from Novartis, Ariad, and Galena, and research funding from Incyte, Gilead, CTI, Promedior, and Celgene. MH declares receiving consulting fees from Novartis. NK has no conflict of interests to disclose. HM declares receiving research funding from Pfizer. YS was an employee of Pfizer at the time of manuscript development and owns stock in Pfizer. NS, XZ, CD, MZ, and GC are employees of and own stock in Pfizer. MT declares receiving research funding from Pfizer. EDAT- 2019/03/09 06:00 MHDA- 2019/12/18 06:00 PMCR- 2021/05/25 CRDT- 2019/03/09 06:00 PHST- 2018/10/24 00:00 [received] PHST- 2019/02/25 00:00 [revised] PHST- 2019/02/27 00:00 [accepted] PHST- 2019/03/09 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2019/03/09 06:00 [entrez] PHST- 2021/05/25 00:00 [pmc-release] AID - S0145-2126(19)30038-4 [pii] AID - 10.1016/j.leukres.2019.02.012 [doi] PST - ppublish SO - Leuk Res. 2019 Apr;79:38-44. doi: 10.1016/j.leukres.2019.02.012. Epub 2019 Feb 28.