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Leuk Res. 2019 Apr;79:38-44. doi: 10.1016/j.leukres.2019.02.012. Epub 2019 Feb 28.

Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib.

Author information

1
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.
2
Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Electronic address: tauchi@tokyomed.ac.jp.
3
Weill Cornell Medical College of Cornell University, 1300 York Ave, New York, NY 10065, USA. Electronic address: ritchie@med.cornell.edu.
4
Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr, Salt Lake City, UT 84112, USA. Electronic address: michael.deininger@hci.utah.edu.
5
Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Dr, La Jolla, CA 92093, USA. Electronic address: cjamieson@ucsd.edu.
6
UT Health San Antonio Cancer Center, 7979 Wurzbach Rd, San Antonio, TX 78229, USA. Electronic address: mesar@uthscsa.edu.
7
Columbia University Medical Center, 630 West 168th St, New York, NY 10032, USA. Electronic address: mlh2192@cumc.columbia.edu.
8
Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: komatsun@juntendo.ac.jp.
9
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.
10
Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: yun_su@msn.edu.
11
Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121 USA. Electronic address: naveed.shaik@pfizer.com.
12
Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: xiaoxi.zhang@pfizer.com.
13
Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: christine.d.dirienzo@pfizer.com.
14
Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, United States. Electronic address: mirjana.zeremski@pfizer.com.
15
Pfizer Inc, 235 East 42nd St, New York, NY 10017, USA. Electronic address: geoffrey.chan@pfizer.com.
16
Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Dr, Ann Arbor, MI 48109, USA. Electronic address: mtalpaz@med.umich.edu.

Abstract

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.

KEYWORDS:

Glasdegib; Hedgehog inhibitor; Myelofibrosis; Smoothened inhibitor

PMID:
30849661
DOI:
10.1016/j.leukres.2019.02.012
[Indexed for MEDLINE]

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