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

Aaron T. Gerds, Tetsuzo Tauchi, Ellen Ritchie, Michael Deininger, Catriona Jamieson, Ruben Mesa, Mark Heaney, Norio Komatsu, Hironobu Minami, Yun Su, Naveed Shaik, Xiaoxi Zhang, Christine DiRienzo, Mirjana Zeremski, Geoffrey Chan, Moshe Talpaz

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)38-44
Number of pages7
JournalLeukemia Research
Volume79
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

Fingerprint

Primary Myelofibrosis
Janus Kinases
Spleen
Dysgeusia
INCB018424
Alopecia
Spasm
Appetite
Fatigue
Anemia
Pharmacokinetics
Safety

Keywords

  • Glasdegib
  • Hedgehog inhibitor
  • Myelofibrosis
  • Smoothened inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. / Gerds, Aaron T.; Tauchi, Tetsuzo; Ritchie, Ellen; Deininger, Michael; Jamieson, Catriona; Mesa, Ruben; Heaney, Mark; Komatsu, Norio; Minami, Hironobu; Su, Yun; Shaik, Naveed; Zhang, Xiaoxi; DiRienzo, Christine; Zeremski, Mirjana; Chan, Geoffrey; Talpaz, Moshe.

In: Leukemia Research, Vol. 79, 01.04.2019, p. 38-44.

Research output: Contribution to journalArticle

Gerds, AT, Tauchi, T, Ritchie, E, Deininger, M, Jamieson, C, Mesa, R, Heaney, M, Komatsu, N, Minami, H, Su, Y, Shaik, N, Zhang, X, DiRienzo, C, Zeremski, M, Chan, G & Talpaz, M 2019, 'Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib', Leukemia Research, vol. 79, pp. 38-44. https://doi.org/10.1016/j.leukres.2019.02.012
Gerds, Aaron T. ; Tauchi, Tetsuzo ; Ritchie, Ellen ; Deininger, Michael ; Jamieson, Catriona ; Mesa, Ruben ; Heaney, Mark ; Komatsu, Norio ; Minami, Hironobu ; Su, Yun ; Shaik, Naveed ; Zhang, Xiaoxi ; DiRienzo, Christine ; Zeremski, Mirjana ; Chan, Geoffrey ; Talpaz, Moshe. / Phase 1/2 trial of glasdegib in patients with primary or secondary myelofibrosis previously treated with ruxolitinib. In: Leukemia Research. 2019 ; Vol. 79. pp. 38-44.
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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.",
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AU - Deininger, Michael

AU - Jamieson, Catriona

AU - Mesa, Ruben

AU - Heaney, Mark

AU - Komatsu, Norio

AU - Minami, Hironobu

AU - Su, Yun

AU - Shaik, Naveed

AU - Zhang, Xiaoxi

AU - DiRienzo, Christine

AU - Zeremski, Mirjana

AU - Chan, Geoffrey

AU - Talpaz, Moshe

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N2 - 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.

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