Elsevier

Leukemia Research

Volume 79, April 2019, Pages 38-44
Leukemia Research

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

https://doi.org/10.1016/j.leukres.2019.02.012Get rights and content

Highlights

  • Glasdegib had an acceptable toxicity profile in patients with myelofibrosis.

  • Most common adverse events were dysgeusia, muscle spasms, and alopecia.

  • Modest improvements in patient-reported symptoms were observed with glasdegib.

  • Spleen volume reduction (SVR) was noted in some patients, but no patient had ≥35% SVR.

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.

Introduction

Primary and secondary (i.e., post-polycythemia vera and post-essential thrombocythemia) myelofibrosis (MF) is characterised by a clonal proliferation of myeloid hematopoietic cells leading to bone marrow fibrosis [1,2]. Clinical features include abnormal blood counts, hepatosplenomegaly, bleeding, thrombosis, and debilitating constitutional symptoms (e.g., fatigue, weight loss, night sweats, fever, pruritus, bone pain, abdominal pain, and early satiety) [2].

Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and JAK2, is approved for first-line treatment of patients with intermediate- or high-risk MF. Ruxolitinib can reduce spleen volume and ameliorate disease-related symptoms [3,4]; however, significant clinical benefit is not seen in all patients. In the COMFORT trials [4]. The proportion of patients with spleen volume reduction (SVR) ranged between 28–42%, and improvement ≥50% in total symptom score (TSS) occurred in 46% of patients. Pooled data from these studies suggest ruxolitinib prolongs survival in some patients, but lacks curative potential [[5], [6], [7]]. Regulatory-approved treatment options following ruxolitinib treatment failure are lacking; hence, second-line therapy for MF is a significant unmet need.

Translational studies have shown a 20- to 100-fold increase in expression of target genes of the Hedgehog (Hh) signalling pathway, including glioma-associated oncogene (GLI1) and protein-patched homolog 1 (PTCH1), in granulocytes isolated from patients with MF [8]. In a preclinical mouse model of MF, inhibition of the Hh pathway combined with ruxolitinib demonstrated greater reduction of mutant allele burden, reduced bone marrow fibrosis, and lowered white blood cells and platelet count compared with ruxolitinib alone [8].

Glasdegib is a potent and selective oral inhibitor of Hh pathway activity that acts by binding to Smoothened (SMO), a G-protein-coupled receptor, and blocking signal transduction. The United States Food and Drug Administration recently approved glasdegib in combination with low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukaemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. This study evaluated safety and tolerability of glasdegib in an open-label, lead-in cohort of patients with MF previously treated with at least one JAK inhibitor (JAKi), followed by a phase 2, randomized portion. Herein, we report data from the lead-in portion of this phase 1b/2 trial.

Section snippets

Study design

This open-label, lead-in study in patients with primary or secondary MF previously treated with one or more JAKi was conducted at ten centres in Japan and the United States. The following were collected at screening: date of diagnosis; Dynamic International Prognosis Scoring System [9] risk category at enrolment; complete history, best response, and reason for discontinuation of prior MF therapies; and events leading to intolerance of prior MF therapies, including severity and outcome of

Patients

A total of 21 patients were screened and treated with glasdegib. Patient demographic and baseline characteristics are presented in Table 1. Fifteen (71.4%) patients received one prior JAKi therapy; three (14.3%) received two prior JAKi therapies, and three (14.3%) received three or more prior JAKi therapies. The most common reason for discontinuing prior JAKi therapy was inadequate response/primary resistance (n = 11 [52.4%]), followed by toxicity and “other” (n = 8 [38.1%], each).

As of the

Discussion

This open-label, lead-in cohort was designed to evaluate the safety and tolerability of glasdegib in patients with primary/secondary MF previously treated with JAKi. Although glasdegib was considered safe and tolerable, prespecified secondary TSS reduction and SVR endpoints were not met. Therefore, this study did not proceed to the randomised phase.

For pre-treated patients with relapsed and refractory MF, glasdegib demonstrated an acceptable toxicity profile. The most commonly reported TEAEs

Funding

This study was sponsored by Pfizer. The sponsor participated in study design and collection, analysis, and interpretation of data. All authors had full access to study data, and the corresponding author had final responsibility for the decision to submit for publication.

Data sharing statement

Upon request, and subject to certain criteria, conditions and exceptions see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all

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

Acknowledgements

Medical writing support was provided by Vardit Dror, PhD, and Emily Balevich, PhD, of Engage Scientific Solutions and was funded by Pfizer.

References (18)

There are more references available in the full text version of this article.

Cited by (26)

  • Myelofibrosis

    2023, Blood
  • Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: A phase 1b/2 dose-finding study

    2020, Blood Advances
    Citation Excerpt :

    Therefore, the expression of Gli1 messenger RNA in tumor or relevant surrogate tissues constitute a reliable indicator of Hh pathway activity.9 Several Hh pathway inhibitors are in clinical development for myeloid malignancies.6,10,11 One such Hh inhibitor, glasdegib, has recently been approved by the US Food and Drug Administration for the treatment of acute myeloid leukemia (AML) in combination with low-dose cytarabine.12

View all citing articles on Scopus
View full text