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Clinical Trial
. 2019 Feb;33(2):379-389.
doi: 10.1038/s41375-018-0312-9. Epub 2018 Dec 16.

Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Jorge E Cortes  1 , Florian H Heidel  2   3 , Andrzej Hellmann  4 , Walter Fiedler  5 , B Douglas Smith  6 , Tadeusz Robak  7 , Pau Montesinos  8   9 , Daniel A Pollyea  10 , Pierre DesJardins  11 , Oliver Ottmann  12 , Weidong Wendy Ma  13 , M Naveed Shaik  13 , A Douglas Laird  13 , Mirjana Zeremski  13 , Ashleigh O'Connell  13 , Geoffrey Chan  13 , Michael Heuser  14
Affiliations
Clinical Trial

Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Jorge E Cortes et al. Leukemia. 2019 Feb.

Abstract

Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9-9.9) months with glasdegib/LDAC and 4.9 (3.5-6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39-0.67, P = 0.0004). Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit-risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

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Conflict of interest statement

JEC received research funding and consulting honoraria from Pfizer, Novartis, Astellas, Daiichi, and Celgene. FHH received honoraria from Pfizer. WF participated in advisory boards for Amgen, Pfizer, Novartis, Jazz, and ARIAD/Incyte; has patents and royalties from Amgen; and received support for meeting attendance from Amgen, Gilead, GSO, Teva, and Jazz and research funding from Amgen and Pfizer. BDS served on an advisory board and was a consultant for Celgene, Jazz Pharmaceuticals, Novartis, and Pfizer. TR received research funding from Pfizer. PM served on an advisory board for Celgene, Jazz, Janssen, and Novartis and has received research funding from Pfizer and Celgene. DAP served on an advisory board for Agios, Celgene, Curis, Takeda, Servier, Jazz, and Gilead and has received research funding from Pfizer and Agios. AH, PD, and OO were investigators for this Pfizer-funded study and received study drugs provided by Pfizer. MH received research funding and honoraria from Pfizer. WWM, MNS, ADL, MZ, AO, and GC are employees of and own stock in Pfizer Inc.

Figures

Fig. 1
Fig. 1
Patient disposition. This study is ongoing; the first patient randomization visit took place on 3 January 2014, and the primary analysis data cutoff was 3 January 2017. The randomization errors in 7/132 patients (5%) were due to patients withdrawing consent or failing to maintain eligibility requirements. Discontinuations were attributed to the last study treatment received. Treated was defined as patients who received at least one non-zero dose of glasdegib or LDAC. AE adverse event, IVRS interactive voice response system, LDAC low-dose cytarabine, PK pharmacokinetic(s)
Fig. 2
Fig. 2
Kaplan–Meier estimate of overall survival, full analysis set. CI confidence interval, HR hazard ratio, LDAC low-dose cytarabine, OS overall survival
Fig. 3
Fig. 3
Kaplan-Meier estimate of overall survival, full analysis set, in patients at A good/intermediate cytogenetic risk and B poor cytogenetic risk. CI confidence interval, HR hazard ratio, LDAC low-dose cytarabine, OS overall survival
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