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Ref Type Journal Article
PMID (29463550)
Authors Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, McCloskey J, Kantarjian HM, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Cortes JE
Title Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-Risk MDS.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 24
Issue 10
Date 2018 May 15
URL
Abstract Text Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D).Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting.Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294-303. ©2018 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown acute myeloid leukemia not applicable Decitabine + Glasdegib Phase Ib/II Actionable In a Phase Ib trial, the combination of Glasdegib (PF-04449913) and Dacogen (decitabine) resulted in an overall survival of 11.5 months in patients with either acute myeloid leukemia (AML) or myelodysplastic syndrome, with 40% (2/5) of AML patients experiencing a complete remission (PMID: 29463550). 29463550
Unknown unknown myelodysplastic syndrome not applicable Cytarabine + Daunorubicin + Glasdegib Phase Ib/II Actionable In a Phase Ib trial, the combination of Glasdegib (PF-04449913), Cytosar-U (cytarabine), and Cerubidine (daunorubicin) resulted in an overall survival of 34.7 months in patients with either acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), with 50% (1/2) of MDS patients experiencing a complete remission (PMID: 29463550). 29463550
Unknown unknown myelodysplastic syndrome not applicable Cytarabine + Glasdegib Phase Ib/II Actionable In a Phase Ib trial, the combination of Glasdegib (PF-04449913) and Cytosar-U (cytarabine) resulted in an overall survival of 4.4 months in patients with either acute myeloid leukemia or myelodysplastic syndrome (MDS), with 33% (1/3) of MDS patients experiencing a complete remission (PMID: 29463550). 29463550
Unknown unknown acute myeloid leukemia not applicable Cytarabine + Glasdegib Phase Ib/II Actionable In a Phase Ib trial, the combination of Glasdegib (PF-04449913) and Cytosar-U (cytarabine) resulted in an overall survival of 4.4 months in patients with either acute myeloid leukemia (AML) or myelodysplastic syndrome, with 5% (1/20) of AML patients experiencing a complete remission (PMID: 29463550). 29463550
Unknown unknown acute myeloid leukemia not applicable Cytarabine + Daunorubicin + Glasdegib Phase Ib/II Actionable In a Phase Ib trial, the combination of Glasdegib (PF-04449913), Cytosar-U (cytarabine), and Cerubidine (daunorubicin) resulted in an overall survival of 34.7 months in patients with either acute myeloid leukemia (AML) or myelodysplastic syndrome, with 55% (11/20) of AML patients experiencing a complete remission (PMID: 29463550). 29463550