Phase ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS

Michael R. Savona, Daniel A. Pollyea, Wendy Stock, Vivian G. Oehler, Mark A. Schroeder, Jeffrey Lancet, James McCloskey, Hagop M. Kantarjian, Weidong Wendy Ma, M. Naveed Shaik, A. Douglas Laird, Mirjana Zeremski, Ashleigh O'Connell, Geoffrey Chan, Jorge E. Cortes

Research output: Contribution to journalArticle

32 Scopus citations


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 ¼ 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 3þ3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n ¼ 23) and C (n ¼ 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.

Original languageEnglish (US)
Pages (from-to)2294-2303
Number of pages10
JournalClinical Cancer Research
Issue number10
StatePublished - May 15 2018
Externally publishedYes


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Savona, M. R., Pollyea, D. A., Stock, W., Oehler, V. G., Schroeder, M. A., Lancet, J., McCloskey, J., Kantarjian, H. M., Ma, W. W., Naveed Shaik, M., Douglas Laird, A., Zeremski, M., O'Connell, A., Chan, G., & Cortes, J. E. (2018). Phase ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clinical Cancer Research, 24(10), 2294-2303.