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

Abstract

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
Volume24
Issue number10
DOIs
StatePublished - May 15 2018

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Myelodysplastic Syndromes
Acute Myeloid Leukemia
Drug Therapy
Cytarabine
decitabine
Dysgeusia
Induction Chemotherapy
Daunorubicin
Alopecia
Spasm
Research Design
Pharmacokinetics
Safety
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. / Savona, Michael R.; Pollyea, Daniel A.; Stock, Wendy; Oehler, Vivian G.; Schroeder, Mark A.; Lancet, Jeffrey; McCloskey, James; Kantarjian, Hagop M.; Ma, Weidong Wendy; Naveed Shaik, M.; Douglas Laird, A.; Zeremski, Mirjana; O'Connell, Ashleigh; Chan, Geoffrey; Cortes, Jorge E.

In: Clinical Cancer Research, Vol. 24, No. 10, 15.05.2018, p. 2294-2303.

Research output: Contribution to journalArticle

Savona, MR, Pollyea, DA, Stock, W, Oehler, VG, Schroeder, MA, Lancet, J, McCloskey, J, Kantarjian, HM, Ma, WW, Naveed Shaik, M, Douglas Laird, A, Zeremski, M, O'Connell, A, Chan, G & Cortes, JE 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, vol. 24, no. 10, pp. 2294-2303. https://doi.org/10.1158/1078-0432.CCR-17-2824
Savona, Michael R. ; Pollyea, Daniel A. ; Stock, Wendy ; Oehler, Vivian G. ; Schroeder, Mark A. ; Lancet, Jeffrey ; McCloskey, James ; Kantarjian, Hagop M. ; Ma, Weidong Wendy ; Naveed Shaik, M. ; Douglas Laird, A. ; Zeremski, Mirjana ; O'Connell, Ashleigh ; Chan, Geoffrey ; Cortes, Jorge E. / Phase ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 10. pp. 2294-2303.
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abstract = "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 3{\th}3 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.",
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T1 - Phase ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS

AU - Savona, Michael R.

AU - Pollyea, Daniel A.

AU - Stock, Wendy

AU - Oehler, Vivian G.

AU - Schroeder, Mark A.

AU - Lancet, Jeffrey

AU - McCloskey, James

AU - Kantarjian, Hagop M.

AU - Ma, Weidong Wendy

AU - Naveed Shaik, M.

AU - Douglas Laird, A.

AU - Zeremski, Mirjana

AU - O'Connell, Ashleigh

AU - Chan, Geoffrey

AU - Cortes, Jorge E.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - 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.

AB - 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.

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