Phase Ib Study of Glasdegib, A Hedgehog Pathway Inhibitor, in Combination With Standard Chemotherapy in Patients With AML or High-Risk MDS
Mené sur 52 patients atteints d'une leucémie myéloïde aiguë ou d'un syndrome myélodysplasique à haut risque, cet essai de phase Ib évalue les caractéristiques pharmacocinétiques et pharmacodynamiques, l'activité antitumorale, la doxe maximale tolérée et la toxicité du glasdégib, un inhibiteur de la voie Hedgehog, en combinaison avec une chimiothérapie standard (cytarabine, décitabine, daunorubicine)
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 non-hematologic adverse events were mostly grades 1-2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, sixteen (31%) patients achieved a complete remission (CR)/CR with incomplete blood count recovery. 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated maximum tolerated dose 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.