A phase I study of Danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy

Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study was conducted in patients with accelerated or blastic phase chronic myeloid leukemia or Philadelphia chromosome positive acute lymphoblastic leukemia. Two dosing schedules were studied: Schedule A: danusertib by 3-hour IV infusion daily for 7 consecutive days (Days 1-7) in a 14-day cycle and Schedule B: danusertib by 3-hour IV infusion daily for 14 consecutive days (Days 1-14) in a 21-day cycle. A total of 37 patients were treated, 29 treated by Schedule A and 8 by Schedule B. The recommended Phase II dose for Schedule A was 180 mg/m2. Enrollment to Schedule B was stopped early because of logistical problems in the frequency of infusions. Febrile neutropenia and mucositis were dose-limiting toxicities in Schedule A. Four patients with T315I ABL kinase mutation, all in Schedule A, responded. Danusertib has an acceptable toxicity profile and is active in patients with Bcr-Abl-associated advanced hematologic malignancies. The study was registered with the European Clinical Trails Data Base (EudraCT Number 2007-004070-18).