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.

Abstract

Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study of danusertib 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, in which danusertib was given by 3-hour intravenous infusion daily for 7 consecutive days (days 1-7) in a 14-day cycle, and schedule B, in which the danusertib was given by 3-hour intravenous infusion daily for 14 consecutive days (days 1-14) in a 21-day cycle. A total of 37 patients were treated, 29 with schedule A and eight with schedule B. The recommended phase 2 dose for schedule A was 180 mg/m(2). Enrollment to schedule B was stopped early because of logistical problems with the frequency of infusions. Febrile neutropenia and mucositis were dose-limiting toxicities in schedule A. Four patients with T315I ABL kinase mutation, all treated with schedule A, responded. Danusertib has an acceptable toxicity profile and is active in patients with Bcr-Abl-associated advanced hematologic malignancies. This study was registered with the European Clinical Trails Data Base (EudraCT number 2007-004070-18).

• Authors: Gautam Borthakur, Herve Dombret, Philippe Schafhausen, Tim Henrik Brummendorf, Nicolas Boissel, Elias Jabbour, Mariangela Mariani, Laura Capolongo, Patrizia Carpinelli, Cristina Davite, Hagop Kantarjian, Jorge E Cortes
• Journal: Haematologica (Haematologica) Vol. 100 Issue 7 Pg. 898-904 (Jul 2015) ISSN: 1592-8721 [Electronic] Italy
• PMID: 25887498 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• Antineoplastic Agents
• Benzamides
• Protein Kinase Inhibitors
• Pyrazoles
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• danusertib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzamides (administration & dosage, adverse effects, pharmacokinetics)
• Blast Crisis (drug therapy, genetics, pathology)
• Drug Administration Schedule
• Febrile Neutropenia (chemically induced, genetics, pathology)
• Female
• Fusion Proteins, bcr-abl (genetics)
• Humans
• Imatinib Mesylate (administration & dosage, adverse effects, pharmacokinetics)
• Leukemia, Myeloid, Accelerated Phase (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Mucositis (chemically induced, genetics, pathology)
• Mutation
• Philadelphia Chromosome
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrazoles (administration & dosage, adverse effects, pharmacokinetics)