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

Gautam Borthakur, Herve Dombret, Philippe Schafhausen, Tim Henrik Brummendorf, Nicolas Boisse, Elias Jabbour, Mariangela Mariani, Laura Capolongo, Patrizia Carpinelli, Cristina Davite, Hagop Kantarjian, Jorge E. Cortes

Research output: Contribution to journalArticle

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/m2. 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).

Original languageEnglish (US)
Pages (from-to)898-904
Number of pages7
JournalHaematologica
Volume100
Issue number7
DOIs
StatePublished - Jul 6 2015
Externally publishedYes

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Leukemia, Myeloid, Chronic Phase
Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Appointments and Schedules
Therapeutics
Intravenous Infusions
Phosphotransferases
Aurora Kinases
Imatinib Mesylate
danusertib
Febrile Neutropenia
Mucositis
Hematologic Neoplasms
Databases
Mutation

ASJC Scopus subject areas

  • Hematology

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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. / Borthakur, Gautam; Dombret, Herve; Schafhausen, Philippe; Brummendorf, Tim Henrik; Boisse, Nicolas; Jabbour, Elias; Mariani, Mariangela; Capolongo, Laura; Carpinelli, Patrizia; Davite, Cristina; Kantarjian, Hagop; Cortes, Jorge E.

In: Haematologica, Vol. 100, No. 7, 06.07.2015, p. 898-904.

Research output: Contribution to journalArticle

Borthakur, Gautam ; Dombret, Herve ; Schafhausen, Philippe ; Brummendorf, Tim Henrik ; Boisse, Nicolas ; Jabbour, Elias ; Mariani, Mariangela ; Capolongo, Laura ; Carpinelli, Patrizia ; Davite, Cristina ; Kantarjian, Hagop ; Cortes, Jorge E. / 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. In: Haematologica. 2015 ; Vol. 100, No. 7. pp. 898-904.
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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/m2. 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).",
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AU - Borthakur, Gautam

AU - Dombret, Herve

AU - Schafhausen, Philippe

AU - Brummendorf, Tim Henrik

AU - Boisse, Nicolas

AU - Jabbour, Elias

AU - Mariani, Mariangela

AU - Capolongo, Laura

AU - Carpinelli, Patrizia

AU - Davite, Cristina

AU - Kantarjian, Hagop

AU - Cortes, Jorge E.

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