title: 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.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Hopital Saint Louis, Paris, France.
authors.forename: Herve
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Department of Internal Medicine II, Hubertus Wald Tumor Center, University Cancer Center, Hamburg, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Schafhausen
authors.affiliation: Department of Internal Medicine II, Hubertus Wald Tumor Center, University Cancer Center, Hamburg, Germany Department of Hematology and Oncology, University Hospital of the RWTH Aachen, Germany.
authors.forename: Tim Henrik
authors.initials: TH
authors.lastname: Brummendorf
authors.affiliation: Hopital Saint Louis, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Clinical Organization for Strategies and Solutions S.r.l.(CLIOSS), Nerviano Medical Sciences, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Mariani
authors.affiliation: Clinical Organization for Strategies and Solutions S.r.l.(CLIOSS), Nerviano Medical Sciences, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Capolongo
authors.affiliation: Oncology, Nerviano Medical Sciences, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carpinelli
authors.affiliation: Clinical Organization for Strategies and Solutions S.r.l.(CLIOSS), Nerviano Medical Sciences, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Davite
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, USA jcortes@mdanderson.org.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001752:Blast Crisis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004334:Drug Administration Schedule; D064147:Febrile Neutropenia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015465:Leukemia, Myeloid, Accelerated Phase / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C523797:danusertib