title: Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib.
abstract: Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.
authors.affiliation: M. D. Anderson Cancer Center, Houston, TX, USA. jcortes@mdanderson.org
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Anna G
authors.initials: AG
authors.lastname: Turkina
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Shen
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pasquini
authors.forename: H Jean
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Steven
authors.initials: S
authors.lastname: Arkin
authors.forename: Angela
authors.initials: A
authors.lastname: Volkert
authors.forename: Nadine
authors.initials: N
authors.lastname: Besson
authors.forename: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Junyuan
authors.initials: J
authors.lastname: Wang
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000009:adverse effects* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects* / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate