Abstract | BACKGROUND: METHODS: : A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. RESULTS: : INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/ nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to- histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to- glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to- isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. CONCLUSIONS: : INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored.
|
Authors | Hagop Kantarjian, Phillipp le Coutre, Jorge Cortes, Javier Pinilla-Ibarz, Arnon Nagler, Andreas Hochhaus, Shinya Kimura, Oliver Ottmann |
Journal | Cancer
(Cancer)
Vol. 116
Issue 11
Pg. 2665-72
(Jun 01 2010)
ISSN: 0008-543X [Print] United States |
PMID | 20310049
(Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
|
Copyright | (c) 2010 American Cancer Society. |
Chemical References |
- Benzamides
- Piperazines
- Protein Kinase Inhibitors
- Pyrimidines
- Imatinib Mesylate
- bafetinib
|
Topics |
- Adolescent
- Adult
- Aged
- Benzamides
- Drug Administration Schedule
- Drug Resistance, Neoplasm
- Female
- Humans
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(drug therapy)
- Male
- Middle Aged
- Piperazines
(therapeutic use)
- Protein Kinase Inhibitors
(pharmacokinetics, therapeutic use)
- Pyrimidines
(adverse effects, pharmacokinetics, therapeutic use)
|