Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure

Jorge Cortes, Alfonso Quintás-Cardama, Guillermo Garcia-Manero, Susan O'Brien, Dan Jones, Stefan Faderl, Theresa Ebarb, Francis Giles, Deborah Thomas, Hagop Kantarjian

Research output: Contribution to journalArticle

Abstract

BACKGROUND. The tolerability and efficacy of the combination of tipifarnib, an orally bioavailable nonpeptidomimetic farnesyl transferase inhibitor, and imatinib was investigated in patients with chronic myelogenous leukemia in chronic phase who had failed imatinib. METHODS. Twenty-six patients (13 [50%] with Abl kinase domain mutations) were treated. The initial dose level was tipifarnib at a dose of 300 mg twice daily and imatinib at a dose of 300 mg daily. Therapy was escalated following a '3 + 3' phase 1 design and the maximum tolerated dose was defined as tipifarnib at a dose of 400 mg twice daily and imatinib at a dose of 400 mg daily. Therapy was administered for a median of 26 weeks (range, 3-150 weeks). RESULTS. Adverse events included diarrhea in 21 patients (81%) and nausea in 18 patients (69%), but were generally grade 2 or less (using the revised National Cancer Institute Common Toxicity Criteria). Grade 3-4 neutropenia and thrombocytopenia occurred in 11 patients (42%) and 8 patients (31%), respectively. Sixteen patients discontinued therapy (5 due to toxicity and 11 due to lack of response or disease progression). Hematologic responses were attained by 17 (68%) of 25 assessable patients. Nine patients (36%) also achieved a cytogenetic response (3 complete responses, 4 partial responses, and 2 minimal responses), including 4 patients harboring mutant Bcr-Abl tyrosine kinases. One patient bearing the highly imatinib-resistant T315I mutant achieved a partial cytogenetic response. The median response duration was 3 months (range, 2-30+ months). CONCLUSIONS. The combination of tipifarnib and imatinib is well tolerated and has activity against several Abl kinase domain mutants. Combinations of tipifarnib with more potent tyrosine kinase inhibitors warrant further investigation.

Original languageEnglish (US)
Pages (from-to)2000-2006
Number of pages7
JournalCancer
Volume110
Issue number9
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Fingerprint

tipifarnib
Leukemia, Myeloid, Chronic Phase
Cytogenetics
Imatinib Mesylate
Phosphotransferases
bcr-abl Fusion Proteins
Maximum Tolerated Dose
National Cancer Institute (U.S.)
Transferases
Neutropenia

Keywords

  • BCR-ABL
  • Chronic myelogenous leukemia
  • Imatinib
  • Mutations
  • Tipifarnib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cortes, J., Quintás-Cardama, A., Garcia-Manero, G., O'Brien, S., Jones, D., Faderl, S., ... Kantarjian, H. (2007). Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure. Cancer, 110(9), 2000-2006. https://doi.org/10.1002/cncr.23006

Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure. / Cortes, Jorge; Quintás-Cardama, Alfonso; Garcia-Manero, Guillermo; O'Brien, Susan; Jones, Dan; Faderl, Stefan; Ebarb, Theresa; Giles, Francis; Thomas, Deborah; Kantarjian, Hagop.

In: Cancer, Vol. 110, No. 9, 01.11.2007, p. 2000-2006.

Research output: Contribution to journalArticle

Cortes, J, Quintás-Cardama, A, Garcia-Manero, G, O'Brien, S, Jones, D, Faderl, S, Ebarb, T, Giles, F, Thomas, D & Kantarjian, H 2007, 'Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure', Cancer, vol. 110, no. 9, pp. 2000-2006. https://doi.org/10.1002/cncr.23006
Cortes, Jorge ; Quintás-Cardama, Alfonso ; Garcia-Manero, Guillermo ; O'Brien, Susan ; Jones, Dan ; Faderl, Stefan ; Ebarb, Theresa ; Giles, Francis ; Thomas, Deborah ; Kantarjian, Hagop. / Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure. In: Cancer. 2007 ; Vol. 110, No. 9. pp. 2000-2006.
@article{bcc19d8789334ac481dcacc0feb5036f,
title = "Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure",
abstract = "BACKGROUND. The tolerability and efficacy of the combination of tipifarnib, an orally bioavailable nonpeptidomimetic farnesyl transferase inhibitor, and imatinib was investigated in patients with chronic myelogenous leukemia in chronic phase who had failed imatinib. METHODS. Twenty-six patients (13 [50{\%}] with Abl kinase domain mutations) were treated. The initial dose level was tipifarnib at a dose of 300 mg twice daily and imatinib at a dose of 300 mg daily. Therapy was escalated following a '3 + 3' phase 1 design and the maximum tolerated dose was defined as tipifarnib at a dose of 400 mg twice daily and imatinib at a dose of 400 mg daily. Therapy was administered for a median of 26 weeks (range, 3-150 weeks). RESULTS. Adverse events included diarrhea in 21 patients (81{\%}) and nausea in 18 patients (69{\%}), but were generally grade 2 or less (using the revised National Cancer Institute Common Toxicity Criteria). Grade 3-4 neutropenia and thrombocytopenia occurred in 11 patients (42{\%}) and 8 patients (31{\%}), respectively. Sixteen patients discontinued therapy (5 due to toxicity and 11 due to lack of response or disease progression). Hematologic responses were attained by 17 (68{\%}) of 25 assessable patients. Nine patients (36{\%}) also achieved a cytogenetic response (3 complete responses, 4 partial responses, and 2 minimal responses), including 4 patients harboring mutant Bcr-Abl tyrosine kinases. One patient bearing the highly imatinib-resistant T315I mutant achieved a partial cytogenetic response. The median response duration was 3 months (range, 2-30+ months). CONCLUSIONS. The combination of tipifarnib and imatinib is well tolerated and has activity against several Abl kinase domain mutants. Combinations of tipifarnib with more potent tyrosine kinase inhibitors warrant further investigation.",
keywords = "BCR-ABL, Chronic myelogenous leukemia, Imatinib, Mutations, Tipifarnib",
author = "Jorge Cortes and Alfonso Quint{\'a}s-Cardama and Guillermo Garcia-Manero and Susan O'Brien and Dan Jones and Stefan Faderl and Theresa Ebarb and Francis Giles and Deborah Thomas and Hagop Kantarjian",
year = "2007",
month = "11",
day = "1",
doi = "10.1002/cncr.23006",
language = "English (US)",
volume = "110",
pages = "2000--2006",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "9",

}

TY - JOUR

T1 - Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure

AU - Cortes, Jorge

AU - Quintás-Cardama, Alfonso

AU - Garcia-Manero, Guillermo

AU - O'Brien, Susan

AU - Jones, Dan

AU - Faderl, Stefan

AU - Ebarb, Theresa

AU - Giles, Francis

AU - Thomas, Deborah

AU - Kantarjian, Hagop

PY - 2007/11/1

Y1 - 2007/11/1

N2 - BACKGROUND. The tolerability and efficacy of the combination of tipifarnib, an orally bioavailable nonpeptidomimetic farnesyl transferase inhibitor, and imatinib was investigated in patients with chronic myelogenous leukemia in chronic phase who had failed imatinib. METHODS. Twenty-six patients (13 [50%] with Abl kinase domain mutations) were treated. The initial dose level was tipifarnib at a dose of 300 mg twice daily and imatinib at a dose of 300 mg daily. Therapy was escalated following a '3 + 3' phase 1 design and the maximum tolerated dose was defined as tipifarnib at a dose of 400 mg twice daily and imatinib at a dose of 400 mg daily. Therapy was administered for a median of 26 weeks (range, 3-150 weeks). RESULTS. Adverse events included diarrhea in 21 patients (81%) and nausea in 18 patients (69%), but were generally grade 2 or less (using the revised National Cancer Institute Common Toxicity Criteria). Grade 3-4 neutropenia and thrombocytopenia occurred in 11 patients (42%) and 8 patients (31%), respectively. Sixteen patients discontinued therapy (5 due to toxicity and 11 due to lack of response or disease progression). Hematologic responses were attained by 17 (68%) of 25 assessable patients. Nine patients (36%) also achieved a cytogenetic response (3 complete responses, 4 partial responses, and 2 minimal responses), including 4 patients harboring mutant Bcr-Abl tyrosine kinases. One patient bearing the highly imatinib-resistant T315I mutant achieved a partial cytogenetic response. The median response duration was 3 months (range, 2-30+ months). CONCLUSIONS. The combination of tipifarnib and imatinib is well tolerated and has activity against several Abl kinase domain mutants. Combinations of tipifarnib with more potent tyrosine kinase inhibitors warrant further investigation.

AB - BACKGROUND. The tolerability and efficacy of the combination of tipifarnib, an orally bioavailable nonpeptidomimetic farnesyl transferase inhibitor, and imatinib was investigated in patients with chronic myelogenous leukemia in chronic phase who had failed imatinib. METHODS. Twenty-six patients (13 [50%] with Abl kinase domain mutations) were treated. The initial dose level was tipifarnib at a dose of 300 mg twice daily and imatinib at a dose of 300 mg daily. Therapy was escalated following a '3 + 3' phase 1 design and the maximum tolerated dose was defined as tipifarnib at a dose of 400 mg twice daily and imatinib at a dose of 400 mg daily. Therapy was administered for a median of 26 weeks (range, 3-150 weeks). RESULTS. Adverse events included diarrhea in 21 patients (81%) and nausea in 18 patients (69%), but were generally grade 2 or less (using the revised National Cancer Institute Common Toxicity Criteria). Grade 3-4 neutropenia and thrombocytopenia occurred in 11 patients (42%) and 8 patients (31%), respectively. Sixteen patients discontinued therapy (5 due to toxicity and 11 due to lack of response or disease progression). Hematologic responses were attained by 17 (68%) of 25 assessable patients. Nine patients (36%) also achieved a cytogenetic response (3 complete responses, 4 partial responses, and 2 minimal responses), including 4 patients harboring mutant Bcr-Abl tyrosine kinases. One patient bearing the highly imatinib-resistant T315I mutant achieved a partial cytogenetic response. The median response duration was 3 months (range, 2-30+ months). CONCLUSIONS. The combination of tipifarnib and imatinib is well tolerated and has activity against several Abl kinase domain mutants. Combinations of tipifarnib with more potent tyrosine kinase inhibitors warrant further investigation.

KW - BCR-ABL

KW - Chronic myelogenous leukemia

KW - Imatinib

KW - Mutations

KW - Tipifarnib

UR - http://www.scopus.com/inward/record.url?scp=35648943275&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35648943275&partnerID=8YFLogxK

U2 - 10.1002/cncr.23006

DO - 10.1002/cncr.23006

M3 - Article

C2 - 17849425

AN - SCOPUS:35648943275

VL - 110

SP - 2000

EP - 2006

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 9

ER -