Phase 1 study of Lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib

Jorge Cortes, Elias Jabbour, George Q. Daley, Susan O'Brien, Srdan Verstovsek, Alessandra Ferrajoli, Charles Koller, Yali Zhu, Paul Statkevich, Hagop Kantarjian

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients. METHODS. The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/ day,plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively. RESULTS. A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered. CONCLUSIONS. The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.

Original languageEnglish (US)
Pages (from-to)1295-1302
Number of pages8
JournalCancer
Volume110
Issue number6
DOIs
StatePublished - Sep 15 2007
Externally publishedYes

Fingerprint

Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Therapeutics
Chronic Disease
Imatinib Mesylate
lonafarnib
Cytogenetics
Diarrhea
Pharmacokinetics
Maximum Tolerated Dose
Hypokalemia
National Cancer Institute (U.S.)
Hematologic Diseases
Myeloid Cells
Transferases
Vomiting
Fatigue

Keywords

  • Chronic myeloid leukemia
  • Farnesyl transferase inhibitor
  • Imatinib
  • Lonafarnib
  • Phase 1 study

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase 1 study of Lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. / Cortes, Jorge; Jabbour, Elias; Daley, George Q.; O'Brien, Susan; Verstovsek, Srdan; Ferrajoli, Alessandra; Koller, Charles; Zhu, Yali; Statkevich, Paul; Kantarjian, Hagop.

In: Cancer, Vol. 110, No. 6, 15.09.2007, p. 1295-1302.

Research output: Contribution to journalArticle

Cortes, J, Jabbour, E, Daley, GQ, O'Brien, S, Verstovsek, S, Ferrajoli, A, Koller, C, Zhu, Y, Statkevich, P & Kantarjian, H 2007, 'Phase 1 study of Lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib', Cancer, vol. 110, no. 6, pp. 1295-1302. https://doi.org/10.1002/cncr.22901
Cortes, Jorge ; Jabbour, Elias ; Daley, George Q. ; O'Brien, Susan ; Verstovsek, Srdan ; Ferrajoli, Alessandra ; Koller, Charles ; Zhu, Yali ; Statkevich, Paul ; Kantarjian, Hagop. / Phase 1 study of Lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. In: Cancer. 2007 ; Vol. 110, No. 6. pp. 1295-1302.
@article{03512a5a35464bf49d3f0511592eb33b,
title = "Phase 1 study of Lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib",
abstract = "BACKGROUND. Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients. METHODS. The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/ day,plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively. RESULTS. A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35{\%}) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered. CONCLUSIONS. The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.",
keywords = "Chronic myeloid leukemia, Farnesyl transferase inhibitor, Imatinib, Lonafarnib, Phase 1 study",
author = "Jorge Cortes and Elias Jabbour and Daley, {George Q.} and Susan O'Brien and Srdan Verstovsek and Alessandra Ferrajoli and Charles Koller and Yali Zhu and Paul Statkevich and Hagop Kantarjian",
year = "2007",
month = "9",
day = "15",
doi = "10.1002/cncr.22901",
language = "English (US)",
volume = "110",
pages = "1295--1302",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Phase 1 study of Lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib

AU - Cortes, Jorge

AU - Jabbour, Elias

AU - Daley, George Q.

AU - O'Brien, Susan

AU - Verstovsek, Srdan

AU - Ferrajoli, Alessandra

AU - Koller, Charles

AU - Zhu, Yali

AU - Statkevich, Paul

AU - Kantarjian, Hagop

PY - 2007/9/15

Y1 - 2007/9/15

N2 - BACKGROUND. Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients. METHODS. The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/ day,plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively. RESULTS. A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered. CONCLUSIONS. The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.

AB - BACKGROUND. Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients. METHODS. The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/ day,plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively. RESULTS. A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered. CONCLUSIONS. The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.

KW - Chronic myeloid leukemia

KW - Farnesyl transferase inhibitor

KW - Imatinib

KW - Lonafarnib

KW - Phase 1 study

UR - http://www.scopus.com/inward/record.url?scp=34548799800&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548799800&partnerID=8YFLogxK

U2 - 10.1002/cncr.22901

DO - 10.1002/cncr.22901

M3 - Article

C2 - 17623836

AN - SCOPUS:34548799800

VL - 110

SP - 1295

EP - 1302

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 6

ER -