A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors

Stacy L. Moulder, John J. Mahany, Richard Lush, Caio Rocha-Lima, Michael Langevin, Karen J. Ferrante, Lisa Michele Bartkowski, Shama M. Kajiji, Dennis A. Noe, Simone Paillet, Daniel M. Sullivan

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent. Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria ≥ grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses. Results: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of ∼3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754. Conclusions: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is ≥640 mg twice per day.

Original languageEnglish
Pages (from-to)7127-7135
Number of pages9
JournalClinical Cancer Research
Volume10
Issue number21
DOIs
StatePublished - Nov 1 2004

Fingerprint

Farnesyltranstransferase
Neoplasms
Maximum Tolerated Dose
Pharmacokinetics
Clinical Trials, Phase I
Pharmaceutical Preparations
Tablets
Half-Life
CP 609754
Blood Cells
Research Design
Bone Marrow
Kidney
Safety
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Moulder, S. L., Mahany, J. J., Lush, R., Rocha-Lima, C., Langevin, M., Ferrante, K. J., ... Sullivan, D. M. (2004). A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors. Clinical Cancer Research, 10(21), 7127-7135. https://doi.org/10.1158/1078-0432.CCR-04-0901

A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors. / Moulder, Stacy L.; Mahany, John J.; Lush, Richard; Rocha-Lima, Caio; Langevin, Michael; Ferrante, Karen J.; Bartkowski, Lisa Michele; Kajiji, Shama M.; Noe, Dennis A.; Paillet, Simone; Sullivan, Daniel M.

In: Clinical Cancer Research, Vol. 10, No. 21, 01.11.2004, p. 7127-7135.

Research output: Contribution to journalArticle

Moulder, SL, Mahany, JJ, Lush, R, Rocha-Lima, C, Langevin, M, Ferrante, KJ, Bartkowski, LM, Kajiji, SM, Noe, DA, Paillet, S & Sullivan, DM 2004, 'A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors', Clinical Cancer Research, vol. 10, no. 21, pp. 7127-7135. https://doi.org/10.1158/1078-0432.CCR-04-0901
Moulder, Stacy L. ; Mahany, John J. ; Lush, Richard ; Rocha-Lima, Caio ; Langevin, Michael ; Ferrante, Karen J. ; Bartkowski, Lisa Michele ; Kajiji, Shama M. ; Noe, Dennis A. ; Paillet, Simone ; Sullivan, Daniel M. / A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 21. pp. 7127-7135.
@article{09669195bb584e109867ad33f94b2cb2,
title = "A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors",
abstract = "Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent. Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria ≥ grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses. Results: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of ∼3 hours. Pharmacodynamic results predict a 95{\%} maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754. Conclusions: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is ≥640 mg twice per day.",
author = "Moulder, {Stacy L.} and Mahany, {John J.} and Richard Lush and Caio Rocha-Lima and Michael Langevin and Ferrante, {Karen J.} and Bartkowski, {Lisa Michele} and Kajiji, {Shama M.} and Noe, {Dennis A.} and Simone Paillet and Sullivan, {Daniel M.}",
year = "2004",
month = "11",
day = "1",
doi = "10.1158/1078-0432.CCR-04-0901",
language = "English",
volume = "10",
pages = "7127--7135",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "21",

}

TY - JOUR

T1 - A phase I open label study of the farnesyltransferase inhibitor CP-609,754 in patients with advanced malignant tumors

AU - Moulder, Stacy L.

AU - Mahany, John J.

AU - Lush, Richard

AU - Rocha-Lima, Caio

AU - Langevin, Michael

AU - Ferrante, Karen J.

AU - Bartkowski, Lisa Michele

AU - Kajiji, Shama M.

AU - Noe, Dennis A.

AU - Paillet, Simone

AU - Sullivan, Daniel M.

PY - 2004/11/1

Y1 - 2004/11/1

N2 - Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent. Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria ≥ grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses. Results: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of ∼3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754. Conclusions: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is ≥640 mg twice per day.

AB - Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent. Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria ≥ grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses. Results: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of ∼3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754. Conclusions: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is ≥640 mg twice per day.

UR - http://www.scopus.com/inward/record.url?scp=8444242092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=8444242092&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-04-0901

DO - 10.1158/1078-0432.CCR-04-0901

M3 - Article

VL - 10

SP - 7127

EP - 7135

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 21

ER -