A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors

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Abstract

Introduction Based on preclinical cytotoxic synergy between tipifarnib and erlotinib, a phase I study of this combination was conducted in patients with advanced solid tumors to evaluate safety, tolerability, maximum tolerated dose (MTD) and preliminary evidence of efficacy. Methods Patient enrollment followed the traditional “3 + 3” dose escalation scheme, through 4 dose levels, ranging from tipifarnib 200 mg twice daily plus erlotinib 75 mg once daily to tipifarnib 300 mg twice daily plus erlotinib 150 mg once daily. After the MTD of the combination was identified, 12 additional patients were treated to better define the pharmacokinetics and pharmacodynamics of these agents. Results A total of 27 patients were enrolled in the study (dose escalation, 15; dose expansion, 12). Dose limiting toxicity was seen in one patient at dose level 4 (grade 3 diarrhea). The MTD was reached at erlotinib 150 mg once daily combined with tipifarnib 300 mg twice daily. The most common side effects of the combination of all grades were diarrhea (85.2%), fatigue (77.8%), rash (70.4%), and anorexia (59.3%). Overall, 2 patients (7.4%; with liver cancer and melanoma, respectively) had partial responses, 10 (37%) had stable disease, 11 had progressive disease (40.7%) and 4 stopped treatment prematurely for assessment. Conclusion The combination of tipifarnib and erlotinib was well tolerated. Erlotinib 150 mg once daily for 28 days combined with tipifarnib 300 mg twice daily for 21 days was identified as the recommended phase 2 dose. Tipifarnib is currently being evaluated in HRAS mutant tumors, providing a potential opportunity to further test this combination.

Original languageEnglish (US)
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - Jan 1 2018

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tipifarnib
Farnesyltranstransferase
Epidermal Growth Factor
Protein-Tyrosine Kinases
Maximum Tolerated Dose
Neoplasms
Diarrhea
Anorexia
Liver Neoplasms
Erlotinib Hydrochloride
Exanthema
Fatigue
Melanoma
Pharmacokinetics
Safety

Keywords

  • Erlotinib
  • Farnesyltransferase inhibitor
  • Phase I
  • RAS
  • Solid tumors
  • Tipifarnib

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

@article{c106181a4b4545aeb5b27926bfde0d07,
title = "A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors",
abstract = "Introduction Based on preclinical cytotoxic synergy between tipifarnib and erlotinib, a phase I study of this combination was conducted in patients with advanced solid tumors to evaluate safety, tolerability, maximum tolerated dose (MTD) and preliminary evidence of efficacy. Methods Patient enrollment followed the traditional “3 + 3” dose escalation scheme, through 4 dose levels, ranging from tipifarnib 200 mg twice daily plus erlotinib 75 mg once daily to tipifarnib 300 mg twice daily plus erlotinib 150 mg once daily. After the MTD of the combination was identified, 12 additional patients were treated to better define the pharmacokinetics and pharmacodynamics of these agents. Results A total of 27 patients were enrolled in the study (dose escalation, 15; dose expansion, 12). Dose limiting toxicity was seen in one patient at dose level 4 (grade 3 diarrhea). The MTD was reached at erlotinib 150 mg once daily combined with tipifarnib 300 mg twice daily. The most common side effects of the combination of all grades were diarrhea (85.2{\%}), fatigue (77.8{\%}), rash (70.4{\%}), and anorexia (59.3{\%}). Overall, 2 patients (7.4{\%}; with liver cancer and melanoma, respectively) had partial responses, 10 (37{\%}) had stable disease, 11 had progressive disease (40.7{\%}) and 4 stopped treatment prematurely for assessment. Conclusion The combination of tipifarnib and erlotinib was well tolerated. Erlotinib 150 mg once daily for 28 days combined with tipifarnib 300 mg twice daily for 21 days was identified as the recommended phase 2 dose. Tipifarnib is currently being evaluated in HRAS mutant tumors, providing a potential opportunity to further test this combination.",
keywords = "Erlotinib, Farnesyltransferase inhibitor, Phase I, RAS, Solid tumors, Tipifarnib",
author = "Khalid Jazieh and Molina, {Julian R} and Jacob Allred and Jun Yin and Reid, {Joel M} and Goetz, {Matthew Philip} and Lim, {Vun Sin} and Kaufmann, {Scott H} and Alex Adjei",
year = "2018",
month = "1",
day = "1",
doi = "10.1007/s10637-018-0662-1",
language = "English (US)",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",

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TY - JOUR

T1 - A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors

AU - Jazieh, Khalid

AU - Molina, Julian R

AU - Allred, Jacob

AU - Yin, Jun

AU - Reid, Joel M

AU - Goetz, Matthew Philip

AU - Lim, Vun Sin

AU - Kaufmann, Scott H

AU - Adjei, Alex

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Introduction Based on preclinical cytotoxic synergy between tipifarnib and erlotinib, a phase I study of this combination was conducted in patients with advanced solid tumors to evaluate safety, tolerability, maximum tolerated dose (MTD) and preliminary evidence of efficacy. Methods Patient enrollment followed the traditional “3 + 3” dose escalation scheme, through 4 dose levels, ranging from tipifarnib 200 mg twice daily plus erlotinib 75 mg once daily to tipifarnib 300 mg twice daily plus erlotinib 150 mg once daily. After the MTD of the combination was identified, 12 additional patients were treated to better define the pharmacokinetics and pharmacodynamics of these agents. Results A total of 27 patients were enrolled in the study (dose escalation, 15; dose expansion, 12). Dose limiting toxicity was seen in one patient at dose level 4 (grade 3 diarrhea). The MTD was reached at erlotinib 150 mg once daily combined with tipifarnib 300 mg twice daily. The most common side effects of the combination of all grades were diarrhea (85.2%), fatigue (77.8%), rash (70.4%), and anorexia (59.3%). Overall, 2 patients (7.4%; with liver cancer and melanoma, respectively) had partial responses, 10 (37%) had stable disease, 11 had progressive disease (40.7%) and 4 stopped treatment prematurely for assessment. Conclusion The combination of tipifarnib and erlotinib was well tolerated. Erlotinib 150 mg once daily for 28 days combined with tipifarnib 300 mg twice daily for 21 days was identified as the recommended phase 2 dose. Tipifarnib is currently being evaluated in HRAS mutant tumors, providing a potential opportunity to further test this combination.

AB - Introduction Based on preclinical cytotoxic synergy between tipifarnib and erlotinib, a phase I study of this combination was conducted in patients with advanced solid tumors to evaluate safety, tolerability, maximum tolerated dose (MTD) and preliminary evidence of efficacy. Methods Patient enrollment followed the traditional “3 + 3” dose escalation scheme, through 4 dose levels, ranging from tipifarnib 200 mg twice daily plus erlotinib 75 mg once daily to tipifarnib 300 mg twice daily plus erlotinib 150 mg once daily. After the MTD of the combination was identified, 12 additional patients were treated to better define the pharmacokinetics and pharmacodynamics of these agents. Results A total of 27 patients were enrolled in the study (dose escalation, 15; dose expansion, 12). Dose limiting toxicity was seen in one patient at dose level 4 (grade 3 diarrhea). The MTD was reached at erlotinib 150 mg once daily combined with tipifarnib 300 mg twice daily. The most common side effects of the combination of all grades were diarrhea (85.2%), fatigue (77.8%), rash (70.4%), and anorexia (59.3%). Overall, 2 patients (7.4%; with liver cancer and melanoma, respectively) had partial responses, 10 (37%) had stable disease, 11 had progressive disease (40.7%) and 4 stopped treatment prematurely for assessment. Conclusion The combination of tipifarnib and erlotinib was well tolerated. Erlotinib 150 mg once daily for 28 days combined with tipifarnib 300 mg twice daily for 21 days was identified as the recommended phase 2 dose. Tipifarnib is currently being evaluated in HRAS mutant tumors, providing a potential opportunity to further test this combination.

KW - Erlotinib

KW - Farnesyltransferase inhibitor

KW - Phase I

KW - RAS

KW - Solid tumors

KW - Tipifarnib

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U2 - 10.1007/s10637-018-0662-1

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