A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer

Peter F. Lebowitz, Jennifer Eng-Wong, Brigitte C. Widemann, Frank M. Balis, Nalini Jayaprakash, Catherine Chow, Geoff Clark, Susan B. Gantz, David Venzon, JoAnne Zujewski

Research output: Contribution to journalArticle

Abstract

Purpose: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed. Patients and Methods: Patients with metastatic, hormone receptor-positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen. Results: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months, Conclusions: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)1247-1252
Number of pages6
JournalClinical Cancer Research
Volume11
Issue number3
StatePublished - Feb 1 2005
Externally publishedYes

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tipifarnib
Farnesyltranstransferase
Tamoxifen
Pharmacokinetics
Breast Neoplasms
Blood Cells
Exanthema
Neutropenia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lebowitz, P. F., Eng-Wong, J., Widemann, B. C., Balis, F. M., Jayaprakash, N., Chow, C., ... Zujewski, J. (2005). A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer. Clinical Cancer Research, 11(3), 1247-1252.

A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer. / Lebowitz, Peter F.; Eng-Wong, Jennifer; Widemann, Brigitte C.; Balis, Frank M.; Jayaprakash, Nalini; Chow, Catherine; Clark, Geoff; Gantz, Susan B.; Venzon, David; Zujewski, JoAnne.

In: Clinical Cancer Research, Vol. 11, No. 3, 01.02.2005, p. 1247-1252.

Research output: Contribution to journalArticle

Lebowitz, PF, Eng-Wong, J, Widemann, BC, Balis, FM, Jayaprakash, N, Chow, C, Clark, G, Gantz, SB, Venzon, D & Zujewski, J 2005, 'A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer', Clinical Cancer Research, vol. 11, no. 3, pp. 1247-1252.
Lebowitz PF, Eng-Wong J, Widemann BC, Balis FM, Jayaprakash N, Chow C et al. A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer. Clinical Cancer Research. 2005 Feb 1;11(3):1247-1252.
Lebowitz, Peter F. ; Eng-Wong, Jennifer ; Widemann, Brigitte C. ; Balis, Frank M. ; Jayaprakash, Nalini ; Chow, Catherine ; Clark, Geoff ; Gantz, Susan B. ; Venzon, David ; Zujewski, JoAnne. / A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 3. pp. 1247-1252.
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abstract = "Purpose: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed. Patients and Methods: Patients with metastatic, hormone receptor-positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen. Results: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42{\%} at 200 mg and 54{\%} at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months, Conclusions: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.",
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AU - Lebowitz, Peter F.

AU - Eng-Wong, Jennifer

AU - Widemann, Brigitte C.

AU - Balis, Frank M.

AU - Jayaprakash, Nalini

AU - Chow, Catherine

AU - Clark, Geoff

AU - Gantz, Susan B.

AU - Venzon, David

AU - Zujewski, JoAnne

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N2 - Purpose: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed. Patients and Methods: Patients with metastatic, hormone receptor-positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen. Results: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months, Conclusions: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.

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