Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies

M. Hidalgo, L. L. Siu, J. Nemunaitis, J. Rizzo, L. A. Hammond, C. Takimoto, S. G. Eckhardt, A. Tolcher, C. D. Britten, L. Denis, K. Ferrante, D. D. Von Hoff, S. Silberman, E. K. Rowinsky

Research output: Contribution to journalArticle

Abstract

Purpose: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. Results: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 μg/mL; clearance rate, 6.33 ± 6.41 L/h; elimination half-life, 24.4 ± 14.6 hours; volume of distribution, 136. 4 ± 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 μg/h/mL). Conclusion: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

Original languageEnglish (US)
Pages (from-to)3267-3279
Number of pages13
JournalJournal of Clinical Oncology
Volume19
Issue number13
StatePublished - Jul 1 2001
Externally publishedYes

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Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Neoplasms
Maximum Tolerated Dose
Appointments and Schedules
Pharmacokinetics
Erlotinib Hydrochloride
Half-Life
Diarrhea

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hidalgo, M., Siu, L. L., Nemunaitis, J., Rizzo, J., Hammond, L. A., Takimoto, C., ... Rowinsky, E. K. (2001). Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. Journal of Clinical Oncology, 19(13), 3267-3279.

Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. / Hidalgo, M.; Siu, L. L.; Nemunaitis, J.; Rizzo, J.; Hammond, L. A.; Takimoto, C.; Eckhardt, S. G.; Tolcher, A.; Britten, C. D.; Denis, L.; Ferrante, K.; Von Hoff, D. D.; Silberman, S.; Rowinsky, E. K.

In: Journal of Clinical Oncology, Vol. 19, No. 13, 01.07.2001, p. 3267-3279.

Research output: Contribution to journalArticle

Hidalgo, M, Siu, LL, Nemunaitis, J, Rizzo, J, Hammond, LA, Takimoto, C, Eckhardt, SG, Tolcher, A, Britten, CD, Denis, L, Ferrante, K, Von Hoff, DD, Silberman, S & Rowinsky, EK 2001, 'Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies', Journal of Clinical Oncology, vol. 19, no. 13, pp. 3267-3279.
Hidalgo, M. ; Siu, L. L. ; Nemunaitis, J. ; Rizzo, J. ; Hammond, L. A. ; Takimoto, C. ; Eckhardt, S. G. ; Tolcher, A. ; Britten, C. D. ; Denis, L. ; Ferrante, K. ; Von Hoff, D. D. ; Silberman, S. ; Rowinsky, E. K. / Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. In: Journal of Clinical Oncology. 2001 ; Vol. 19, No. 13. pp. 3267-3279.
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abstract = "Purpose: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. Results: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 μg/mL; clearance rate, 6.33 ± 6.41 L/h; elimination half-life, 24.4 ± 14.6 hours; volume of distribution, 136. 4 ± 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 μg/h/mL). Conclusion: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.",
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T1 - Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies

AU - Hidalgo, M.

AU - Siu, L. L.

AU - Nemunaitis, J.

AU - Rizzo, J.

AU - Hammond, L. A.

AU - Takimoto, C.

AU - Eckhardt, S. G.

AU - Tolcher, A.

AU - Britten, C. D.

AU - Denis, L.

AU - Ferrante, K.

AU - Von Hoff, D. D.

AU - Silberman, S.

AU - Rowinsky, E. K.

PY - 2001/7/1

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N2 - Purpose: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. Results: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 μg/mL; clearance rate, 6.33 ± 6.41 L/h; elimination half-life, 24.4 ± 14.6 hours; volume of distribution, 136. 4 ± 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 μg/h/mL). Conclusion: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

AB - Purpose: To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. Results: Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 ± 0.62 μg/mL; clearance rate, 6.33 ± 6.41 L/h; elimination half-life, 24.4 ± 14.6 hours; volume of distribution, 136. 4 ± 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 ± 0.12 μg/h/mL). Conclusion: The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

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