Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced Solid Malignancies
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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Cells bearing Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD, and H773_V774insH are not inhibited by clinically achievable doses of gefitinib, erlotinib, or afatinib.
“We characterized Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD and H773_V774insH using in vitro models and found that cells bearing these mutant EGFR proteins are not inhibited by clinically-achievable doses of gefitinib, erlotinib 12,35,52–54 or the irreversible EGFR inhibitor afatinib 35,55.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [54]
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- Authors
- 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.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- From the Institute for Drug Development, Cancer Therapy and Research Center, and the University of Texas Health Science Center at San Antonio, San Antonio, TX; U.S. Oncology, and Baylor University Medical Center, Dallas, TX; and Pfizer Pharmaceuticals, Inc, Groton, CT.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2001-07-01
- Volume
- 19
- Issue
- 13
- Pages
- 3267-3279
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2135836172
- Cited by
- 1,001
- References
- 14
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 12 · 2023: 20 · 2022: 17 · 2021: 19 · 2020: 22 · 2019: 12 · 2018: 19 · 2017: 26 · 2016: 30 · 2015: 27 · 2014: 37 · 2013: 43 · 2012: 42
- FWCI
- 30.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Research Resources (MO1‐RR‐01346, M01RR001346)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- epidermal growth factor receptor tyrosine kinase inhibitors, advanced solid tumors, maximum tolerated dose, pharmacokinetics, continuous daily dosing, diarrhea, skin toxicity, O-demethylation, dose escalation, anticancer activity, oral anticancer drugs, drug accumulation, elimination half-life, volume of distribution
- MeSH terms
- Administration, Oral, Adult, Aged, Analysis of Variance, Antineoplastic Agents, Biological Availability, Drug Eruptions, Diarrhea, Dose-Response Relationship, Drug, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasms, Statistics, Nonparametric, Maximum Tolerated Dose, ErbB Receptors
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