Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced Solid Malignancies

Hidalgo, Manuel; Siu, Lillian L.; Nemunaitis, John; Rizzo, Jinee; Hammond, Lisa A.; Takimoto, Chris H.; Eckhardt, S. Gail; Tolcher, Anthony W.; Britten, Carolyn D.; Denis, L.; Ferrante, Karen J.; Hoff, Daniel D. Von; Silberman, Sandra; Rowinsky, Eric K.

doi:10.1200/jco.2001.19.13.3267

Cited by 928 publications

(609 citation statements)

References 9 publications

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“…1 Moreover, other EGFR inhibitors have caused similar corneal changes in preclinical models. 2,3 These preclinical findings are consistent with the pharmacological actions of gefitinib. The EGFR is strongly expressed in the basal epithelial cells of limbal and conjunctival epithelia and throughout the corneal epithelium; however, little or no EGFR is seen in the superficial conjunctival or limbal epithelia, demonstrating that EGFR is preferentially expressed in basal epithelial cells that have the greatest proliferative potential.…”

Section: Introductionsupporting

confidence: 60%

Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Phase I and II clinical trials

Tullo

Esmaeli

Murray

et al. 2005

Eye

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Purpose To describe the strategy used for large-scale ophthalmological monitoring in the clinical development of the novel anticancer agent gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, which had demonstrated ocular effects in preclinical animal models. Methods In this extensive clinical trial programme, patients in Phase I and II trials underwent frequent and intensive ophthalmological monitoring at baseline and during the trials. Data were reviewed by an external independent Ophthalmology Advisory Board. Results Ophthalmological data for 221 patients in Phase I trials of gefitinib and 425 patients in Phase II trials revealed no evidence of any consistent or drug-related ophthalmological toxicity. Interestingly, the baseline data revealed that, in an asymptomatic population, transient ophthalmological events are identified during monitoring. Conclusions This study reports the methodology and normative data in an ophthalmological screening programme that should prove useful for future studies.

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Section: Introductionsupporting

confidence: 60%

Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Phase I and II clinical trials

Tullo

Esmaeli

Murray

et al. 2005

Eye

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“…Many novel agents have shown responses in treated and untreated populations (Kerr, 2004). The dose of targeted agents may be important for activity, however; the dose of erlotinib used in this study was based on phase I data (Hidalgo et al, 2001) and the toxicity from our study suggest that it would not be possible to increase the dose further in this patient population.…”

Section: Discussionmentioning

confidence: 96%

Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer

et al. 2006

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Erlotinib (Tarcevat, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108 -329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre-and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P ¼ 0.008) and phospho-extracellular signal-regulated kinase (ERK) (P ¼ 0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.

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“…At the moment, the previously established preclinical threshold of >500 ng/mL still seems the most rational target for TDM 1, 33…”

Section: Practical Recommendations For Tdm Of Kis In Oncologymentioning

confidence: 99%

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Verheijen

Schellens

et al. 2017

Clin Pharma and Therapeutics

216

255

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Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs.

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Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced Solid Malignancies

Cited by 928 publications

References 9 publications

Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Phase I and II clinical trials

Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Phase I and II clinical trials

Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

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