ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial Journal Article
| Authors: | Ranson, M.; Hammond, L. A.; Ferry, D.; Kris, M.; Tullo, A.; Murray, P. I.; Miller, V.; Averbuch, S.; Ochs, J.; Morris, C.; Feyereislova, A.; Swaisland, H.; Rowinsky, E. K. |
| Article Title: | ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial |
| Abstract: | Purpose: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD 1839 in patients with solid malignant tumors. Patients and Methods: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. Results: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for ≥ 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for ≥ 6 months. Conclusion: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839. © 2002 by American Society of Clinical Oncology. |
| Keywords: | adult; cancer chemotherapy; treatment outcome; aged; middle aged; major clinical study; clinical trial; area under the curve; diarrhea; drug efficacy; solid tumor; antineoplastic agents; gemcitabine; neoplasms; enzyme inhibition; lung non small cell cancer; receptor, epidermal growth factor; dose-response relationship, drug; protein tyrosine kinase inhibitor; rash; chemotherapy induced emesis; multicenter study; acne; gefitinib; area under curve; protein-tyrosine kinases; phase 1 clinical trial; drug half life; navelbine; administration, oral; quinazolines; drug induced disease; epidermal growth factor receptor kinase; dose time effect relation; tablet formulation; humans; human; male; female; priority journal; article |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 20 |
| Issue: | 9 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2002-05-01 |
| Start Page: | 2240 |
| End Page: | 2250 |
| Language: | English |
| DOI: | 10.1200/jco.2002.10.112 |
| PUBMED: | 11980995 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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