A phase I study of oral ZD 1839 given daily in patients with solid tumors: IND.122, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group

Purpose: To define the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), the biological active ( BA) dose and the pharmacokinetics (PK) of the epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitor ZD1839 (Iressa(TM)) when administered continuously as a once daily dose in patients with advanced, incurable solid tumours. Patients and methods: Twenty-eight patients were enrolled in cohorts of three from three National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) centers. ZD1839 was given at doses from 150 to 800 mg daily orally and patients underwent a pretreatment and a 28 day post treatment tumor biopsy, while PK sampling was performed on days 8, 15, 22, 29, and a toxicity assessment every 28 days. Results: All twenty-eight patients were evaluable for non-hematological and hematological toxicity. Twenty-seven were evaluable for response. The MTD was not reached but DLT included reversible rash and diarrhea. One patient with urachal cancer had a transient 55% decrease in tumor size and two other patients (breast and non-small cell lung cancer) had minor responses; three additional patients had pharmacodynamic evidence of target effect. PK demonstrated steady state within the first 2 weeks of dosing and dose dependent exposure. Conclusion: It appears that ZD 1839 at a dose of 800 mg/day was tolerable, although some patients required dose modification for diarrhea. Doses above 250 mg/day demonatrate biologic activity and could be consider for future study in a variety of EGFR positive tumor types.