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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Mary Crowley Medical Research Center/Texas Oncology PA, Dallas, Texas; 2 Pfizer Global Research and Development, Ann Arbor, Michigan, and 3 M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: John Nemunaitis, Mary Crowley Medical Research Center, 1717 Main Street, 60th Floor, Dallas, TX 75201. Phone: 214-658-1964; Fax: 214-658-1992; E-mail: jnemunaitis{at}mcmrc.com.
Purpose: To determine the tolerability and pharmacokinetics of oral CI-1033, a pan-erbB tyrosine kinase inhibitor, administered over 14 consecutive days of a 21-day cycle.
Design: Phase 1, multicenter trial involving patients with solid tumors that are refractory to standard therapy. CI-1033 was administered initially at 300 mg/day to a minimum cohort of three patients. Dose escalation proceeded at 
40% increments. Patients were evaluated for toxicity, pharmacokinetic profile, and evidence of response.
Results: Thirty-two patients entered the trial and were evaluable for safety assessment. Dose-limiting toxicity (diarrhea, rash, and/or anorexia) occurred at the 560 mg dose level; the maximum tolerated dose was 450 mg. No patients achieved objective responses and six patients achieved stable disease. Plasma CI-1033 concentrations increased with increasing dose. CI-1033 was not eliminated in urine to any appreciable extent.
Conclusions: CI-1033 is suitable for phase 2 testing at the 450 mg/day dose level when administered for 14 days in a 21-day cycle. The pharmacokinetic profile is consistent with biologically relevant plasma concentrations over the dosing interval.
Key Words: epidermal growth factor receptor • erbB • CI-1033 • pharmacokinetics • Phase 1 • cancer
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