Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma

Abstract

Small cell lung carcinoma (SCLC) cell lines commonly express KIT and its ligand, stem cell factor, suggesting an autocrine loop promoting cell growth. Imatinib inhibits KIT kinase activity. SCLC cells treated with imatinib in vitro undergo cell cycle arrest. Imatinib reduces resistance to irinotecan in vitro. Common metabolic pathways suggest there may be drug interactions between imatinib and irinotecan or cisplatin. In the current study, the authors investigated the feasibility of combining these drugs in the treatment of patients with SCLC. Two Phase I studies were conducted independently at two institutions. Patients with extensive-disease SCLC underwent therapy with cisplatin, irinotecan, and imatinib using two similar regimens. In one study, immunohistochemical analysis of the expression of potential imatinib targets was performed on pretreatment biopsy specimens, and blood specimens were collected and analyzed for imatinib, irinotecan, and cisplatin pharmacokinetic parameters. Nine patients were enrolled and were evaluable for toxicity. A high incidence of neutropenia, diarrhea, and thrombosis was observed that precluded dose escalation. Six patients were evaluable for response after four cycles; five patients experienced a partial response and the other patient had developed progressive disease. Four of six tumor specimens tested expressed platelet-derived growth factor receptor-alpha and two expressed KIT. Irinotecan clearance was found to be significantly decreased by imatinib (P < 0.04). No significant alteration in the disposition of cisplatin was observed. The maximum tolerated dose for this combination with granulocyte-colony-stimulating factor support was identified as imatinib at a dose of 300 mg/day with irinotecan (at a dose of 65 mg/m(2)) and cisplatin (at a dose of 30 mg/m(2)) given on Days 1 and 8, every 21 days. The decreased irinotecan clearance may explain the high incidence of diarrhea and neutropenia noted in the current study.