Skin Rashes Research Today is a free monthly online journal that collates and summarizes the latest research about Skin Rashes, including details on dermatitis, itches, creams, medication, treatment. | ||||||||
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Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.Rodriguez-Galindo C, Crews KR, Stewart CF, Furman W, Panetta JC, Daw NC, Cain A, Tan M, Houghton PH, Santana VM Department of Hematology-Oncology, St Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN, 38105-2795, USA. Purpose: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. Methods: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m(2)/d). Topotecan and irinotecan pharmacokinetics were determined. Results: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n=3) and 9 (level -2; n=3) mg/m(2)/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n=2). DLTs were neutropenia (n=8), typhlitis (n=5), and skin rash (n=1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m(2) and 27.6 (14.7-55.9) l/h/m(2), respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. Conclusion: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity. Published 7 July 2005 in Cancer Chemother Pharmacol.
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