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/m2/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/m2/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/m2 and 27.6 (14.7-55.9) l/h/m2, 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.
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/m2/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/m2/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/m2 and 27.6 (14.7-55.9) l/h/m2, 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.
Authors: R C Brennan; W Furman; S Mao; J Wu; D C Turner; C F Stewart; V Santana; L M McGregor Journal: Cancer Chemother Pharmacol Date: 2014-09-26 Impact factor: 3.333
Authors: Eun Hye Ji; Young Min Kim; Soo Jeong Kim; Soo Jeong Yeom; Sung Eun Ha; Hyeon Hui Kang; Ji Young Kang; Sang Haak Lee; Hwa Sik Moon Journal: Tuberc Respir Dis (Seoul) Date: 2012-11-30
Authors: Christopher L Cubitt; Jiliana Menth; Jana Dawson; Gary V Martinez; Parastou Foroutan; David L Morse; Marilyn M Bui; G Douglas Letson; Daniel M Sullivan; Damon R Reed Journal: Sarcoma Date: 2013-10-24