Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.
OBJECTIVE
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.


CONCLUSIONS
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.
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2795, USA. carlos.rodriguez-galindo@stjude.org
Carlos
C
Rodriguez-Galindo
Kristine R
KR
Crews
Clinton F
CF
Stewart
Wayne
W
Furman
J Carl
JC
Panetta
Najat C
NC
Daw
Alvida
A
Cain
Ming
M
Tan
Peter H
PH
Houghton
Victor M
VM
Santana
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019772:Topotecan / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin