Journal of Clinical Oncology, Vol 16, 3858-3865, Copyright © 1998 by American Society of Clinical Oncology
Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors
LB Saltz, D Spriggs, LJ Schaaf, GK Schwartz, D Ilson, N Kemeny, J Kanowitz, C Steger, M Eng, P Albanese, D Semple, CK Hanover, GL Elfring, LL Miller and D Kelsen
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. saltzl@mskcc.org
PURPOSE: In vitro synergy between cisplatin and irinotecan (CPT-11) has
been reported. We designed a combination schedule of these agents to
maximize the potential for synergistic interaction. PATIENTS AND METHODS:
To maximize the opportunity for synergy, we divided the cisplatin into four
consecutive weekly treatments, followed by a 2-week rest. Each dose of
cisplatin was immediately followed by a dose of irinotecan. The dose of
cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50
mg/m2/wk and this was escalated by 30% increments in successive cohorts of
three to six patients to establish the maximum-tolerated dose (MTD).
Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38
glucuronide (SN-38G), were analyzed. RESULTS: Of 35 patients with solid
tumors enrolled onto this trial, 30 were assessable for toxicity and
response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50
mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of
cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients.
Neutropenia was the dose- limiting toxicity (DLT) encountered in this
trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30
assessable patients achieved a partial response. No alteration in
irinotecan, SN-38, or SN- 38G pharmacokinetics resulted from the
administration of cisplatin with irinotecan. CONCLUSION: The administration
of cisplatin and irinotecan on this weekly schedule provides a practical
and well-tolerated regimen that has the potential to maximize any clinical
synergy between the two agents. Evidence of substantial clinical activity
was seen in this phase I study.
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