Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Saltz
L B
LB
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. saltzl@mskcc.org
Spriggs
D
D
Schaaf
L J
LJ
Schwartz
G K
GK
Ilson
D
D
Kemeny
N
N
Kanowitz
J
J
Steger
C
C
Eng
M
M
Albanese
P
P
Semple
D
D
Hanover
C K
CK
Elfring
G L
GL
Miller
L L
LL
Kelsen
D
D
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D005965:Glucuronates / Q000493:pharmacokinetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D005965:Glucuronates; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin