Cyclosporin enhancement of cisplatin chemotherapy in patients with refractory gynecologic cancer. A Gynecologic Oncology Group Study.
BACKGROUND
Cyclosporin has been demonstrated to reverse resistance to several antineoplastic agents including cisplatin in vitro. The purpose of this Phase I trial was to study the potential clinical application of cyclosporin modulation of cisplatin and to establish a tolerable dose of cyclosporin when combined with a standard dose of cisplatin of 75 mg/m2.


METHODS
A course of therapy consisted of two cyclosporin infusions over 2 hours each, 24 hours apart, with cisplatin given 6 hours after the first dose. Treatment was repeated every 21 days. Cyclosporin was studied in a Phase I fashion at five different levels, from 1-5 mg/kg per dose. Twenty patients with refractory gynecologic cancer received 81 courses of therapy. All patients had received extensive prior chemotherapy containing cisplatin.


RESULTS
Grade 4 nephrotoxicity was seen in 4 of 20 patients: 1 treated at 1 mg/kg, 1 at 2 mg/kg, and 2 at 5 mg/kg of cyclosporin. The patient treated at the 1 mg/kg level was a partial clinical responder and tolerated six courses. The patient at the 2 mg/kg level had received 14 prior courses of cisplatin and tolerated only two additional courses before a Grade 4 renal toxicity developed. Grade 4 nephrotoxicity developed in the two patients receiving 5 mg after two courses of chemotherapy. Two of the 20 patients achieved a complete response (CR) and 3 patients achieved a partial response (PR), for a total response rate of 25% (5 of 20). The two women who achieved CR started treatment with symptomatic ascites; one of whom also had multiple pulmonary lesions that were no longer evident after three courses of therapy.


CONCLUSIONS
Cyclosporin at a dose of 4 mg/kg per day given for 2 consecutive days in association with 75 mg/m2 of cisplatin can be given with reasonable assurance of safety.
Manetta
A
A
Division of Gynecologic Oncology, University of California Medical Center at Irvine, California.
Boyle
J
J
Berman
M L
ML
DiSaia
P J
PJ
Lentz
S
S
Liao
S Y
SY
Mutch
D
D
Slater
L
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage*; D003404:Creatinine / Q000652:urine; D016572:Cyclosporine / Q000008:administration & dosage*; D018283:Cystadenocarcinoma, Papillary / Q000188:drug therapy; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy; D004357:Drug Synergism; D004361:Drug Tolerance; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy*; D006801:Humans; D007668:Kidney / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012074:Remission Induction
D016572:Cyclosporine; D003404:Creatinine; D002945:Cisplatin