Phase II trial of carboplatin and infusional cyclosporine in platinum-resistant recurrent ovarian cancer.
OBJECTIVE
To determine the response rate to 26-h continuous infusion cyclosporine A (CSA) combined with a fixed dose level of carboplatin (CBDCA) in patients with recurrent ovarian cancer, and to determine the effect of CSA on the pharmacokinetics of CBDCA.


METHODS
To examine the effect of duration of CSA exposure on reversal of CBDCA resistance, clonogenic assays were performed in vitro in platinum-resistant A2780 cells. CBDCA (AUC 4) with CSA repeated every 3 weeks was then administered to patients on this phase II study. Pharmacokinetics of CSA and CBDCA were determined in a subset of patients.


RESULTS
Preincubation of platinum-resistant A2780 cells with CSA reversed CBDCA resistance in a concentration-dependent and time-dependent manner. A group of 23 patients received 58 courses of CBDCA/CSA therapy. One partial response was observed. Eight patients achieved disease stabilization. Toxicity was similar to that observed in our previous phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean +/- SD end-of-infusion CSA level (HPLC assay) was 1253 +/- 400 microg/ml. The pharmacokinetic studies suggest that CSA does not increase CBDCA AUC.


CONCLUSIONS
Steady-state levels of >1 microg/ml CSA (HPLC assay) are achievable in vivo. Modest partial reversal of platinum resistance (in one patient with an objective response and in eight patients with stable disease noted) is achievable in vivo in patients pretreated with CSA. This phenomenon is not explained by alterations in CBDCA pharmacokinetics.
Morgan
Robert J
RJ
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Rd, Duarte, CA 91010, USA. rmorgan@coh.org
Synold
Timothy W
TW
Gandara
David
D
Muggia
Franco
F
Scudder
Sidney
S
Reed
Eddie
E
Margolin
Kim
K
Raschko
James
J
Leong
Lucille
L
Shibata
Stephen
S
Tetef
Merry
M
Vasilev
Steven
S
McGonigle
Kathryn
K
Longmate
Jeff
J
Yen
Yun
Y
Chow
Warren
W
Somlo
George
G
Carroll
Mary
M
Doroshow
James H
JH
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D016572:Cyclosporine; D016190:Carboplatin