Phase II trial of the combination of bryostatin-1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study.
OBJECTIVE
Bryostatin-1 is a macrocyclic lactone that has been shown to regulate protein kinase C (PKC) activity and thereby potentially inhibit tumor invasion, angiogenesis, cell adhesion, and multidrug resistance. In preclinical experiments, bryostatin-1 induces tumor growth inhibition and enhances cytotoxicity when combined with other agents including cisplatin in cervical cancer cells. It was therefore anticipated that combination bryostatin-1-cisplatin therapy would be effective in patients with cervical cancer. The current study was conducted to evaluate this therapeutic approach in patients with recurrent or advanced-stage cervical carcinoma.


METHODS
An IRB-approved New York Gynecologic Oncology Group (NYGOG) trial was activated for patients with a histological diagnosis of metastatic cervical cancer or in patients with recurrent disease not eligible for surgery or radiation. Enrolled patients received bryostatin-1 (50-65 microg/m(2)) as a 1-h infusion followed by cisplatin (50 mg/m(2)). The combined treatment was administered every 21 days.


RESULTS
Fourteen patients were enrolled. The majority of patients had squamous cell carcinoma. Ten out of fourteen patients had recurrent disease. Fifty percent of the patients received bryostatin at 50 microg/m(2) and 50% received bryostatin at 65 microg/m(2). Seventy-one percent completed two cycles of treatment. The most common grade II-III toxicities were myalgia, anemia, and nausea or vomiting. One patient developed a hypersensitivity reaction and one developed grade III nephrotoxicity. Seventy-one percent (10/14) of patients were evaluated for tumor response. Eight out of ten (80%) of patients had progressive disease and 2/10 (20%) had stable disease. There were no treatment responses.


CONCLUSIONS
Despite promising preclinical data, this clinical trial indicates that the combination of cisplatin and bryostatin-1 at the doses and schedule used is not effective in patients with advanced-stage or recurrent cervical cancer. There is even the possibility of therapeutic antagonism. The development of a serum assay for bryostatin-1 and additional mechanistic studies would be useful for future bryostatin clinical trials.
Nezhat
Farr
F
Mount Sinai School of Medicine, New York, NY 10029, USA. farr.nezhat@mssm.edu
Wadler
Scott
S
Muggia
Franco
F
Mandeli
John
J
Goldberg
Gary
G
Rahaman
Jamal
J
Runowicz
Carolyn
C
Murgo
Anthony J
AJ
Gardner
Ginger J
GJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054713:Bryostatins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage; D018942:Macrolides; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D011446:Prospective Studies; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; C046785:bryostatin 1; D002945:Cisplatin