Phase I study of tirapazamine and cisplatin in patients with recurrent cervical cancer.
OBJECTIVE
Tirapazamine (SR 4233) is a benzotriazine compound exhibiting substantial differential toxicity for hypoxic cells. A large enhancement in tumor cell killing has been demonstrated in preclinical studies when tirapazamine was combined with cisplatin. This phase I study was undertaken to establish a safe dose combination of tirapazamine and cisplatin when administered to patients with recurrent cervical carcinoma.


METHODS
Tirapazamine was administered as an intravenous infusion over 2 hr, followed 1 hr later by cisplatin intravenously over 1 hr, every 21 days. All patients received prophylactic antiemetics consisting of ondansetron, dexamethasone, and lorazepam. The planned dose escalation levels of tirapazamine were 195, 260, 330, and 390 mg/m2. The cisplatin dose was fixed at 75 mg/m2.


RESULTS
A total of 12 patients were treated with 43 courses of therapy. Patients were heavily pretreated. Eleven of the 12 had prior radiotherapy and 5 of the 12 had prior cisplatin-based chemotherapy. A maximally tolerated dose of 330 mg/m2 was defined for this patient population. The dose-limiting toxicity was nausea and vomiting. All 12 patients were also evaluated for response. Two major responses were seen (17%). In addition, there were three minor responses (25%) and 4 patients achieved disease stabilization (33%). All major and minor responses were seen at the highest dose level tested of 330 mg/m2.


CONCLUSIONS
Tirapazamine and cisplatin is an interesting drug combination in the treatment of cervical cancer. Phase II testing is planned.
Aghajanian
C
C
Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Brown
C
C
O'flaherty
C
C
Fleischauer
A
A
Curtin
J
J
Roemeling
R
R
Spriggs
D R
DR
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage* / Q000009:adverse effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin