Dose finding study for combination treatment with topotecan and gemcitabine of patients with recurrent ovarian cancer after failure of first-line chemotherapy with Paclitaxel and platinum.
OBJECTIVE
Topotecan and gemcitabine have shown mono-activity against different solid tumors including recurrent ovarian cancer after failure of platinum- and paclitaxel-containing therapies. Both drugs affect DNA replication, topotecan additionally inhibits the DNA repair process. Efficacy profiles and different mechanisms of action make the combination of both drugs a promising regimen. Therefore the following dose-finding study was conducted to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of this combination. Based on the monotherapy schedules topotecan was given on day 1-5, and gemcitabine on day 1 + 8 every 21 days.


METHODS
Patients with histologically proven ovarian cancer who relapsed after platinum- and paclitaxel-containing therapy were enrolled. 3 different dose levels were investigated. No individual dose escalation or primary use of cytokines were allowed.


RESULTS
23 patients were enrolled, 50% were pretreated with at least 2 platinum-containing therapies; 80 courses were analyzed for toxicity. Thrombocytopenia and leucopenia were the major DLTs. The MTD for phase II trials is 0.50 mg/m(2) topotecan and 800/600 mg/m(2) gemcitabine. In this dose level only one therapy-related non-hematological adverse event >grade 2 (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in 6 and stable disease in 4 out of 12 evaluable patients. Median survival was 15.3 (95% CI: 13.2-28.6) months.


CONCLUSIONS
The results of this phase I study demonstrate the feasibility and tolerability of this new combination in heavily pretreated patients. Based on these results a phase II study was initiated to evaluate the efficacy of this regimen.
Department of Gynecology and Obstetrics, Charité, Campus Virchow-Klinikum, Humboldt University of Berlin, Germany.
J
J
Sehouli
D
D
Stengel
G
G
Oskay
J
J
Blohmer
S
S
Kaubitzsch
W
W
Lichtenegger
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000633:toxicity; D019233:Retreatment; D019772:Topotecan / Q000008:administration & dosage / Q000633:toxicity; D017211:Treatment Failure; D000093542:Gemcitabine
D003841:Deoxycytidine; D019772:Topotecan; D016190:Carboplatin; D017239:Paclitaxel; D000093542:Gemcitabine