576 Phase I dose-finding study of the combination of alimta (pemetrexed) and paclitaxel in patients with solid tumors

Abstract

Objective.Irinotecan (CPT-11) is a DNA topoisomerase I inhibitor which has shown activityin vitroagainst several cancer cell lines and some promising clinical responses in phase I and II trials in various solid tumors. The cytotoxicity of CPT-11 on human ovarian epithelial malignancies was testedin vitroutilizing the ATP chemosensitivity assay. Flow cytometry was also performed on the fresh carcinoma specimens.Methods.Fresh tumor samples were obtained at laparotomy from 20 patients with primary adenocarcinoma of the ovary and 1 patient with heavily pretreated recurrent ovarian carcinoma. Tumors were plated in anin vitrosystem and treated with varying doses of both CPT-11 and its active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin), in addition to a panel of standard chemotherapeutic agents used in treating ovarian cancer. On the sixth day after incubation, ATP levels in remaining cells were measured using a luminometer as an indication of the amount of cell kill compared to untreated controls.Results.Twelve of the 21 tumors were evaluable for a response to CPT-11. Of the 12 tumors tested, 7 were found to have median effect doses of CPT-11 significantly under the clinically achievable peak plasma concentration (range 1.00 × 10−4to 44.67 μM) and 11 of the 12 tumors showed sensitivity to the active metabolite SN38 with median effect doses ranging from 2.00 × 10−4to 0.147 μM. Some of these tumors showed resistance to the standard agents, such as platinum, based on our assay. The heavily pretreated recurrent tumor tested was very sensitive to both CPT-11 and SN38 by our assay. The results of flow cytometry showed that the tumors were composed of heterogeneous populations of cells with mean S phase fractions varying from 7.0 to 17.3%. The only tumor not sensitive to SN38 showed the highest mean S phase activity of 17.3%.Conclusions.Overall, these results suggest that CPT-11 deserves further investigation as a clinically useful chemotherapeutic agent for ovarian cancer.