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A Phase I Trial of Pemetrexed Plus Gemcitabine Given Biweekly with B-Vitamin Support in Solid Tumor Malignancies or Advanced Epithelial Ovarian Cancer

Authors' Affiliations: ¹ Memorial Sloan-Kettering Cancer Center, New York, New York and ² Eli Lilly and Company, Indianapolis, Indiana

Requests for reprints: Martee L. Hensley, Gynecologic Medical Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Phone: 212-639-6902; Fax: 212-717-3272; E-mail: hensleym{at}mskcc.org.

Purpose: To determine the maximally tolerated dose (MTD) of biweekly pemetrexed with gemcitabine plus B₁₂ and folate supplementation in patients with advanced solid tumors and ovarian cancer.

Experimental Design: Patients with no prior pemetrexed or gemcitabine therapy enrolled in cohorts of three, expanding to six if dose-limiting toxicity (DLT) was observed. Pemetrexed, escalated from to 700 mg/m², was given before gemcitabine 1,500 mg/m² every 14 days. DLTs were grade 4 neutropenia lasting >7 days or febrile neutropenia, grade 4 or 3 thrombocytopenia (with bleeding), grade 3 nonhematologic toxicity, or treatment delay of 1 week due to unresolved toxicity.

Results: The ovarian cancer cohort enrolled 24 patients with unlimited prior cytotoxic chemotherapies. MTD was observed at pemetrexed 600 mg/m², with 2 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (83%), leukopenia (67%), lymphopenia (73%), and febrile neutropenia (12%). Median cycle per patient was 8 (range, 1-16). Six of 21 (28%) patients had confirmed partial responses. Study protocol was modified for the solid tumor cohort (n = 30) to enroll patients with two or more prior cytotoxic regimens. MTD was observed at pemetrexed 500 mg/m², with 1 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (63%), lymphopenia (43%), leukopenia (70%) and febrile neutropenia (6.6%). Median cycle per patient was 4 (range, 1-20). Three of 29 (10.3%) response-evaluable patients had confirmed partial responses: 2 squamous cell carcinomas of head and neck and 1 nasopharyngeal cancer.

Conclusion: MTDs for the solid tumor and ovarian cancer cohorts were reached at pemetrexed 500 and 600 mg/m², respectively, given biweekly with gemcitabine 1,500 mg/m².