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

• Published in: Clinical cancer research Vol. 14; no. 19; pp. 6310 - 6316
• Main Authors: HENSLEY, Martee L, LARKIN, Joseph, FURY, Matthew, GERST, Scott, FRITZ TAI, D, SABBATINI, Paul, KONNER, Jason, ORLANDO, Mauro, GOSS, Tiana L, AGHAJANIAN, Carol A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2008
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; biweekly; Cohort Studies; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dietary Supplements; Drug Administration Schedule; Female; Female genital diseases; Folic Acid - therapeutic use; gemcitabine; Glutamates - administration & dosage; Guanine - administration & dosage; Guanine - analogs & derivatives; Gynecology. Andrology. Obstetrics; Humans; Maximum Tolerated Dose; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neutropenia; ovarian cancer; Ovarian Neoplasms - drug therapy; Pemetrexed; Pharmacology. Drug treatments; solid tumor; Treatment Outcome; Tumors; Vitamin B Complex - therapeutic use; Antineoplastic agent; Human; Solid tumor; Ovary carcinoma; Gemcitabine; Ovary cancer; Malignancy; B-Vitamins; Malignant tumor; Pemetrexed; Female genital diseases; Antifolate; Ovarian diseases; Antimetabolic; Phase I trial; Pyrimidine derivatives; Advanced stage; Fluorine Organic compounds; Pyrimidine nucleoside; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0338

Purpose: To determine the maximally tolerated dose (MTD) of biweekly pemetrexed with gemcitabine plus B 12 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/m 2 , was given before gemcitabine 1,500 mg/m 2 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/m 2 , 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/m 2 , 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/m 2 , respectively, given biweekly with gemcitabine 1,500 mg/m 2 .