A phase I trial of pemetrexed plus gemcitabine given biweekly with B-vitamin support in solid tumor malignancies or advanced epithelial ovarian cancer.
OBJECTIVE
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.


METHODS
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 > or =3 nonhematologic toxicity, or treatment delay of > or =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.


CONCLUSIONS
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).
Hensley
Martee L
ML
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. hensleym@mskcc.org
Larkin
Joseph
J
Fury
Matthew
M
Gerst
Scott
S
Tai
D Fritz
DF
Sabbatini
Paul
P
Konner
Jason
J
Orlando
Mauro
M
Goss
Tiana L
TL
Aghajanian
Carol A
CA
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019587:Dietary Supplements; D004334:Drug Administration Schedule; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D000068437:Pemetrexed; D016896:Treatment Outcome; D014803:Vitamin B Complex / Q000627:therapeutic use*; D000093542:Gemcitabine
D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D014803:Vitamin B Complex; D006147:Guanine; D005492:Folic Acid; D000093542:Gemcitabine