A phase I study of pemetrexed (ALIMTA) and cyclophosphamide in patients with locally advanced or metastatic breast cancer.
OBJECTIVE
Determine the maximum tolerated dose (MTD) of pemetrexed and cyclophosphamide combination therapy for patients with locally advanced or metastatic breast cancer.


METHODS
Patients with locally advanced or metastatic breast cancer and WHO performance status 0 to 2 were eligible. Pemetrexed (range, 400-2,400 mg/m(2)) was administered on day 1 of a 21-day schedule followed by cyclophosphamide (range, 400-800 mg/m(2)). Folic acid and vitamin B(12) supplementation began 1 to 2 weeks before the first pemetrexed dose.


RESULTS
Fifty-seven pretreated patients were enrolled and received 342 cycles (median, 4 cycles; range, 1-26) through 14 dose levels. The MTD of pemetrexed was 2,400 mg/m(2) (combined with cyclophosphamide, 600 mg/m(2)) with dose-limiting toxicities of grade 4 neutropenia with grade 4 infection and grade 3 diarrhea. Other grade 3 or 4 toxicities included (febrile) neutropenia, thrombocytopenia, anemia, elevated alanine aminotransferase/aspartate aminotransferase, and diarrhea. Pharmacokinetic analysis indicated that pemetrexed clearance and central volume of distribution were 40% lower than single-agent reference data, yielding a 68% increase in total systemic exposure and a 56% increase in maximal plasma concentration. Among the 50 patients evaluable for efficacy, 13 (26%) patients had a partial response and 17 (34%) patients had stable disease.


CONCLUSIONS
Pemetrexed was generally well tolerated. The observed toxicities were consistent with the known toxicity profiles of pemetrexed and cyclophosphamide. Considering the MTD and the toxicity and efficacy results in this and prior studies, a low (600 mg/m(2)) and a high (1,800 mg/m(2)) dose of pemetrexed with cyclophosphamide (600 mg/m(2)) will be evaluated in the consecutive prospective randomized phase II study.
Dittrich
Christian
C
Ludwig Boltzmann Institute for Applied Cancer Research and Applied Cancer Research-Institution for Translational Research Vienna, Kaiser Franz Josef-Spital, Austria. ch.dittrich@chello.at
Petruzelka
Lubos
L
Vodvarka
Pavel
P
Gneist
Margit
M
Janku
Filip
F
Kysela
Tamara
T
Melemed
Allen
A
Latz
Jane
J
Simms
Lorinda
L
Krejcy
Kurt
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000556:secondary*; D000068437:Pemetrexed; D011237:Predictive Value of Tests; D016896:Treatment Outcome
D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D003520:Cyclophosphamide