TY - JOUR
T1 - A phase I study of pemetrexed (ALIMTA) and cyclophosphamide in patients with locally advanced or metastatic breast cancer
AU - Dittrich, Christian
AU - Petruzelka, Lubos
AU - Vodvarka, Pavel
AU - Gneist, Margit
AU - Janku, Filip
AU - Kysela, Tamara
AU - Melemed, Allen
AU - Latz, Jane
AU - Simms, Lorinda
AU - Krejcy, Kurt
PY - 2006/12/1
Y1 - 2006/12/1
N2 - Purpose: Determine the maximum tolerated dose (MTD) of pemetrexed and cyclophosphamide combination therapy for patients with locally advanced or metastatic breast cancer. Experimental Design: 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.
AB - Purpose: Determine the maximum tolerated dose (MTD) of pemetrexed and cyclophosphamide combination therapy for patients with locally advanced or metastatic breast cancer. Experimental Design: 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.
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U2 - 10.1158/1078-0432.CCR-05-2829
DO - 10.1158/1078-0432.CCR-05-2829
M3 - Article
C2 - 17145830
AN - SCOPUS:33845758522
SN - 1078-0432
VL - 12
SP - 7071
EP - 7078
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -