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A Phase I Study of Pemetrexed (ALIMTA) and Cyclophosphamide in Patients with Locally Advanced or Metastatic Breast Cancer

Authors' Affiliations: ¹ Ludwig Boltzmann Institute for Applied Cancer Research and Applied Cancer Research-Institution for Translational Research Vienna, Kaiser Franz Josef-Spital; ² Eli Lilly and Company, Vienna, Austria; ³ Charles University, Prague, Czech Republic; ⁴ Faculty Hospital and Policlinic Ostrava, Ostrava, Czech Republic; and ⁵ Eli Lilly and Company, Indianapolis, Indiana

Requests for reprints: Christian Dittrich, 3rd Medical Department, Center for Oncology and Hematology, Kaiser Franz Josef-Spital, Kundratstrasse 3, A-1100 Vienna, Austria. Phone: 43-1-60191-2303; E-mail: ch.dittrich{at}chello.at.

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/m²) was administered on day 1 of a 21-day schedule followed by cyclophosphamide (range, 400-800 mg/m²). Folic acid and vitamin B₁₂ 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/m² (combined with cyclophosphamide, 600 mg/m²) 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/m²) and a high (1,800 mg/m²) dose of pemetrexed with cyclophosphamide (600 mg/m²) will be evaluated in the consecutive prospective randomized phase II study.

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