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Annals of Oncology 10:601-603, 1999
© 1999 European Society for Medical Oncology

brief-report

Phase I study of the sequential administration of edatrexate and paclitaxel in patients with advanced solid tumors

J. R. Rigas1,2, M. G. Kris1,, V. A. Miller1, K. M. W. Pisters1, R. T. Heelan4, S. C. Grant1, D. W. Fennelly3, Ting-Chao Chou5 and F. M. Sirotnak5

1Thoracic Oncology, Cornell University Medical College New York, NY, USA
2Developmental Chemotherapy, Cornell University Medical College New York, NY, USA
3Breast and Gynecological Oncology Services, Division of Solid Tumor Oncology, Department of Medicine, Cornell University Medical College New York, NY, USA
4Department of Radiology, Cornell University Medical College New York, NY, USA
5Laboratory of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettenng Cancer Center, and Cornell University Medical College New York, NY, USA

Correspondence to: Memorial Sloan-Kettering Cancer 1275 York Avenue New York, NY 10021 USA E-mail: krism{at}mskcc.org

Background: The antifolate edatrexate and the microtubule-stabilizing agent paclitaxel have both demonstrated single-agent activity in lung and breast cancer. In vitro, the sequential combination of edatrexate followed by paclitaxel produced synergistic antitumor effects. This trial was designed to find the maximum tolerated doses of edatrexate and paclitaxel when given every two weeks utilizing this sequential schedule.

Patients and methods: Thirty-four patients with solid tumors received edatrexate intravenously on days 1 and 15 and paclitaxel intravenously as a three-hour infusion on days 2 and 16 of each 28-day cycle. Edatrexate was escalated from 40 to 120 mg/m2 and the paclitaxel dose fixed at 135 mg/m2. When the maximum-tolerated dose was not reached, edatrexate was fixed at 120 mg/m2 and paclitaxel escalated to 175 and 210 mg/m2.

Results: All 34 patients were assessable. The maximum tolerated doses were 120 mg/m2 of edatrexate and 210 mg/m2of paclitaxel. Grade 3 myalgia, peripheral neuropathy, leuko-penia, and an infusion-related reaction occurred. Eight patients with non-small-cell lung cancer and one with bladder cancer achieved major objective responses.

Conclusions: The recommended phase II doses are 120 mg/m2 of edatrexate days 1 and 15 and 175 mg/m2 of paclitaxel as a three-hour infusion days 2 and 16 of a 28 day cycle. These results warrant phase II trials of the combination leading to phase III studies comparing the two drugs to a single agent to confirm the preclinical evidence of synergy.

chemotherapy, edatrexate, paclitaxel, synergism


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