This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kris, M. G. Articles by Sirotnak, F. M. Search for Related Content PubMed PubMed Citation Articles by Kris, M. G. Articles by Sirotnak, F. M.

Phase I Trial and Clinical Pharmacological Evaluation of 10-Ethyl-10-deazaaminopterin in Adult Patients with Advanced Cancer¹

Developmental Chemotherapy Service, Department of Medicine [M. G. K., R. J. G., M. S. W., J. P. O., M. P. F., L. D. M., C. W. Y.], Clinical Pharmacology Laboratory [J. J. K., L. W., F. F.], and Laboratory of Molecular Therapeutics [F. M. S.], Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York, New York 10021

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m². The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m² with escalation or attenuation in accordance with patient tolerance, or 100 mg/m² weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m² dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: = 12.9 min, ß = 1.5 h, and = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.

¹ Supported in part by Public Health Service Grants CA-05826 and CA-18856 from the National Cancer Institute, NIH, Department of Health and Human Services, and Fellowship Grants from the American Cancer Society (M. G. K.) and the J. M. Foundation (M. P. F.). Presented in part at the 76th annual meeting of the American Association for Cancer Research, May 22–25, 1985, Houston, Texas.

² To whom requests for reprints should be addressed at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

³ Present address: 3262 Paddington Lane, Winston Salem, NC 27106.

⁴ Present address: 2215 Nebraska Avenue, Fort Pierce, FL 33450.

⁵ Present address: 60 Temple Street, New Haven, CT 06510.

Received 2/16/88. Revised 6/20/88. Accepted 6/21/88.

This article has been cited by other articles:

				S. A. Laurie, D. G. Pfister, M. G. Kris, W. P. Tong, G. Chronowski, K. M. W. Pisters, R. T. Heelan, and F. M. Sirotnak Phase I and Pharmacological Study of Two Schedules of the Antifolate Edatrexate in Combination with Cisplatin Clin. Cancer Res., March 1, 2001; 7(3): 501 - 509. [Abstract] [Full Text]

				L. M. Krug, K. K. Ng, M. G. Kris, V. A. Miller, W. Tong, R. T. Heelan, L. Leon, D. Leung, J. Kelly, and F. M. Sirotnak Phase I and Pharmacokinetic Study of 10-Propargyl-10-deazaaminopterin, a New Antifolate Clin. Cancer Res., September 1, 2000; 6(9): 3493 - 3498. [Abstract] [Full Text]

				G. D'Andrea, D. Fennelly, L. Norton, J. Baselga, T. Gilewski, C. Hudis, M. E. Moynahan, G. Raptis, N. Sklarin, A. Surbone, et al. Phase I Study of Escalating Doses of Edatrexate in Combination with Paclitaxel in Patients with Metastatic Breast Cancer Clin. Cancer Res., February 1, 1999; 5(2): 275 - 279. [Abstract] [Full Text] [PDF]

				C. H. Takimoto New Antifolates: Pharmacology and Clinical Applications Oncologist, February 1, 1996; 1(1): 68 - 81. [Abstract] [Full Text] [PDF]