Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer

M. G. Kris, J. J. Kinahan, Richard J. Gralla, M. P. Fanucchi, M. S. Wertheim, J. P. O'Connell, L. D. Marks, L. Williams, F. Farag, C. W. Young, F. M. Sirotnak

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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 transaminase, 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: α = 12.9 min, β = 1.5 h, and γ = 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.

Original languageEnglish (US)
Pages (from-to)5573-5579
Number of pages7
JournalCancer Research
Volume48
Issue number19
StatePublished - 1988
Externally publishedYes

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Clinical Trials, Phase I
Pharmacology
Polyglutamic Acid
Neoplasms
Pharmaceutical Preparations
Neoplasm Metastasis
Methotrexate
Appointments and Schedules
Pharmacokinetics
Breast Neoplasms
Skin
Stomatitis
Partial Thromboplastin Time
Kidney Neoplasms
Leukopenia
Prothrombin
Aspartate Aminotransferases
Exanthema
Non-Small Cell Lung Carcinoma
Thrombocytopenia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kris, M. G., Kinahan, J. J., Gralla, R. J., Fanucchi, M. P., Wertheim, M. S., O'Connell, J. P., ... Sirotnak, F. M. (1988). Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer. Cancer Research, 48(19), 5573-5579.

Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer. / Kris, M. G.; Kinahan, J. J.; Gralla, Richard J.; Fanucchi, M. P.; Wertheim, M. S.; O'Connell, J. P.; Marks, L. D.; Williams, L.; Farag, F.; Young, C. W.; Sirotnak, F. M.

In: Cancer Research, Vol. 48, No. 19, 1988, p. 5573-5579.

Research output: Contribution to journalArticle

Kris, MG, Kinahan, JJ, Gralla, RJ, Fanucchi, MP, Wertheim, MS, O'Connell, JP, Marks, LD, Williams, L, Farag, F, Young, CW & Sirotnak, FM 1988, 'Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer', Cancer Research, vol. 48, no. 19, pp. 5573-5579.
Kris, M. G. ; Kinahan, J. J. ; Gralla, Richard J. ; Fanucchi, M. P. ; Wertheim, M. S. ; O'Connell, J. P. ; Marks, L. D. ; Williams, L. ; Farag, F. ; Young, C. W. ; Sirotnak, F. M. / Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer. In: Cancer Research. 1988 ; Vol. 48, No. 19. pp. 5573-5579.
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