Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Phase II trial of trimetrexate in patients with advanced soft-tissue sarcoma


Trimetrexate, a lipophilic, 2,4-diaminoquinazoline derivative of methotrexate, enters cells by passive diffusion rather than via a transport system. Trimetrexate has shown promising activity in animal model systems. A total of 16 patients with metastatic soft-tissue sarcoma who had received only one prior chemotherapy regimen were treated with trimetrexate (8 mg/m2 given intravenously daily for 5 days) every 3 weeks. Treatment-related toxicity included ≥ grade 2 neutropenia (8/16), thrombocytopenia (3/16), mucositis (4/16) and skin rash (3/16). No partial or complete responses were observed in 15 evaluable patients (95% confidence interval for true response rate, 0–22%) Six subjects showed stabilization of disease for periods ranging from 2 to 9 months. At this dose and on this schedule, trimetrexate appears to have little activity against refractory soft-tissue sarcomas.

This is a preview of subscription content, log in to check access.


  1. 1.

    Bertino JR, Sawicki NL, Moroson BA, Cashmore AR, Elslager EF (1979) 2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanlino) methyl] quinazoline, a potent non-classical folate antagonist inhibitor. Its effect on DHFR and growth of rodent tumors in vitro and in vivo. Biochem Pharmacol 28: 1983–1987

  2. 2.

    Bertino JR, Lin JT, Cashmore AR, Fanucchi MP, Tong WP, Stewart JA, McCormack JJ (1988) Clinical pharmacology and metabolism of trimetrexate. Semin Oncol 15 [Suppl 2]: 8–9

  3. 3.

    Chang A, Rosenberg SA, Glatstein E, Antman K (1990) Sarcomas of soft tissue. In: De Vita VT, Hellman S, Rosenberg SA (eds) Cancer principlas and practice of oncology, 3rd edn. J. B. Lippincott, Philadelphia, pp 1345–1398

  4. 4.

    Chawla SP, Kavanagh JJ, Freedman RS, Raber M, Gershenson D, Edwards C, Wharton TJ (1988) Pulmonary toxicity and limited activity of trimetrexate in recurrent carcinoma of the uterine cervix (abstract). Proc Am Assoc Cancer Res 29: 207

  5. 5.

    Diddens H, Niethammer D, Jackson RC (1983) Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate and CB 3717 in human lymphoma and osteosarcoma cells resistant to methotrexate. Cancer Res 43: 5286–5292

  6. 6.

    Jolivet J, Chabner BA (1983) Intracellular pharmacokinetics of methotrexate polyglutamates in human beast cancer cells; selective retention and less dissociable binding of 4-NH2-10-CH3-pteroylglutamate5 to dihydrofolate reductase. J Clin Invest 72: 773–778

  7. 7.

    Lin JT, Bertino JR (1987) Trimetrexate: a second generation folate antagonist in clinical trial. J Clin Oncol 5: 2032–2040

  8. 8.

    Lin JT, Cashmore AR, Baker M, Dreyer RN, Ernstoff M, Marsh JC, Bertino JR, Whitfield LR, Delap R, Grillo-Lopez A (1987) Phase I studies with trimetrexate: clinical pharmacology, analytical methodology and pharmacokinetics. Cancer Res 47: 609–616

  9. 9.

    Quirt I, Eisenhauer E, Knowling M, Warr D, Bramwell V, Rusthoven J, Wierzbicki P, Verma S (1988) A phase II study of trimetrexate in metastatic soft tissue sarcoma (abstract). Proc Am Soc Clin Oncol 7: 275

  10. 10.

    Weiss R, James WD, Major WB, Porter MD Allegra W, Curt GA (1986) Skin reactions induced by trimetrexate, an analog of methotrexate. Invest New Drugs 4: 159–163

  11. 11.

    Zar JH (1984) Biostatistical analysis, 2nd edn. Prentice-Hall-Engle-wood Cliffs, New Jersey

Download references

Author information

Correspondence to Jonathan D. Licht.

Additional information

J. D. L. is supported by a physician-scientist award from the National Cancer Institute

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Licht, J.D., Gonin, R. & Antman, K.H. Phase II trial of trimetrexate in patients with advanced soft-tissue sarcoma. Cancer Chemother. Pharmacol. 28, 223–225 (1991). https://doi.org/10.1007/BF00685515

Download citation


  • Sarcoma
  • Methotrexate
  • Neutropenia
  • Thrombocytopenia
  • Chemotherapy Regimen