Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

A phase I study of trimetrexate (NSC 352122) administered by 5-day continuous intravenous infusion

Summary

Trimetrexate (TMTX) is a potent inhibitor of dihydrofolate reductase that circumvents the transport resistance seen with methotrexate and has a wide spectrum of preclinical activity. A total of 18 patients with advanced cancer were treated in a clinical and pharmacological phase I trial with TMTX given as a continuous 5-day intravenous infusion. Neutropenia, thrombocytopenia and stomatitis were the dose-limiting toxicities at the maximum tolerated dose of 50 mg/m2 per 120 h (10 mg/m2 per day for 5 days). There was one septic death associated with neutropenia. Other toxicities were mild rash, mild nausea and transiently raised serum transminase levels. Significant relationships between the dose given and the AUC of plasma TMTX and the steady-state plasma level were established. Significant, although weak, relationships between the percentage of change in neutrophils and platelets and both the AUC and steady-state plasma level of TMTX were also observed. No objective tumour responses were seen, although six patients had stable disease. The recommended phase II dose for a continuous infusion of trimetrexate is 40 mg/m2 per 120 h.

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

References

  1. 1.

    Ackerly CC, Harshorn J, Tong WP, McCormack JJ (1985) A rapid and sensitive method for determination of trimetrexate from biological fluids. J Liqu Chromatogr 8: 125

  2. 2.

    Bertino JR, Sawicki WL, Moroson BA, Cashmore AR, Elslager EF (1979) 2,4-Diamino-5-methyl-6-[3,4,5-trimethoxyanilo methyl] quinazoline (TMQ), a potent non-classical folate antagonist inhibitor: I. Effect on dihydrofolate reductase and growth of rodent tumours in vitro and in vivo. Biochem Pharmacol 28: 1983

  3. 3.

    Curt GA, Carney DN, Cowan KH, Jolivet J, Bailey BD, Drake JC, Kao-Shan CS, Minna JD, Chabner BA (1983) Unstable methotrexate resistance in human small-cell lung carcinoma associated with double-minute chromosomes. N Engl J Med 308: 199

  4. 4.

    Curt GA, Clendenin NJ, Chabner BA (1984) Drug resistance in cancer. Cancer Treat Rep 68: 87

  5. 5.

    Diddens H, Niethammer D, Jackson RC (1983) Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate, and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate. Cancer Res 43: 5286

  6. 6.

    Donehower RC, Graham ML, Thompson GE, Dole GB, Ettinger DS (1985) Phase I and pharmacokinetic study of trimetrexate (TMTX) in patients with advanced breast cancer. Proc Am Soc Clin Oncol 4: 32

  7. 7.

    Fanucchi M, Fleisher M, Vidal P, Williams L, Bauer T, Cassidy C, Chou TC, Yang C (1985) Phase I and pharmacokinetic study of trimetrexate (TMTX). Proc Am Soc Cancer Res 26: 179

  8. 8.

    Heusner J, McCormick J (1981) Enzymatic assays for 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilmo)methyl] quinazoline, a promising new “non-classical” antifolate. J Pharm Sci 70: 827

  9. 9.

    Kamen BA, Eibl B, Cashmore AR (1984) Uptake and efficacy of trimetrexate (TMQ,2,4-diamino-5-methyl-6-[3,4,5-trimethoxyanilino]methyl quinazoline), a non-classical antifolate in methotrexate-resistant leukemia in vitro. Biochem Pharmacol 33(10): 1697

  10. 10.

    Latham B, Von Hoff DD, Elslager E (1984) Use of a human tumour cloning system to evaluate analogues of methotrexate and mitoxantrone. Cancer Treat Rep 68: 733

  11. 11.

    Lin JT, Cashmore AR, Baker M, Dreyer RN, Erstoff 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

  12. 12.

    Miller AB, Hoogstraaten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47: 207

  13. 13.

    O'Dwyer J, Shoemaker DD, Plowman I, Cradock J, Grillo-Lopez A, Leyland-Jones B (1985) Trimetrexate: a new antifol entering clinical trials. Invest New Drugs 3: 71

  14. 14.

    Reece PA, Morris RG, Bishop JF, Olver IN, Raghavan D (1987) Pharmacokinetics of trimetrexate administered as a five day continuous infusion to patients with advanced cancer. Cancer Res 47: 2996

  15. 15.

    Rosen M, Ohnuma T, Zimet A, Coffey V, Zhing N, Holland JF (1986) Phase I study of trimetrexate (TMTX, TMQ, JB-11) gluconate in a 5-day infusion schedule. Proc Am Assoc Cancer Res 27: 172

  16. 16.

    Wier EG, Cashmore AR, Dreyer RN, Graham MS, Hsiao N, Moroson BA, Sawacki WL, Bertino JR (1982) Pharmacology and toxicity of potent “non-classical” 2,4-diaminoquinazoline folate antagonist, trimetrexate, in normal dogs. Cancer Res 42: 1696

Download references

Author information

Correspondence to James F. Bishop.

Additional information

This study was supported by the AntiCancer Council of Victoria

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bishop, J.F., Raghavan, D., Olver, I.N. et al. A phase I study of trimetrexate (NSC 352122) administered by 5-day continuous intravenous infusion. Cancer Chemother. Pharmacol. 24, 246–250 (1989). https://doi.org/10.1007/BF00257627

Download citation

Keywords

  • Methotrexate
  • Neutropenia
  • Thrombocytopenia
  • Continuous Infusion
  • Intravenous Infusion