A Phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors

Clinical Cancer Research

Volumn 5, Issue 9, 1999, Pages 2381-2391

  Grem, Jean L ^a   Sorensen, J Mel ^a   Cullen, Ellen ^a   Takimoto, Chris H ^a   Steinberg, Seth M ^a   Chen, Alice P ^a   Hamilton, J Michael ^a   Arbuck, Susan G ^a   McAtee, Nanette ^a   Lawrence, David ^b,c   Goldspiel, Barry ^d   Johnston, Patrick G ^a   Allegra, Carmen J ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

^b WALTER REED ARMY MEDICAL CENTER   (United States)

^c UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES   (United States)

^d Pharmacy Department   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CREATININE; RALTITREXED;

ADULT; ADVANCED CANCER; AGED; AREA UNDER THE CURVE; ARTICLE; ASTHENIA; CLINICAL ARTICLE; CLINICAL TRIAL; CREATININE CLEARANCE; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG CLEARANCE; ENZYME INHIBITION; FEMALE; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; MALE; NEUTROPENIA; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; SOLID TUMOR;

ADULT; AGED; ANTIMETABOLITES, ANTINEOPLASTIC; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; ENZYME INHIBITORS; FEMALE; FOLIC ACID ANTAGONISTS; HUMANS; MALE; MIDDLE AGED; NEOPLASMS; QUINAZOLINES; THIOPHENES; THYMIDYLATE SYNTHASE;

EID: 0032834995     PISSN: 10780432     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (62)

1. Grem, J. L. Fluoropyrimidines. In: B. A. Chabner and D. L. Longo (eds.), Cancer Chemotherapy and Biotherapy: Principles and Practice, Ed. 2, pp. 149-211. Philadelphia: Lippincott-Raven Publishers, 1996.
2. Harrap, K. R. Initiatives with platinum- and quinazoline-based antitumor molecules: Fourteenth Bruce F. Cain Memorial Award Lecture. Cancer Res., 55: 2761-2768, 1995.
3. Jackman, A. L., and Calvert, A. H. Folate-based thymidylate synthase inhibitors as anticancer drugs. Ann. Oncol., 6: 871-881, 1995.
4. Rustum, Y. M., Harstrick, A., Cao, S-S., Vanhoefer, U., Yin, M-B., Wilke, H., and Seeber, S. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. J. Clin. Oncol., 15: 289-400, 1997.
5. Jones, T. R., Calvert, A. H., Jackman, A. L., Brown, S. J., Jones, M., and Harrap, K. R. A potent antitumour quinazoline inhibitor of thymidylate synthetase: Synthesis, biological properties and therapeutic results in mice. Eur. J. Cancer., 17: 11-19, 1981.
6. Jackman, A. L., Taylor, G. A., Calvert, A. H., Harrap, K. R. Modulation of anti-metabolite effects. Effects of thymidine on the efficacy of the quinazoline-based thymidylate synthetase inhibitor, CB3717. Biochem. Pharmacol., 33: 3269-3275, 1984.
7. Jackman, A. L., Taylor, G. A., O'Connor, B. M., Bishop, J. A., Morn, R. G., and Calvert, A. H. Activity of the thymidylate synthase inhibitor 2-desamino-n10-propargyl-5,8-dideazafolic acid and related compounds in murine (L1210) and human (WIL2) systems in vitro and in L1210 in vivo. Cancer Res., 50: 5212-5218, 1990.
8. 10-propargyl-5,8-dideazofolic acid, CB3717. J. Clin. Oncol., 4: 1245-1252, 1986.
9. Sessa, C., Zucchetti, M., Ginier, M., Willems, Y., D'Incalci, M., and Cavalli, F. Phase I study of the antifolate N-10-propargyl-5,8-dideazafolic acid, CB 3717. Eur. J. Cancer Clin. Oncol., 24: 769-775, 1988.
10. Vest, S., Bork, E., and Hansen, H. H. Phase I evaluation of N-10-propargyl-5,8-dideazafolic acid. Eur. J. Cancer Clin. Oncol., 24: 201-204, 1988.
11. 10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer. Eur. J. Cancer Clin. Oncol., 24: 733-736, 1988.
12. Bassendine, M. F., Curtin, N. J., Loose, H., Harris, A. L., and James, O. F. W. Induction of remission in hepatocellular carcinoma with a new thymidylate synthase inhibitor, CB3717. A Phase II study. J. Hepatol., 4: 349-356, 1987.
13. 10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue, ICI D1694, in mice. Br. J. Cancer, 64: 833-838, 1991.
14. Jackman, A. L., Taylor, G. A., Gibson, W., Kimbell, R., Brown, M., Calvert, A. H., Judson, I. R., and Hughes, L. R. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res., 51: 5579-5586, 1991.
15. Freemantle, S. J., Jackman, A. L., Kelland, L. R., Calvert, A. H., and Lunec, J. Molecular characterisation of two cell lines selected for resistance to the folate-based thymidylate synthase inhibitor, ZD1694. Br. J. Cancer, 71: 925-930, 1995.
16. Jackman, A. L., Kelland, L. R., Kimbell, R., Brown, M., Gibson, W., Aherne, G. W., Hardcastle, A., and Boyle, F. T. Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (raltitrexed) in one mouse and three human cell lines. Br. J. Cancer, 71: 914-924, 1995.
17. Yin, M-B., Guimaraes, M. A., Zhang, Z-G., Arredondo, M. A., and Rustum, Y. M. Time dependence of DNA lesions and growth inhibition by ICI D1694, a new quinazoline antifolate thymidylate synthase inhibitor. Cancer Res., 52: 5900-5905, 1992.
18. Lu, K., Yin, M-B., McGuire, J. J., Bonmassar, E., and Rustum, Y, M. Mechanisms of resistance to N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2- thenoyl]-L-glutamic acid (ZD1694), a folate-based thymidylate synthase inhibitor, in the HCT-8 human ileocecal adenocarcinoma cell line. Biochem. Pharmacol., 50: 391-398, 1995.
19. Howell, S. B., Mansfield, S. J., and Taetle, R. Significance of variation in serum thymidine concentration for the marrow toxicity of methotrexate. Cancer Chemother. Pharmacol., 5: 221-226, 1981.
20. Jackman, A. L., Taylor, G. A., Calvert, A. H., and Harrap, K. R. Modulation of antimetabolite effects: effect of thymidine on the efficacy of the quinazoline-based thymidylate synthase inhibitor CB 3717. Biochem. Pharmacol., 33: 3269-3275, 1984.
21. Jackman, A. L., and Judson, I. R. The new generation of thymidylate synthase inhibitors in clinical study. Exp. Opin. Invest. Drugs, 5: 719-736, 1996.
22. Jackman, A. L., Boyle, F. T., and Harrap, K. R. Tomudex (ZD1694): from concept to care, a programme in rational drug discovery. Invest. New Drugs, 14: 305-316, 1996.
23. Stephens, T. C., Smith, M. N., Waterman, S. E., McCloskey, M. L., and Boyle, F. T. Use of murine L5178Y lymphoma thymidine kinase mutants for in vitro and in vivo antitumour efficacy evaluation of novel thymidylate synthase inhibitors. In: J. E. Ayling, M. G. Nair, and C. M. Baugh (eds.), Chemistry and Biology of Pteridines and Folates. Advances in Experimental Medicine and Biology, Vol. 338, pp. 589-592. New York: Plenum Press, 1993.
24. Jodrell, D. I., Newell, D. R., Gibson, W., Hughes, L. R., and Calvert, A. H. The pharmacokinetics of the quinazoline antifolate ICI D1694 in mice and rats. Cancer Chemother. Pharmacol., 28: 331-338, 1991.
25. Clarke, S. J., Hanwell, J., de Boer, M., Planting, A., Verweij, J., Walker, M., Smith, R., Jackman, A. L., Hughes, L. R., Harrap, K. R., Kennealey, G. T., and Judson, I. R. Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors. J. Clin. Oncol., 14: 1495-1503, 1996.
26. In. Macdonald, J. S., Haller, D. G., and Mayer, R. J. (eds.), Manual of Oncologic Therapeutics, Ed. 3, pp. 519-523. Philadelphia: J. B. Lippincott, 1995.
27. Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., and Carbone, P. P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. J. Clin. Oncol., 5: 649-655, 1982.
28. Johnston, P. G., Lenz, H. J., Leichman, C. G., Danenberg, K. D., Allegra, C. J., Danenberg, P. V., and Leichman, L. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res., 55: 1407-1412, 1995.
29. Lehmann, E. Nonparametrics. Statistical Methods Based on Ranks, pp. 306-309. San Francisco: Holden-Day, 1975.
30. Hochberg, Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika, 75: 800-802, 1988.
31. O'Rourke, T. J., Weiss, G. R., New, P., Burris, H. A., III, Rodriguez, G., Eckhardt, J., Hardy, J., Kuhn, J. G., Fields, S., Clark, G. M., and Von Hoff, D. D. Phase I clinical trial of ormaplatin (tetraplatin, NSC 363812). Anticancer Drugs, 5: 520-526, 1994.
32. Schilder, R. J., LaCreta, F. P., Perez, R. P., Johnson, S. W., Brennan, J. M., Rogatko, A., Nash, S., McAleer, C., Hamilton, T. C., Roby, D., Young, R. C., and Ozols, R. F. Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule. Cancer Res., 54: 709-717, 1994.
33. Cocconi, G., Cunningham, D., van Cutsem, E., Francois, E., Gustavsson, B., van Hazel, G., Kerr, D., Possinger, K., and Heitschold, S. M., on behalf of the Tomudex Colorectal Cancer Study Group. Open, randomized multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. J. Clin. Oncol., 16: 2943-2952, 1998.
34. Cunningham, D., Zalcberg, J. R., Rath, U., Oliver, I., van Cutsem, E., Svensson, C., Seitz, J. F., Harper, P., Kerr, D., Pérez-Manga, G., and the "Tomudex" Colorectal Cancer Study Group. Final results of a randomised trial comparing "Tomudex" (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann. Oncol., 7: 961-965, 1996.
35. Pazdur, R., and Vincent, M. Raltitrexed versus 5-fluorouracil and leucovorin in patients with advanced colorectal cancer: results of a randomized, multicenter, North American trial. Proc. Am. Soc. Clin. Oncol., 16: 228a, 1997.
36. Cunningham, D. Mature results from three large controlled studies with raltitrexed ("Tomudex"). Br. J. Cancer, 77 (Suppl. 2): 15-21, 1998.
37. Zalcberg, J. R., Cunningham, D., Van Cutsem, E., Francois, E., Schornagel, J., Adenis, A., Green, M., Iveson, A., Azab, M., and Seymour, I., for the Tomudex Colorectal Study Group. ZD1694: a novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. J. Clin. Oncol., 14: 716-721, 1996.
38. Zalcberg, J. R., Ibrahaim, J., Johnston, PlG., Locker, G. Y., O'Dwyer, P. J., Weiner, L. M., Hochster, H. S., Rao, S., and Benson, A. B., III. ECOG Phase II study of Tomudex® in advanced colorectal cancer. Proc. Am. Soc. Clin. Oncol., 16: 268a, 1997.
39. Meropol, N. J., Pazdur, R., Vincent, M., Willson, J. K. V., Kelsen, D. P., and Douglass, H. O., Jr. Phase II study of ZD1694 in patients with advanced gastric cancer. Am. J. Clin. Oncol., 19: 628-630, 1996.
40. Gore, M. E., Earl, H. M., Cassidy, J., Tattersall, M., Mansi, J., Seymour, L., and Azab, M. A Phase II study of Tomudex in relapsed epithelial ovarian cancer. Ann. Oncol., 6: 724-725, 1995.
41. Muggia, F. M., Blessing, J. A., Homesley, H. D., and Sorosky, J. Tomudex (ZD1694, NSC 639186) in platinum-pretreated recurrent epithelial ovarian cancer: a Phase II study by the Gynecologic Oncology Group. Cancer Chemother. Pharmacol., 42: 68-70, 1998.
42. Woll, P. J., Basser, R., Le Chevalier, T., Drings, P., Pérez-Manga, G., Adenis, A., Serumoir, L., Smith, F., and Tatcher, N. Phase II trial of raltitrexed ("Tomudex") in advanced small-cell lung cancer. Br. J. Cancer, 76: 264-265, 1998.
43. Smith, I., Jones, A., Speilmann, M., Namer, M., Green, M. D., Bonneterre, J., Wander, H. E., Hatschek, T., Wiling, N., Zalcberg, J. R., Spiers, S., and Seymour, L. A Phase II study in advanced breast cancer: ZD1694 ("Tomudex"), a novel direct and specific thymidylate synthase inhibitor. Br. J. Cancer, 74: 479-481, 1996.
44. Pazdur, R., Meropol, N. J., Casper, E. S., Fuchs, C., Douglass, H. O., Jr, Vincent, M., and Abbruzzese, J. L. Phase II trial of ZD1694 (Tomudex™) in patients with advanced pancreatic cancer. Invest. New Drugs, 13: 355-358, 1996.
45. Rougier, P., Ducreux, M., Kerr, D., Carr, B. I., Francois, E., Adenis, A., and Seymour L. A Phase II study of raltitrexed ("Tomudex") in patients with hepatocellular carcinoma. Ann. Oncol., 8: 500-502, 1997.
46. O'Dwyer, P. J., Laub, P. B., DeMaria, D., Qian, M., Reilly, D., Giantonio, B., Johnston, A. L., Wu, E. Y., Bauman, L., Clendeninn, N. J., and Gallo, J. M. Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion. Clin. Cancer Res., 2: 1685-1692, 1996.
47. Rinaldi, D. A., Burris, H. A., Dorr, F. A., Woodworth, J. R., Kuhn, J. G., Echardt, J. R., Rodriguez, G., Corso, S. W., Fields, S. M., Langley, C., Clark, G., Faries, D., Lu, P., and Von Hoff, D. D. Initial Phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J. Clin. Oncol., 13: 2842-2850, 1995.
48. Aapro, M. S., Martin, C., and Hatty, S. Gemcitabine: a safety review. Anticancer Drugs, 9: 191-201, 1998.
49. Miller, A. B., Hoogstraten, B., Staquet, M., and Winkler, A. Reporting results of cancer treatment. Cancer (Phila.), 47: 207-214, 1981.
50. 14C]-raltitrexed in cancer patients. Cancer Chemother. Pharmacol., 42: 71-76, 1998.
51. Synold, T. W., Newman, E. M., Carroll, M., Muggia, F. M., Groshen, S., Johnson, K., and Doroshow, J. H. Cellular but not plasma pharmacokinetics of lometrexol correlate with the occurrence of cumulative hematological toxicity. Clin. Cancer Res., 10: 2349-2355, 1998.
52. Aherne, G. W., Ward, E., Lawrence, N., Dobinson, D., Clarke, S. J., Musgrove, H., Sutcliffe, F., Stephens, T., and Jackman, A. L. Comparison of plasma and tissue levels of ZD1695 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models. Br. J. Cancer, 77: 221-226, 1998.
53. Beardsley, G. P., Moroson, B. A., Taylor, E. C., and Moran, R. G. A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis. J. Biol. Chem., 264: 328-333, 1989.
54. Alati, T., Worzalla, J. F., Shih, C., Bewley, J. R., Lewis, S., Moran, R. G., and Grindey, G. B. Augmentation of therapeutic activity of lometrexol-(6-R)5,10-dideazatetrahydrofolate by oral folic acid. Cancer Res., 56: 2331-2335, 1996.
55. Gates, S. B., Worzalla, J. F., Shih, C., Grindey, G. B., and Mendelsohn, L. G. Dietary folate and folylpolyglutamate synthetase activity in normal and neoplastic murine tissues and human tumor xenografts. Biochem. Pharmacol., 52: 1477-1479, 1996.
56. Mendelsohn, L. G., Gates, S, B., Habeck, L. L., Shackelford, K. A., Worzalla, J., Shih, C., and Grindey, G. B. The role of dietary folate in modulation of folate receptor expression, folylpolyglutamate synthetase activity and the efficacy and toxicity of lometrexol. Adv. Enzyme Regul., 36: 365-381, 1996.
57. Laohavinij, S., Wedge, S. R., Lind, M. J., Bailey, N., Humphreys, A., Proctor, M., Chapman, F., Simmons, D., Oakley, A., Robson, L., Gumbrell, L., Taylor, G. A., Thomas, H. D., Boddy, A. V., Newell, D. R., and Calvert, A. H. A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid. Invest. New Drugs, 14: 325-335, 1996.
58. Takimoto, C. H., Lu, Z-H., Zhang, R. Liang, M. D., Larson, L. V., Cantilena, L. R., Jr., Grem, J. L., Allegra, C. J., Diasio, R. B., and Chu, E. Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency. Clin. Cancer Res., 2: 477-482, 1996.
59. Köhne, C-H., Thuss-Patience, P., Friedrich, M., Daniel, P. T., Kretzschmar, A., Benter, T., Bauer, B., Dietz, R., and Dörken, B. Raltitrexed (Tomudex). an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity. Br. J. Cancer, 77: 973-977, 1998.
60. Judson, I., Maughan, T., Beale, P., Primrose, J., Hoskin, P., Hanwell, J., Berry, C., Walker, M., and Sutcliffe, F. Effects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694). Br. J. Cancer, 78: 1188-1193, 1998.
61. 2) raltitrexed (Tomudex) in advanced colorectal cancer. Proc. Am. Soc. Clin. Oncol., 18: 289a, 1999.
62. 2 as second- and third-line therapy in patients with metastatic colorectal cancer. Proc. Am. Soc. Clin. Oncol., 18: 299a. 1999.