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Development of Target-Based Antineoplastic Agents

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Abstract

The elucidation of multiple potential targets in cancer cells andthe development of multiple target-based antineoplastic agentsprovide unique challenges in clinical trial design. Many of theseagents are predicted to have cytostatic as opposed to cytotoxiceffects and thus the traditional surrogate endpoint of radiologictumor shrinkage may be inadequate. The ethical and safety issuesof obtaining multiple tumor biopsies further complicate theassessment of appropriate target inhibition in patients. Wediscuss specific issues that need to be addressed duringpreclinical, phase I, II, and III testing of these agents. Wepropose clinical trial designs, including a randomizeddiscontinuation design during phase II evaluation, that may beparticularly useful for cytostatic antineoplastic agents.

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References

  1. Yang W, Del-Villar K, Urano J, et al.: Advances in the development of farnesyltransferase inhibitors: substrate recognition by protein famesyltransferase. J Cell Biochem Suppl 27: 12-19, 1997

    Google Scholar 

  2. Denis LJ, Verweij J: Matrix metalloproteinase inhibitors: present achievements and future prospects. Invest New Drugs 15: 175-185, 1997

    Google Scholar 

  3. Harris AL: Antiangiogenesis for cancer therapy. Lancet 349 (Suppl 2): SII13-5, 1997

    Google Scholar 

  4. Biggs JR, Kraff AS: Inhibitors of cyclin-dependent kinase and cancer. J Mol Med 73: 509-514, 1995

    Google Scholar 

  5. Ingber D, Fujita T, Kishimoto S, et al.: Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 348: 55-57, 1990

    Google Scholar 

  6. Sledge GW Jr, Qulali M, Goulet R, et al.: Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 87: 1546-1550, 1995

    Google Scholar 

  7. Kohn EC, Reed E, Sarosy G, et al.: Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers. Cancer Res 56: 569-573, 1996

    Google Scholar 

  8. Davis KL, Thal LJ, Gamzu ER, et al.: A double blind, placebocontrolled multicenter study of tacrine for Alzheimer's disease. N Engl J Med 327: 1306-1308, 1992

    Google Scholar 

  9. Holford NH, Peace KE: Results and validation of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci USA 89: 11471-11475, 1992

    Google Scholar 

  10. Bensimon G, Lacomblez L, Meininger V: A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 330: 585-591, 1994

    Google Scholar 

  11. Paulus HE, Egger MJ, Ward JR, et al.: Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum 33: 477-484, 1990

    Google Scholar 

  12. Porter DR, Capell HA: The ‘natural’ history of active rheumatoid arthritis over 36 months-an analysis of patients enrolled into trials of potential disease-modifying anti-rheumatic drugs, and treated with placebo. Br J Rheumatol 32: 463-466, 1993

    Google Scholar 

  13. Kirwan JR: The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 333: 142-146, 1995

    Google Scholar 

  14. Ferraccioli GF, Della-Casa-Alberighi O, Marubini E, et al.: Is the control of disease progression within our grasp? Review of the GRISAR study. (Gruppo Reumatologi Italiani Studio Artrite Reumatoide). Br J Rheumatol 35 Suppl 2: 8-13, 1996

    Google Scholar 

  15. Ratain MJ, Mick R, Schilsky RL, et al.: Statistical and ethical issues in the design and conduct of phase I and II clinical trials of new anticancer agents. J Natl Cancer Inst. 85: 1637-1643, 1993

    Google Scholar 

  16. Millar AW, Brown PD, Moore J, et al.: Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. Br J Clin Pharmacol 45: 21-26, 1998

    Google Scholar 

  17. Mani S, Ratain MJ: New phase I trial methodology. Semin Oncol 24: 253-261, 1997

    Google Scholar 

  18. Paxton JW, Kim SN, Whitfield LR: Pharmacokinetic and toxicity scaling of the antitumor agents amsacrine and CI-921, a new analogue, inmice, rats, rabbits, dogs, and humans. Cancer Res 50: 2692-2697, 1990

    Google Scholar 

  19. DeMario MD, Ratain MJ: Oral chemotherapy: rationale and future directions. J Clin Oncol 16: 2557-2567, 1998

    Google Scholar 

  20. Merry C, Barry MG, Mulcahy F, et al.: Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS 11: F29-33, 1997

    Google Scholar 

  21. Keogh A, Spratt P, McCosker C, et al.: Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med 333: 628-633, 1995

    Google Scholar 

  22. Floren LC, Bekersky I, Benet LZ, et al.: Tacrolimus oral bioavailability doubles with coadminstration of ketoconazole. Clin Pharmacol Ther 62: 41-49, 1997

    Google Scholar 

  23. Spiro TP, Gerson SL, Hoppel CL, et al.: O6-Benzylguanine totally depletes alkylguanine DNA alkyltransferase in tumor tissue: A phase I phannacokinetic/pharmacodynamic study. Proc Amer Soc Clin Oncol 17: 212a, 1998

    Google Scholar 

  24. Eisenhauer EA: Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and existentialism. Am Oncol 9: 1047-1052, 1998

    Google Scholar 

  25. Von Hoff DD: There are no bad anticancer agents, only bad clinical trial designs-twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin Cancer Res 4: 1079-1086, 1998

    Google Scholar 

  26. Nemunaitis J, Poole C, Primrose J, et al.: Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin Cancer Res 4: 1101-1109, 1998

    Google Scholar 

  27. Lippman SM, Hong WK, Benner SE. The chemoprevention of cancer, in Greenwals P, Kramer BS, Weed DL (eds). Cancer Prevention and Control. New York, NY: Marcel Dekker, Inc, 1995, pp 329-352

    Google Scholar 

  28. Kopec JA, Abrahamowicz M, Esdaile JM: Randomized discontinuation trials: Utility and efficiency. J Clin Epidemiol 46: 959-971, 1993

    Google Scholar 

  29. Tannock IF, Osoba D, Stockier MR, Ernst DS, Neville AJ, Moore MJ, Annitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 6: 1756-1764, 1996

    Google Scholar 

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Stadler, W.M., Ratain, M.J. Development of Target-Based Antineoplastic Agents. Invest New Drugs 18, 7–16 (2000). https://doi.org/10.1023/A:1006371512390

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