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Maximum tolerated dose: clinical endpoint for a bygone era?

Targeted Oncology volume 4, pages 143–147 (2009)Cite this article

Abstract

The maximum tolerated dose (MTD) has been the classically recommended phase II dose for cytotoxic chemotherapy anticancer agents. However, the development of molecular targeted therapies with highly specific mechanisms of action has raised questions about the paradigm of dosing at the MTD. Inhibition of the molecular target may occur at dose levels substantially below those producing dose limiting toxicities. The impact of targeted therapies on our dose selection strategies has been immense; however, defining the MTD in phase I oncology trials still provides valuable information for future drug development. But, the MTD should not be selected blindly as the recommended phase II dose for efficacy testing. Optimal dose selection for targeted cancer agents needs to be evaluated using all available information collected during the early stages of drug development. Definition of the optimal dose may need to be deferred until randomized phase II trials can be conducted. Future clinical trail designs in oncology drug development need to reflect this paradigm shift.

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References

  1. DeVita VT Jr, Chu E (2008) A history of cancer chemotherapy. Cancer Res 68:8643–8653

    Article  CAS  PubMed  Google Scholar 

  2. Hryniuk WM (1988) More is better. J Clin Oncol 6:1365–1367

    CAS  PubMed  Google Scholar 

  3. Takimoto CH, Rowinsky EK (2003) Dose-intense paclitaxel: deja vu all over again? J Clin Oncol 21:2810–2814

    Article  CAS  PubMed  Google Scholar 

  4. Lippman ME (2000) High-dose chemotherapy plus autologous bone marrow transplantation for metastatic breast cancer. N Eng J Med 342:1119–1120

    Article  CAS  Google Scholar 

  5. Haines IE (2008) Dose selection in phase I studies: why we should always go for the most effective. J Clin Oncol 26:3650–3652 author reply 2–3

    Article  PubMed  Google Scholar 

  6. Druker BJ (2004) Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91:1–30

    Article  CAS  PubMed  Google Scholar 

  7. Parulekar WR, Eisenhauer EA (2004) Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice. J Nat Cancer Inst 96:990–997

    CAS  PubMed  Article  Google Scholar 

  8. El-Maraghi RH, Eisenhauer EA (2008) Review of phase II trial designs used in studies of molecular targeted agents: outcomes and predictors of success in phase III. J Clin Oncol 26:1346–1354

    Article  PubMed  Google Scholar 

  9. Dowlati A, Robertson K, Radivoyevitch T et al (2005) Novel phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416. Clin Cancer Res 11:7938–7944

    Article  CAS  PubMed  Google Scholar 

  10. Kummar S, Gutierrez M, Doroshow JH, Murgo AJ (2006) Drug development in oncology: classical cytotoxics and molecularly targeted agents. Br J Clin Pharm 62:15–26

    Article  CAS  Google Scholar 

  11. Goulart BH, Clark JW, Pien HH, Roberts TG, Finkelstein SN, Chabner BA (2007) Trends in the use and role of biomarkers in phase I oncology trials. Clin Cancer Res 13:6719–6726

    Article  CAS  PubMed  Google Scholar 

  12. Sleijfer S, Wiemer E (2008) Dose selection in phase I studies: why we should always go for the top. J Clin Oncol 26:1576–1578

    Article  PubMed  Google Scholar 

  13. Emmenegger U, Kerbel RS (2005) A dynamic de-escalating dosing strategy to determine the optimal biological dose for antiangiogenic drugs. Clin Cancer Res 11:7589–7592

    Article  CAS  PubMed  Google Scholar 

  14. Kummar S, Kinders R, Rubinstein L et al (2007) Compressing drug development timelines in oncology using phase '0' trials. Nature reviews 7:131–139

    Article  CAS  PubMed  Google Scholar 

  15. Takimoto CH (2008) Phase 0 clinical trials in oncology: a paradigm shift for early drug development? Cancer Chem Pharm . doi:10.1007/s00280-008-0789-4

    Google Scholar 

  16. Ratain MJ, Glassman RH (2007) Biomarkers in phase I oncology trials: signal, noise, or expensive distraction? Clin Cancer Res 13:6545–6548

    Article  CAS  PubMed  Google Scholar 

  17. Workman P (2003) How much gets there and what does it do?: The need for better pharmacokinetic and pharmacodynamic endpoints in contemporary drug discovery and development. Current Pharm Design 9:891–902

    Article  CAS  Google Scholar 

  18. Sarker D, Workman P (2007) Pharmacodynamic biomarkers for molecular cancer therapeutics. Adv Cancer Res 96:213–268

    Article  CAS  PubMed  Google Scholar 

  19. Yamazaki S, Skaptason J, Romero D et al (2008) Pharmacokinetic-pharmacodynamic modeling of biomarker response and tumor growth inhibition to an orally available cMet kinase inhibitor in human tumor xenograft mouse models. Drug Metab Dispos 36:1267–1274

    Article  CAS  PubMed  Google Scholar 

  20. Ratain MJ, Sargent DJ (2008) Optimising the design of phase II oncology trials: The importance of randomisation. Eur J Cancer 45(2):275–280

    Article  PubMed  Google Scholar 

  21. Fukuoka M, Yano S, Giaccone G et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 21:2237–2246

    Article  CAS  PubMed  Google Scholar 

  22. Atkins MB, Hidalgo M, Stadler WM et al (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909–918

    Article  CAS  PubMed  Google Scholar 

  23. Workman P (2003) Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: unfolding the relationship between pharmacokinetics and pharmacodynamics. Molecular Cancer Therapeutics 2:131–138

    CAS  PubMed  Google Scholar 

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Conflict of interest statement

No funds were received in support of this work, however the author is a full time employee of Ortho Biotech Oncology R&D, a Johnson and Johnson company.

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  1. Translational Medicine, Ortho Biotech Oncology R&D, 145 King of Prussia Road, Mailstop RA-2-2, Radnor, PA, 19087, USA

    Chris H. Takimoto

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  1. Chris H. Takimoto
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Correspondence to Chris H. Takimoto.

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Takimoto, C.H. Maximum tolerated dose: clinical endpoint for a bygone era?. Targ Oncol 4, 143–147 (2009). https://doi.org/10.1007/s11523-009-0108-y

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  • DOI: https://doi.org/10.1007/s11523-009-0108-y

Keywords

  • Maximum tolerated dose
  • Phase II trials
  • Molecular targeted therapies
  • Optimal dose selection