Advertisement

A Global Perspective on First-in-Man Dose Selection: Oncology and Beyond

  • Peng ZouEmail author
  • Sau Lee
  • Min Li
  • Lawrence Yu
  • Duxin SunEmail author
Chapter

Abstract

First-in-human (FIH) studies of anticancer products differ from that of other drug products in that they are usually evaluated in cancer patients rather than healthy volunteers. The FIH dose for anticancer drugs is expected to have pharmacological effects in cancer patients and is reasonably safe to use. Therefore, it is challenging to estimate the starting dose for an anticancer drug. Furthermore, the emergence of targeted agents such as small molecule molecularly targeted agents (MTAs), monoclonal antibodies, and antibody–drug conjugates (ADCs) in oncology has posed additional challenges in FIH dose selection. Traditional FIH dose selection methods were developed in the era of cytotoxic drugs and these doses were determined by methods using preclinical toxicity data. For targeted agents, the interspecies variability in safety and efficacy, dose–efficacy curve, and dose–toxicity curve may differ from those for cytotoxic agents, and efficacy may occur at doses that do not reach the maximum tolerated dose (MTD). Therefore, traditional preclinical toxicological studies may be inadequate to support the selection of a safe and active FIH dose of targeted agents. The strategy for FIH dose determination has shifted from a primary focus on toxicity to identifying a dose that optimally inhibits the molecular target. This chapter reviews various approaches for determining FIH dose of anticancer drug products as well as preclinical studies to support the FIH dose selection.

Keywords

First-in-human dose Anticancer drug Monoclonal antibody Molecularly targeted agent Antibody–drug conjugate 

Notes

Disclaimer

This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

References

  1. Agoram BM (2009) Use of pharmacokinetic/pharmacodynamic modelling for starting dose selection in first-in-human trials of high-risk biologics. Br J Clin Pharmacol 67(2):153–160CrossRefPubMedGoogle Scholar
  2. Brennan FR, Morton LD, Spindeldreher S, Kiessling A, Allenspach R, Hey A, Muller PY, Frings W, Sims J (2010) Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs 2(3):233–255CrossRefPubMedPubMedCentralGoogle Scholar
  3. Collins JM, Grieshaber CK, Chabner BA (1990) Pharmacologically guided phase-I clinical-trials based upon preclinical drug development. J Natl Cancer Inst 82(16):1321–1326CrossRefPubMedGoogle Scholar
  4. Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S (2011) Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? MAbs 3(1):61–66CrossRefPubMedPubMedCentralGoogle Scholar
  5. Deslandes A (2014) Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human phase 1 studies. MAbs 6(4):859–870CrossRefPubMedPubMedCentralGoogle Scholar
  6. EMA (2007) Guideline on the strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf
  7. EMA (2012) Guideline on the evaluation of anticancer medicinal products in man. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/01/WC500137128.pdf
  8. FDA (2005) Guidance for industry—estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf
  9. FDA (2006) Guidance for industry, investigators, and reviewers—exploratory IND studies. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078933.pdf
  10. Greaves P, Williams A, Eve M (2004) First dose of potential new medicines to humans: how animals help. Nat Rev Drug Discov 3(3):226–236CrossRefPubMedGoogle Scholar
  11. ICH (1997) ICH guideline S6 preclinical safety evaluation of biotechnology-derived pharmaceuticals. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074957.pdf
  12. ICH (2010) ICH guideline S9 on nonclinical evaluation for anticancer pharmaceuticals. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500043471.pdf
  13. ICH (2012) ICH guideline S6 addendum to preclinical safety evaluation of biotechnology-derived pharmaceuticals. http://www.fda.gov/downloads/Drugs/…/Guidances/UCM194490.pdf
  14. National Cancer Institute (2014) Targeted cancer therapies. Accessed 25 Apr 2015Google Scholar
  15. Kenter MJH, Cohen AF (2015) The return of the prodigal son and the extraordinary development route of antibody TGN1412-lessons for drug development and clinical pharmacology. Br J Clin Pharmacol 79(4):545–547CrossRefPubMedPubMedCentralGoogle Scholar
  16. Le Tourneau C, Stathis A, Vidal L, Moore MJ, Siu LL (2010) Choice of starting dose for molecularly targeted agents evaluated in first-in-human phase I cancer clinical trials. J Clin Oncol 28(8):1401–1407CrossRefPubMedGoogle Scholar
  17. Lowe PJ, Hijazi Y, Luttringer O, Yin H, Sarangapani R, Howard D (2007) On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development. Xenobiotica 37(10–11):1331–1354CrossRefPubMedGoogle Scholar
  18. Lowe PJ, Tannenbaum S, Wu K, Lloyd P, Sims J (2010) On setting the first dose in man: quantitating biotherapeutic drug-target binding through pharmacokinetic and pharmacodynamic models. Basic Clin Pharmacol Toxicol 106(3):195–209CrossRefPubMedGoogle Scholar
  19. Millar AW, Brown PD, Moore J, Galloway WA, Cornish AG, Lenehan TJ, Lynch KP (1998) Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. Br J Clin Pharmacol 45(1):21–26CrossRefPubMedPubMedCentralGoogle Scholar
  20. Muller PY, Brennan FR (2009) Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies. Clin Pharmacol Ther 85(3):247–258CrossRefPubMedGoogle Scholar
  21. Penta JS, Rozencweig M, Guarino AM, Muggia FM (1979) Mouse and large-animal toxicology studies of twelve antitumor agents: relevance to starting dose for phase I clinical trials. Cancer Chemother Pharmacol 3(2):97–101CrossRefPubMedGoogle Scholar
  22. Reigner BG, Blesch KS (2002) Estimating the starting dose for entry into humans: principles and practice. Eur J Clin Pharmacol 57(12):835–845CrossRefPubMedGoogle Scholar
  23. Rosenfeldt H, Kropp T, Benson K, Ricci MS, McGuinn WD, Verbois SL (2010) Regulatory aspects of oncology drug safety evaluation: past practice, current issues, and the challenge of new drugs. Toxicol Appl Pharmacol 243(2):125–133CrossRefPubMedGoogle Scholar
  24. Rozencweig M, Von Hoff DD, Staquet MJ, Schein PS, Penta JS, Goldin A, Muggia FM, Freireich EJ, DeVita VT Jr (1981) Animal toxicology for early clinical trials with anticancer agents. Cancer Clin Trials 4(1):21–28PubMedGoogle Scholar
  25. Saber H, Leighton JK (2015) An FDA oncology analysis of antibody-drug conjugates. Regul Toxicol Pharmacol 71(3):444–452CrossRefPubMedGoogle Scholar
  26. Scott AM, Wolchok JD, Old LJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12(4):278–287CrossRefPubMedGoogle Scholar
  27. Senderowicz AM (2010) Information needed to conduct first-in-human oncology trials in the United States: a view from a former FDA medical reviewer. Clin Cancer Res 16(6):1719–1725CrossRefPubMedGoogle Scholar
  28. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355(10):1018–1028CrossRefPubMedGoogle Scholar
  29. Tam K (2013) Estimating the “First in human” dose—a revisit with particular emphasis on oncology drugs. ADMET & DMPK 1(4):63–75Google Scholar
  30. Tibbitts J, Cavagnaro JA, Haller CA, Marafino B, Andrews PA, Sullivan JT (2010) Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals. Regul Toxicol Pharmacol 58(2):243–251CrossRefPubMedGoogle Scholar
  31. Tomaszewski JE (2004) Multi-species toxicology approaches for oncology drugs: the US perspective. Eur J Cancer 40(6):907–913CrossRefPubMedGoogle Scholar
  32. Vugmeyster Y, Xu X, Theil FP, Khawli LA, Leach MW (2012) Pharmacokinetics and toxicology of therapeutic proteins: advances and challenges. World J Biol Chem 3(4):73–92CrossRefPubMedPubMedCentralGoogle Scholar
  33. Zou P, Yu YK, Zheng N, Yang YS, Paholak HJ, Yu LX, Sun DX (2012) Applications of human pharmacokinetic prediction in first-in-human dose estimation. Aaps J 14(2):262–281CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Office of Pharmaceutical Quality, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  2. 2.Department of Pharmaceutical SciencesCollege of Pharmacy, The University of MichiganAnn ArborUSA

Personalised recommendations