SpringerLink
Log in

Efficacy-Driven Dose Finding with Toxicity Control in Phase I Oncology Studies

  • Published:
Statistics in Biosciences Aims and scope Submit manuscript

Abstract

Traditionally, dose-finding process for oncology compound is carried out in phase I dose escalation study and is driven by safety in order to find maximum tolerated dose (MTD). However, with the recent paradigm shift from cytotoxic drugs to new generation of targeted therapies and immuno-oncology therapies, it may be difficult or unnecessary to identify the MTD because of the possible non-monotonic dose–response curves, and efficacy data should be incorporated into the dose-finding process. In this article, we have proposed efficacy-driven dose-finding designs with a safety-driven warm-up phase. Both local investigation and adaptive randomization using the framework of double-sided isotonic regression are investigated. Simulation studies are used to compare the proposed design to the original double-sided isotonic design. The results show that a safety-driven warm-up phase at the beginning can significantly improve the performance of double-sided isotonic regression, and both local investigation and adaptive randomization have good operating characteristics for finding the best dose/dose range under different tested scenarios.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ananthakrishnan R, Green S, Li D, LaValley M (2019) 2D (2 dimensional) TEQR design for determining the optimal dose for safety and efficacy. Contemp Clin Trials Commun 16:100461

    Article  Google Scholar 

  2. Babb J, Rogatko A, Zacks S (1998) Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 17(10):1103–1120

    Article  Google Scholar 

  3. FDA (2011) Guidance for industry: clinical considerations for therapeutic cancer vaccine

  4. Ji Y, Liu P, Li Y, Nebiyou Bekele B (2010) A modified toxicity probability interval method for dose-finding trials. Clin Trials 7(6):653–663

    Article  Google Scholar 

  5. Korn EL, Midthune D, Chen TT, Rubinstein LV, Christian MC, Simon RM (1994) A comparison of two phase I trial designs. Stat Med 13(18):1799–1806

    Article  Google Scholar 

  6. Li DH, Whitmore JB, Guo W, Ji Y (2017) Toxicity and efficacy probability interval design for phase I adoptive cell therapy dose-finding clinical trials. Clin Cancer Res 23(1):13–20

    Article  Google Scholar 

  7. Lin Y, Shih WJ (2001) Statistical properties of the traditional algorithm-based designs for phase I cancer clinical trials. Biostatistics 2(2):203–215

    Article  Google Scholar 

  8. Liu S, Yuan Y (2015) Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc 64(3):507–523

    Article  MathSciNet  Google Scholar 

  9. Mandrekar SJ, Qing R, Sargent DJ (2010) Model-based phase I designs incorporating toxicity and efficacy for single and dual agent drug combinations: methods and challenges. Stat Med 29(10):1077–1083

    Article  MathSciNet  Google Scholar 

  10. Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the bayesian approach to phase I cancer trials. Stat Med 27(13):2420–2439

    Article  MathSciNet  Google Scholar 

  11. Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ (2010) Summarizing historical information on controls in clinical trials. Clin Trials 7(1):5–18

    Article  Google Scholar 

  12. O’Quigley J, Pepe M, Fisher L (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 33–48

  13. Ratain MJ, Doi T, De Jonge MJ, LoRusso P, Dunbar M, Chiney M, Motwani M, Glasgow J, Petrich AM, Rasco DW et al (2019) Phase 1, first-in-human study of trail receptor agonist fusion protein abbv-621

  14. Schmidli H, Gsteiger S, Roychoudhury S, O’Hagan A, Spiegelhalter D, Neuenschwander B (2014) Robust meta-analytic-predictive priors in clinical trials with historical control information. Biometrics 70(4):1023–1032

    Article  MathSciNet  Google Scholar 

  15. Storer BE (1989) Design and analysis of phase I clinical trials. Biometrics 45(3):925–937

    Article  MathSciNet  Google Scholar 

  16. Thall PF, Cook JD, Estey EH (2006) Adaptive dose selection using efficacy-toxicity trade-offs: illustrations and practical considerations. J Biopharm Stat 16(5):623–638

    Article  MathSciNet  Google Scholar 

  17. Turner T, Wollan P (1997) Locating a maximum using isotonic regression. Comput Stat Data Anal 25(3):305–320

    Article  Google Scholar 

  18. Woolley PV, Schein PS (1979) Clinical pharmacology and phase I trial design. Methods Cancer Res 17:177–198

    Google Scholar 

  19. Zang Y, Lee JJ, Yuan Y (2014) Adaptive designs for identifying optimal biological dose for molecularly targeted agents. Clin Trials 11(3):319–327

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Connecticut, Storrs, CT, USA

    Qingyang Liu

  2. Boehringer-Ingelheim Pharmaceutical Inc., Ridgefield, CT, USA

    Junxian Geng & Qiqi Deng

  3. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

    Frank Fleischer

Authors
  1. Qingyang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junxian Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank Fleischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiqi Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junxian Geng.

Appendix 1: Sample Size Allocations

Appendix 1: Sample Size Allocations

See Tables 7, 8, and 9.

Table 7 Zero toxicity
Full size table
Table 8 Lox toxicity
Full size table
Table 9 Regular toxicity
Full size table

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Q., Geng, J., Fleischer, F. et al. Efficacy-Driven Dose Finding with Toxicity Control in Phase I Oncology Studies. Stat Biosci 14, 413–431 (2022). https://doi.org/10.1007/s12561-021-09327-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12561-021-09327-1

Keywords

Search

Navigation