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Combining cytotoxic agents with continuous dose levels in seamless phase I‐II clinical trials

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  • José L. Jiménez
  • Mourad Tighiouart

Abstract

Phase I‐II cancer clinical trial designs are intended to accelerate drug development. In cases where efficacy cannot be ascertained in a short period of time, it is common to divide the study in two stages: (i) a first stage in which dose is escalated based only on toxicity data and we look for the maximum tolerated dose (MTD) set and (ii) a second stage in which we search for the most efficacious dose within the MTD set. Current available approaches in the area of continuous dose levels involve fixing the MTD after stage I and discarding all collected stage I efficacy data. However, this methodology is clearly inefficient when there is a unique patient population present across stages. In this article, we propose a two‐stage design for the combination of two cytotoxic agents assuming a single patient population across the entire study. In stage I, conditional escalation with overdose control is used to allocate successive cohorts of patients. In stage II, we employ an adaptive randomisation approach to allocate patients to drug combinations along the estimated MTD curve, which is constantly updated. The proposed methodology is assessed with extensive simulations in the context of a real case study.

Suggested Citation

  • José L. Jiménez & Mourad Tighiouart, 2022. "Combining cytotoxic agents with continuous dose levels in seamless phase I‐II clinical trials," Journal of the Royal Statistical Society Series C, Royal Statistical Society, vol. 71(5), pages 1996-2013, November.
    • Handle: RePEc:bla:jorssc:v:71:y:2022:i:5:p:1996-2013
    DOI: 10.1111/rssc.12598
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    References listed on IDEAS

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    2. Mourad Tighiouart & André Rogatko, 2012. "Number of Patients per Cohort and Sample Size Considerations Using Dose Escalation with Overdose Control," Journal of Probability and Statistics, Hindawi, vol. 2012, pages 1-16, October.
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