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  • Review Article
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The changing landscape of phase I trials in oncology

Nature Reviews Clinical Oncology volume 13, pages 106–117 (2016)Cite this article

Subjects

Key Points

  • Several aspects of the design of phase I trials have evolved in the era of molecular targeted agents to enable better assessment of these novel therapies and maximize the efficiency of drug development

  • Current phase I trial designs increasingly use new dose-escalation approaches and biomarker-driven patient selection, while expanding study objectives to include efficacy evaluation and pharmacokinetics/ pharmacodynamics (PK/PD), in addition to safety

  • Preclinical evidence supporting a biological or pharmacological rationale and exploration of PK/PD interactions between drug partners are necessary for phase I trials of combination therapies that include targeted agents

  • Changes to the regulatory approval process help to expedite drug development, particularly for novel agents with a well-established biological mechanism, a predictive biomarker, and clear evidence of efficacy in early trials

  • Changes in the goals and conduct of phase I trials have resulted in a shift towards multi-institutional studies and centralized management, with a significant impact on the structure of phase I programmes

  • Both the efficiency and rate of drug approval need to improve despite the limited acceptance of novel trial designs and difficulties associated with early phase biomarker integration

Abstract

Advances in our knowledge of the molecular pathogenesis of cancer have led to increased interest in molecularly targeted agents (MTAs), which target specific oncogenic drivers and are now a major focus of cancer drug development. MTAs differ from traditional cytotoxic agents in various aspects, including their toxicity profiles and the potential availability of predictive biomarkers of response. The landscape of phase I oncology trials is evolving to adapt to these novel therapies and to improve the efficiency of drug development. In this Review, we discuss new strategies used in phase I trial design, such as novel dose-escalation schemes to circumvent limitations of the classic 3 + 3 design and enable faster dose escalation and/or more-precise dose determinations using statistical modelling; improved selection of patients based on genetic or molecular biomarkers; pharmacokinetic and pharmacodynamic analyses; and the early evaluation of efficacy — in addition to safety. Indeed, new expedited approval pathways that can accelerate drug development require demonstration of efficacy in early phase trials. The application of molecular tumour profiling for matched therapy and the testing of drug combinations based on a strong biological rationale are also increasingly seen in phase I studies. Finally, the shift towards multi-institutional trials and centralized study management results in consequent implications for institutions and investigators. These issues are also highlighted herein.

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Figure 1: Considerations for the evolution of phase I oncology trials in the MTA era.

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Authors and Affiliations

  1. Division of Medical Oncology/Department of Medicine, Developmental Therapeutics Program, University of Colorado Cancer Center, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, 80045, Colorado, USA

    Kit Man Wong, Anna Capasso & S. Gail Eckhardt

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  1. Kit Man Wong
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K.M.W. performed the literature search, planned the sections of the review, and wrote the entire manuscript and subsequent revisions, A.C. reviewed the manuscript before submission. S.G.E. contributed to the contents of the manuscript and reviewed the manuscript before submission.

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Correspondence to S. Gail Eckhardt.

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Wong, K., Capasso, A. & Eckhardt, S. The changing landscape of phase I trials in oncology. Nat Rev Clin Oncol 13, 106–117 (2016). https://doi.org/10.1038/nrclinonc.2015.194

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