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Randomised Phase 1 clinical trials in oncology


The aims of Phase 1 trials in oncology have broadened considerably from simply demonstrating that the agent/regimen of interest is well tolerated in a relatively heterogeneous patient population to addressing multiple objectives under the heading of early-phase trials and, if possible, obtaining reliable evidence regarding clinical activity to lead to drug approvals via the Accelerated Approval approach or Breakthrough Therapy designation in cases where the tumours are rare, prognosis is poor or where there might be an unmet therapeutic need. Constructing a Phase 1 design that can address multiple objectives within the context of a single trial is not simple. Randomisation can play an important role, but carrying out such randomisation according to the principles of equipoise is a significant challenge in the Phase 1 setting. If the emerging data are not sufficient to definitively address the aims early on, then a proper design can reduce biases, enhance interpretability, and maximise information so that the Phase 1 data can be more compelling. This article outlines objectives and design considerations that need to be adhered to in order to respect ethical and scientific principles required for research in human subjects in early phase clinical trials.

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Fig. 1: Dose escalation (carried out in cohorts of 3 patients) followed sequentially by dose expansion after the maximum-tolerated dose (MTD) has been determined.
Fig. 2: Dose escalation and dose expansion carried out concurrently prior to determination of the maximum-tolerated dose (MTD).


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We appreciate the feedback and ideas discussed on protocol review and activation of early phase trials that involve randomization with Drs. Hyman and Chapman from Memorial Sloan Kettering Cancer Center and their comments on an earlier version of this manuscript. We also thank the reviewers and the Editor for their extensive input.

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A.I. contributed to the conception of the review; the collection, analysis and interpretation of the information included within; the drafting of the review; played an important role in interpreting the results; and critically revising the review for important intellectual content. Figures were conceived and developed by A.I. J.O. contributed to the conception of the review; the collection, analysis and interpretation of the information included within; played an important role in interpreting the results; and critically revising the review for important intellectual content. Both authors approved the final version of this review and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Alexia Iasonos.

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This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

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Iasonos, A., O’Quigley, J. Randomised Phase 1 clinical trials in oncology. Br J Cancer (2021).

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