A Bayesian model-free approach to combination therapy phase I trials using censored time-to-toxicity data.

Graham M Wheeler,Adrian P Mander,Michael J Sweeting

doi:10.1111/rssc.12323

Abstract

The product of independent beta probabilities escalation (PIPE) design for dual-agent phase I dose-escalation trials is a Bayesian model-free approach for identifying multiple maximum tolerated dose combinations of novel combination therapies. Despite only being published in 2015, the PIPE design has been implemented in at least two oncology trials. However, these trials require patients to have completed follow-up before clinicians can make dose-escalation decisions. For trials of radiotherapy or advanced therapeutics, this may lead to impractically long trial durations due to late-onset treatment-related toxicities. In this paper, we extend the PIPE design to use censored time-to-event (TITE) toxicity outcomes for making dose escalation decisions. We show via comprehensive simulation studies and sensitivity analyses that trial duration can be reduced by up to 35%, particularly when recruitment is faster than expected, without compromising on other operating characteristics.

Highlights

The majority of anticancer therapeutic strategies consist of giving patients two or more treatments together to provide improved treatment effects relative to individual therapies given alone
Illustrative single trial Before presenting the results from the simulation study, we provide a single illustrative trial of 40 patients (Fig. 4). 16 dose combinations formed from four dose levels each of drug A and drug B were under investigation, with the aim of targeting one or more maximum tolerated dose combinations (MTDCs) with θ = 0:20
We conducted this trial by using the TITE–product of independent probabilities escalation (PIPE)–C method and required two patients to have completed treatment on a dose combination before another combination may be considered for exploration

Summary

Introduction

The majority of anticancer therapeutic strategies consist of giving patients two or more treatments together to provide improved treatment effects relative to individual therapies given alone. In phase I trials of novel combination therapies, the aim is to identify one or more maximum tolerated dose combinations (MTDCs), i.e. one or more dose combinations with an expected probability of causing a severe drug-related adverse event equal to or close to a target of interest, known as the target toxicity level (TTL). Larger comparative trials are conducted to compare the efficacy of the MTDC(s) of the new combined treatment regimen with standard care, in the hope of improving patient response and survival outcomes. To phase I trials for monotherapies, trials of two treatments combined are conducted as dose escalation studies. On the basis of these data, the cohort of patients may receive the same combination or a different combination; if the current dose combination is considered tolerable (e.g. no adverse events reported), the cohort may receive a combination with only one drug increased, or both drugs increased simultaneously. By gradually exploring the dose–toxicity grid, we aim to identify MTDCs while minimizing the chance of overdosing patients in the trial

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