Dataset Information

Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control.

ABSTRACT: We present a Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials. The goal is to estimate the maximum tolerated dose (MTD) as a curve in the two-dimensional Cartesian plane. We use a logistic model to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re-parameterized in terms of parameters clinicians can easily interpret. Trial design proceeds using univariate escalation with overdose control, where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. At the end of the trial, an estimate of the MTD curve is proposed as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial design and percent of dose recommendation at dose combination neighborhoods around the true MTD curve. We also examine the performance of the approach under model misspecifications for the true dose-toxicity relationship.

SUBMITTER: Tighiouart M

PROVIDER: S-EPMC4156522 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control.

Tighiouart Mourad M Piantadosi Steven S Rogatko André A

Statistics in medicine 20140513 22

We present a Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials. The goal is to estimate the maximum tolerated dose (MTD) as a curve in the two-dimensional Cartesian plane. We use a logistic model to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re-parameterized in terms of parameters clinicians can easily interpret. Trial design proceeds using univariate escalation ...[more]

PMID: 24825779

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Project description:IntroductionEarly phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements.Methods and analysisA methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions.Ethics and disseminationThis project was approved by ICR's Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites.Registration detailsSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.

Dataset Information

Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control.

Publications

Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control.

Similar Datasets

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