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An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials.

ABSTRACT: Dose-finding in cancer clinical trials has been dominated by algorithmic designs on the principle that the highest tolerable dose is also the most effective dose. This assumption no longer applies to the biologic treatments that are characterized by different toxicity and/or efficacy profiles to the extent that the best therapeutic dose might be well below any dose that produces serious toxicity. As such, we propose a two-stage design with focus on immunotherapy trials, incorporating both safety and efficacy information. The 1st stage establishes the safety profile of each dose, with escalation decisions based on likelihood principles. Continuous immunologic outcomes are used to evaluate the relative efficacy of the doses. The 2nd stage employs an adaptive randomization to assign patients to doses showing higher efficacy. Safety is being continuously monitored throughout stage 2, where some doses may be 'closed' due to unacceptable toxicity. The proposed design is compared to the modified toxicity probability interval (mTPI) design using percent dose allocation and estimation of outcomes under different scenarios. We show that by using an efficacy-driven adaptive randomization with safety constraints, the allocation distribution is skewed towards more efficacious doses, and thus limit the number of patients exposed to toxic or non-therapeutic doses.

SUBMITTER: Chiuzan C

PROVIDER: S-EPMC6277027 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials.

Chiuzan Cody C Garrett-Mayer Elizabeth E Nishimura Michael M

Statistics in biopharmaceutical research 20180430 3

Dose-finding in cancer clinical trials has been dominated by algorithmic designs on the principle that the highest tolerable dose is also the most effective dose. This assumption no longer applies to the biologic treatments that are characterized by different toxicity and/or efficacy profiles to the extent that the best therapeutic dose might be well below any dose that produces serious toxicity. As such, we propose a two-stage design with focus on immunotherapy trials, incorporating both safety ...[more]

PMID: 30524665

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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

An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials.

Publications

An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials.

Similar Datasets

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