Incorporating Biomarker Stratification into STAMPEDE: an Adaptive Multi-arm, Multi-stage Trial Platform

Gilson, Clare; Parmar, Mahesh; Sydes, Matthew R.; Investigators, Stampede

doi:10.1016/j.clon.2017.10.004

Cited by 15 publications

(14 citation statements)

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“…As a result, patients can be misclassified using genomic analysis based on a single mpMRI-targeted biopsy. These findings have implications for management decisions made on the basis of genomic tests from a single biopsy [9], [10], [11], [38], [39], [40].…”

Section: Discussionmentioning

confidence: 99%

Genomic Evaluation of Multiparametric Magnetic Resonance Imaging-visible and -nonvisible Lesions in Clinically Localised Prostate Cancer

Parry

Srivastava

Ali

et al. 2019

European Urology Oncology

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Background The prostate cancer (PCa) diagnostic pathway is undergoing a radical change with the introduction of multiparametric magnetic resonance imaging (mpMRI), genomic testing, and different prostate biopsy techniques. It has been proposed that these tests should be used in a sequential manner to optimise risk stratification. Objective To characterise the genomic, epigenomic, and transcriptomic features of mpMRI-visible and -nonvisible PCa in clinically localised disease. Design, setting, and participants Multicore analysis of fresh prostate tissue sampled immediately after radical prostatectomy was performed for intermediate- to high-risk PCa. Intervention Low-pass whole-genome, exome, methylation, and transcriptome profiling of patient tissue cores taken from microscopically benign and cancerous areas in the same prostate. Circulating free and germline DNA was assessed from the blood of five patients. Outcome measurement and statistical analysis Correlations between preoperative mpMRI and genomic characteristics of tumour and benign prostate samples were assessed. Gene profiles for individual tumour cores were correlated with existing genomic classifiers currently used for prognostication. Results and limitations A total of 43 prostate cores (22 tumour and 21 benign) were profiled from six whole prostate glands. Of the 22 tumour cores, 16 were tumours visible and six were tumours nonvisible on mpMRI. Intratumour genomic, epigenomic, and transcriptomic heterogeneity was found within mpMRI-visible lesions. This could potentially lead to misclassification of patients using signatures based on copy number or RNA expression. Moreover, three of the six cores obtained from mpMRI-nonvisible tumours harboured one or more genetic alterations commonly observed in metastatic castration-resistant PCa. No circulating free DNA alterations were found. Limitations include the small cohort size and lack of follow-up. Conclusions Our study supports the continued use of systematic prostate sampling in addition to mpMRI, as avoidance of systematic biopsies in patients with negative mpMRI may mean that clinically significant tumours harbouring genetic alterations commonly seen in metastatic PCa are missed. Furthermore, there is inconsistency in individual genomics when genomic classifiers are applied. Patient summary Our study shows that tumour heterogeneity within prostate tumours visible on multiparametric magnetic resonance imaging (mpMRI) can lead to misclassification of patients if only one core is used for genomic analysis. In addition, some cancers that were missed by mpMRI had genomic aberrations that are commonly seen in advanced metastatic prostate cancer. Avoiding biopsies in mpMRI-negative cases may mean that such potentially lethal cancers are missed.

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Section: Discussionmentioning

confidence: 99%

Genomic Evaluation of Multiparametric Magnetic Resonance Imaging-visible and -nonvisible Lesions in Clinically Localised Prostate Cancer

Parry

Srivastava

Ali

et al. 2019

European Urology Oncology

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“…Redrawn from Gilson et al260 Reused in accordance with the terms of Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). No changes to the original figure were made.…”

Section: The Ace Checklistmentioning

confidence: 99%

The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

Dimairo

Pallmann

Wason

et al. 2020

BMJ

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Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits.

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“…162e165 The investigators planned to include biomarker-stratified randomization in the future. 152 The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2) trial 166e168 is an ongoing, Phase II, response-adaptive, randomized, multicenter trial evaluating new drugs or drug combinations in the context of neoadjuvant treatment for women with locally advanced breast cancer. The primary endpoint is pathologic complete response.…”

Section: Planned and Conducted Trialsmentioning

confidence: 99%

The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review

Meyer

Mesenbrink

Dunger-Baldauf

et al. 2020

Clinical Therapeutics

100

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Purpose: Recent years have seen a change in the way that clinical trials are being conducted. There has been a rise of designs more flexible than traditional adaptive and group sequential trials which allow the investigation of multiple substudies with possibly different objectives, interventions, and subgroups conducted within an overall trial structure, summarized by the term master protocol. This review aims to identify existing master protocol studies and summarize their characteristics. The review also identifies articles relevant to the design of master protocol trials, such as proposed trial designs and related methods. Methods: We conducted a comprehensive systematic search to review current literature on master protocol trials from a design and analysis perspective, focusing on platform trials and considering basket and umbrella trials. Articles were included regardless of statistical complexity and classified as reviews related to planned or conducted trials, trial designs, or statistical methods. The results of the literature search are reported, and some features of the identified articles are summarized. Findings: Most of the trials using master protocols were designed as single-arm (n ¼ 29/50), Phase II trials (n ¼ 32/50) in oncology (n ¼ 42/50) using a binary endpoint (n ¼ 26/50) and frequentist decision rules (n ¼ 37/50). We observed an exponential increase in publications in this domain during the last few years in both planned and conducted trials, as well as relevant methods, which we assume has not yet reached its peak. Although many operational and statistical challenges associated with such trials remain, the general consensus seems to be that master protocols provide potentially enormous advantages in efficiency and flexibility of clinical drug development. Implications: Master protocol trials and especially platform trials have the potential to revolutionize clinical drug development if the methodologic and operational challenges can be overcome.

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Incorporating Biomarker Stratification into STAMPEDE: an Adaptive Multi-arm, Multi-stage Trial Platform

Cited by 15 publications

References 50 publications

Genomic Evaluation of Multiparametric Magnetic Resonance Imaging-visible and -nonvisible Lesions in Clinically Localised Prostate Cancer

Genomic Evaluation of Multiparametric Magnetic Resonance Imaging-visible and -nonvisible Lesions in Clinically Localised Prostate Cancer

The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design

The Evolution of Master Protocol Clinical Trial Designs: A Systematic Literature Review

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