Design and Evaluation of an External Control Arm Using Prior Clinical Trials and Real-World Data

Ventz, Steffen; Lai, Albert; Cloughesy, Timothy F.; Wen, Patrick Y.; Trippa, Lorenzo; Alexander, Brian M.

doi:10.1158/1078-0432.ccr-19-0820

Cited by 65 publications

(95 citation statements)

References 51 publications

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“…Although some specific explanations may be proposed for the high degree of these clinical trial failures (see below), improved clinical trial design is also needed. For exemple, Phase II trials may contain a control arm to assess the efficacy of new therapies and to reduce false positive results which remains difficult to establish in the case of recurrent disease in absence of standard treatment; historical control data became obsolete due to the improvement of patient standard of care in the clinic [ 358 , 359 ]. GBM is a rare disease and enrollment of patients in trials remains too low, promotion of participation must be planned to increase the number of high-quality trials [ 360 ].…”

Section: Discussion-guidance Towards Future Gbm Targeted Therapiesmentioning

confidence: 99%

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Silva

Mercier

Étienne-Selloum

et al. 2021

Cancers

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Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis.

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Section: Discussion-guidance Towards Future Gbm Targeted Therapiesmentioning

confidence: 99%

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Silva

Mercier

Étienne-Selloum

et al. 2021

Cancers

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“…Our contribution is distinct from the growing body of literature on trial designs that incorporate external data in the study analyses (Psioda and Ibrahim, 2018; Ventz et al ., 2019). In contrast, we leverage early‐phase data only during the design stage of the late‐phase trial.…”

Section: Discussionmentioning

confidence: 99%

Optimality of testing procedures for survival data in the nonproportional hazards setting

2020

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Most statistical tests for treatment effects used in randomized clinical trials with survival outcomes are based on the proportional hazards assumption, which often fails in practice. Data from early exploratory studies may provide evidence of nonproportional hazards, which can guide the choice of alternative tests in the design of practice‐changing confirmatory trials. We developed a test to detect treatment effects in a late‐stage trial, which accounts for the deviations from proportional hazards suggested by early‐stage data. Conditional on early‐stage data, among all tests that control the frequentist Type I error rate at a fixed α level, our testing procedure maximizes the Bayesian predictive probability that the study will demonstrate the efficacy of the experimental treatment. Hence, the proposed test provides a useful benchmark for other tests commonly used in the presence of nonproportional hazards, for example, weighted log‐rank tests. We illustrate this approach in simulations based on data from a published cancer immunotherapy phase III trial.

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“…482 Moreover, the plentiful amount of EHR data allows for significant statistical significance. 483,484 Retrospective clinical analysis is the most commonly used computational approach based on RWD and the data are mainly obtained from EHRs. 485,486 A classic case of repurposing a noncancer drug for cancer treatment from retrospective clinical analysis is that of metformin which can decrease cancer mortality in a dose dependent manner.…”

Section: Technological Approaches To Drug Repurposing For Cancer Therapymentioning

confidence: 99%

Overcoming cancer therapeutic bottleneck by drug repurposing

Zhang

Zhou

Xie

et al. 2020

Sig Transduct Target Ther

391

315

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Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The "treasure trove" of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono-or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

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Design and Evaluation of an External Control Arm Using Prior Clinical Trials and Real-World Data

Cited by 65 publications

References 51 publications

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Optimality of testing procedures for survival data in the nonproportional hazards setting

Overcoming cancer therapeutic bottleneck by drug repurposing

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