I-SPY 2: a Neoadjuvant Adaptive Clinical Trial Designed to Improve Outcomes in High-Risk Breast Cancer

Wang, Haiyun; Yee, Douglas

doi:10.1007/s12609-019-00334-2

Cited by 70 publications

(47 citation statements)

References 39 publications

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“…To facilitate a patient-centred consent process, randomisation is performed prior to consent. This order of the randomization and consent process has worked well in I-SPY 2 and has the advantages of avoiding a two-step consent process and simplifying patient information 6 7. That is, an individual patient interested in the trial only receives information about the one investigational agent that they are randomised to receive (which could also be the control arm).…”

Section: Methods and Analysismentioning

confidence: 99%

I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations

et al. 2022

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IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysisThe ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes—time to recovery and mortality. The statistical design uses a Bayesian model with ‘stopping’ and ‘graduation’ criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing.Ethics and disseminationISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals.Trial registration numberNCT04488081.

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Section: Methods and Analysismentioning

confidence: 99%

I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations

et al. 2022

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“…This order of the randomization and consent process has worked well in I-SPY 2 and has the advantages of avoiding a two-step consent process and simplifying patient information. 6 7 That is, an individual patient interested in the trial only receives information about the one investigational agent that they are randomized to receive (which could also be the control arm). The disadvantage of this consent approach is that there is a risk of generating different accrual patterns across the trial arms, due to different perceived risks by participants during consent.…”

Section: Methods and Analysismentioning

confidence: 99%

The I-SPY COVID Adaptive Platform Trial for COVID-19 Acute Respiratory Failure: Rationale, Design and Operations

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Matthay

Calfee

et al. 2022

Preprint

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IntroductionThe COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalized with severe COVID-19. The ISPY COVID trial was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation, and challenges of the ISPY COVID trial during the first phase of trial activity from April 2020 until December 2021.Methods and analysisThe ISPY COVID Trial is a multi-center open label phase 2 platform trial in the United States designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID Trial network includes academic and community hospitals with significant geographic diversity across the country. Enrolled patients are randomized to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes—time to recovery and mortality. The statistical design uses a Bayesian model with “stopping” and “graduation” criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrolls to a maximum of 125 patients per arm and is compared to concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrollment and adaptation of the trial design is ongoing.Ethics and disseminationISPY COVID operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer reviewed medical journals.Trial registration numberClinicaltrials.gov registration number NCT04488081Strengths and limitations of this studyThe ISPY COVID Trial was developed in early 2020 to rapidly and simultaneously evaluate therapeutics for severe COVID-19 on an adaptive open label phase 2 platformThe ISPY COVID Adaptive Platform Trial Network is an academic-industry partnership that includes academic and community hospitals spanning a wide geographic area across the United StatesOf December 2021, 11 investigational agent arms have been activated on the ISPY COVID Trial PlatformThe ISPY COVID Trial was designed to identify therapeutic agents with a large clinical effect for further testing in definitive efficacy trials—limitations to this approach include the risk of a type 2 error

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“…According to the original ISPY2 plan, for each signature, investigational regimens showing a low Bayesian predictive probability of being superior to the standard treatment will be dropped from the trial for futility reasons, while drugs reaching a sufficient level of predictive probability of success in a confirmatory phase III trial will graduate, ultimately allowing these successful compounds to be tested in smaller and more cost-effective phase III trials, which, probably, would otherwise be larger and more dispersive [52]. The possibility to simultaneously test multiple drugs as well as to provide a large biomarker collection represent innovative features that make the I-SPY2 an appealing platform, currently adopted also in other oncological and non-oncological settings [53]. Interestingly, over 10 years of I-SPY-2 history, while 7 agents have graduated, as many I-SPY2 attempts were stopped due to futility (n = 5) or toxicity (n = 2), thus therefore preventing the unnecessary deployment of further human, economic and social resources in bigger/longer trials.…”

Section: Adaptive Trials: the I-spy2 Platformmentioning

confidence: 99%

Neoadjuvant approach as a platform for treatment personalization: focus on HER2-positive and triple-negative breast cancer

Miglietta

Dieci

Griguolo

et al. 2021

Cancer Treatment Reviews

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The neoadjuvant setting provides unquestionable clinical benefits for high-risk breast cancer (BC) patients, mainly in terms of expansion of locoregional treatment options and prognostic stratification. Additionally, it is also emerging as a strategical tool in the research field. In the present review, by focusing on HER2-positive and triple-negative subtypes, we examined the role of the neoadjuvant setting as a research platform to facilitate and rationalize the placement of escalation strategies, promote the adoption of biomarker-driven approaches for the investigation of de-escalated treatments, and foster the conduction of comprehensive translational analyses, thus ultimately aiming at pursuing treatment personalization. The solid prognostic role of pathologic complete response after neoadjuvant therapy, and its use as a surrogate endpoint to accelerate the drug approval process were discussed. In this context, available data on escalated treatment strategies capable of enhancing pathologic complete response (pCR) rate or improving prognosis of patients with residual disease (RD) after neoadjuvant treatment, were comprehensively reviewed. We also summarized evidence regarding the possibility of obtaining pCR with de-escalated strategies, with particular emphasis on the role of biomarker-driven approaches for patient selection. Pitfalls of the dichotomy of pCR/RD were also deepened, and data on alternative/complementary biomarkers with a possible clinical relevance in this regard were reviewed.

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I-SPY 2: a Neoadjuvant Adaptive Clinical Trial Designed to Improve Outcomes in High-Risk Breast Cancer

Cited by 70 publications

References 39 publications

I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations

I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations

The I-SPY COVID Adaptive Platform Trial for COVID-19 Acute Respiratory Failure: Rationale, Design and Operations

Neoadjuvant approach as a platform for treatment personalization: focus on HER2-positive and triple-negative breast cancer

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