Advantages of multi-arm non-randomised sequentially allocated cohort designs for Phase II oncology trials

Abstract Background Efficient trial designs are required to prioritise promising drugs within Phase II trials. Adaptive designs are examples of such designs, but their efficiency is reduced if there is a delay in assessing patient responses to treatment. Methods Motivated by the WIRE trial in renal cell carcinoma (NCT03741426), we compare three trial approaches to testing multiple treatment arms: (1) single-arm trials in sequence with interim analyses; (2) a parallel multi-arm multi-stage trial and (3) the design used in WIRE, which we call the Multi-Arm Sequential Trial with Efficient Recruitment (MASTER) design. The MASTER design recruits patients to one arm at a time, pausing recruitment to an arm when it has recruited the required number for an interim analysis. We conduct a simulation study to compare how long the three different trial designs take to evaluate a number of new treatment arms. Results The parallel multi-arm multi-stage and the MASTER design are much more efficient than separate trials. The MASTER design provides extra efficiency when there is endpoint delay, or recruitment is very quick. Conclusions We recommend the MASTER design as an efficient way of testing multiple promising cancer treatments in non-comparative Phase II trials.

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Adaptive designs for single-arm phase II trials in oncology

Pharmaceutical Statistics ◽

10.1002/pst.541 ◽

2012 ◽

Vol 11 (3) ◽

pp. 241-249 ◽

Cited By ~ 11

Author(s):

Stefan Englert ◽

Meinhard Kieser

Keyword(s):

Phase Ii ◽

Adaptive Designs ◽

Phase Ii Trials

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Design Issues in Randomized Phase II/III Trials

Journal of Clinical Oncology ◽

10.1200/jco.2011.38.5732 ◽

2012 ◽

Vol 30 (6) ◽

pp. 667-671 ◽

Cited By ~ 37

Author(s):

Edward L. Korn ◽

Boris Freidlin ◽

Jeffrey S. Abrams ◽

Susan Halabi

Keyword(s):

Phase Ii ◽

Phase Iii ◽

Control Treatment ◽

Design Parameters ◽

Phase Ii Trials ◽

Screening Designs ◽

Randomized Phase Ii ◽

Adaptive Trial Design ◽

Target Treatment ◽

New Treatment

Phase II trials are used to show sufficient preliminary activity of a new treatment (in single-arm designs or randomized screening designs) or to select among treatments with demonstrated activity (in randomized selection designs). The treatments prioritized in a phase II trial are then tested definitively against a control treatment in a randomized phase III trial. Randomized phase II/III trials use an adaptive trial design that combines these two types of trials in one, with potential gains in time and reduced numbers of patients required to be treated. Two key considerations in designing a phase II/III trial are whether to suspend accrual while the phase II data mature and the choice of phase II target treatment effect. We discuss these phase II/III design parameters, give examples of phase II/III trials, and provide recommendations concerning efficient phase II/III trial designs.

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The transition from phase II to phase III studies

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6514 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6514-6514 ◽

Cited By ~ 2

Author(s):

I. Tannock ◽

A. Gulamhusein ◽

D. R. Berthold

Keyword(s):

Phase Ii ◽

Phase Iii ◽

Phase 2 ◽

Phase Ii Trials ◽

Phase 3 ◽

Phase 2 Trial ◽

Time Period ◽

Phase 2 Study ◽

New Treatment ◽

Background Phase

6514 Background: Phase II trials are performed to detect potential anti-tumor effects of a new treatment and should be used to decide whether to proceed to a phase 3 trial or not. However, many phase 2 trials never lead to a phase 3 trial despite encouraging results. Here we sought to determine how often (i) positive phase 2 trials have led to phase 3 trials, and (ii) how often phase 2 trials were designed to lead to a phase 3 trial. Methods: We reviewed 200 phase 2 trials, presented at ASCO meetings in 1995–1996, and 2006, selecting randomly 20 abstracts with encouraging results for 5 cancer sites (breast, lung, GI, GU, Gyn) in each time period. For those presented in 1995–1996, we searched systematically for subsequent randomized studies where one treatment arm was similar to that in the phase 2 study. For those presented in 2006, a questionnaire was sent to authors asking whether they recommend evaluating the regimen in a phase 3 trial, whether a phase 3 trial is planned and whether resources (budget, patients, drugs) are available to conduct a phase 3 trial. Results: Ten years after presenting phase 2 trials with positive results, only 13 regimens have been evaluated in a phase 3 trial. Of 100 investigators who presented a phase 2 trial in 2006, 42 returned the questionnaire, 36 confirmed that the results met criteria of efficacy and 25 thought the regimen should be evaluated in a phase 3 trial. Only 10 investigators plan to undertake a phase 3 trial, and 8 stated they had resources to do so. Reasons for not planning a phase 3 study included insufficient efficacy (7), insufficient access to patients (5) or financial support (5), lack of interest from colleagues (6), and lack of support from the company (8). Conclusions: Few (∼13%) phase 2 trials with promising activity are followed by phase 3 trials and this is not increasing with time. Reasons include lack of resources such as money, drugs and patients. Many of these limitations are known when planning the phase 2 study, implying that many phase 2 trials are not planned as precursors of phase 3 trials. Resources spent on such trials would be better applied to practice-changing phase 3 trials. No significant financial relationships to disclose.

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Multistage phase II design for mixed tumor response and time-to-event endpoints: An application for screening new drugs in hepatocellular carcinoma (HCC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14706 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14706-e14706

Author(s):

Benny C. Y. Zee ◽

Xin Lai ◽

Ann Sing Lee ◽

Maria Lai ◽

Marc Chong ◽

...

Keyword(s):

Phase Ii ◽

Null Hypothesis ◽

Tumor Response ◽

Response Rate ◽

Stopping Rule ◽

Mixed Tumor ◽

Time To Event ◽

Phase Ii Trials ◽

Multi Stage ◽

Randomized Phase Ii

e14706 Background: Phase II trials aim to assess the anti-tumor activity of investigational therapies, and consider if they warrant further study. In some instances such as a study treatment added to standard therapy in HCC, tumor response alone may not provide a clear picture on its effectiveness (e.g. biologics and targeted therarpy). Other endpoints such as progression-free survival (PFS) in addition to conventional tumor response would increase the chance of detecting useful treatment and also be able to terminate a study earlier if the treatment was deemed ineffective. Methods: Following a similar rationale for multinomial endpoints in phase II trials by Zee (1999), we have developed a multi-stage phase II stopping rule for "mixed tumor response and time-to-event endpoints". We used a study entitled, “Randomized Phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced HCC” as an illustration. We applied this multi-stage stopping rule for mixed endpoints in a randomized phase II setting, where the control arm was being used here as a way to set up the null hypothesis. We defined the null hypothesis by a mixture of response rate of 5% and PFS of 2.6 months versus an alternative hypothesis of response rate of 20% and PFS of 5.2 months. Results: The stopping rule was such that the null hypothesis would be rejected at a correlation of 0.5 for the mixed endpoints and conclude that the treatment is effective if we have 0-1 responders and a PFS>=4.0 months, or 2 responders and PFS>=3.8 months, or 3 responders and a PFS>=3.6 months, or 4 responders and a PFS>=3.0 months, or 5 responders with any PFS. Conclusions: In the AEG35156 study, we had 3 responders (based on Choi’s criteria), and 1 responder even if we used RECIST criteria. A PFS of 4.0 months. Therefore, we concluded that the study treatment in combination with sorafenib has a positive effect and warrants further investigation. This methodology would greatly improve the efficiency for phase II screening especially on new biologics on top of a standard or for diseases where tumor response alone does not reflect the full effectiveness of the new treatment.

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Adaptive designs for dose-finding in non-cancer phase II trials: influence of early unexpected outcomes

Clinical Trials ◽

10.1177/1740774508098788 ◽

2008 ◽

Vol 5 (6) ◽

pp. 595-606 ◽

Cited By ~ 15

Author(s):

Matthieu Resche-Rigon ◽

Sarah Zohar ◽

Sylvie Chevret

Keyword(s):

Phase Ii ◽

Adaptive Designs ◽

Dose Finding ◽

Phase Ii Trials ◽

Unexpected Outcomes

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Phase II Trials including Multi-stage Designs

Wiley StatsRef: Statistics Reference Online ◽

10.1002/9781118445112.stat04955 ◽

2014 ◽

Author(s):

Richard Simon ◽

Peter F. Thall

Keyword(s):

Phase Ii ◽

Phase Ii Trials ◽

Multi Stage

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Response adaptive designs for Phase II trials with binary endpoint based on context-dependent information measures

Computational Statistics & Data Analysis ◽

10.1016/j.csda.2021.107187 ◽

2021 ◽

Vol 158 ◽

pp. 107187

Author(s):

Ksenia Kasianova ◽

Mark Kelbert ◽

Pavel Mozgunov

Keyword(s):

Phase Ii ◽

Adaptive Designs ◽

Phase Ii Trials ◽

Information Measures ◽

Context Dependent ◽

Response Adaptive Designs

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Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing’s sarcoma

Statistical Methods in Medical Research ◽

10.1177/0962280216662070 ◽

2016 ◽

Vol 27 (5) ◽

pp. 1451-1463 ◽

Cited By ~ 1

Author(s):

P Dutton ◽

SB Love ◽

L Billingham ◽

AB Hassan

Keyword(s):

Phase Ii ◽

Rare Diseases ◽

Best Interests ◽

Research Progress ◽

Phase Ii Trials ◽

Multiple Endpoints ◽

Interim Analyses ◽

Rare Cancers ◽

Design Flexibility ◽

Additional Value

Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency.

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