Objective:

Goal of the poster presentation is to show how different adaptive features can be combined in one overall adaptive trial design, allowing sponsors to explore various options and still provide confirmatory evidence to assist regulatory decision making.

Method: 

After a Phase I study with promising results, an adaptive trial for Phase IIB is planned; it includes dose selection, sample size re-assessment, and a potential enrichment. Type-1-error control is achieved by splitting the significance level, p-value adjustment, and closed testing principle. 

Results: 

The trial is planned as a randomized, double-blind, placebo-controlled, 3 parallel arms adjuvant trial to assess the efficacy of two doses of 2-hydroxyoleic acid (2-OHOA) versus placebo in patients with newly diagnosed GBM IDH wildtype.  In all arms patients will receive the Standard of Care and will be randomized to receive either placebo, low-dose or high-dose 2-OHOA.

The primary endpoints of the study are progression free survival (PFS) and overall survival (OS) as assessed after observing at least 150 PFS events and 133 OS events, respectively. It is expected that the analysis for PFS can be performed about 2 years earlier than the analysis for OS.

One formal interim analysis will be performed by an independent statistical group and reviewed by an independent Data Monitoring Committee (iDMC) when 75 PFS events are observed. After reviewing the interim results, the DMC will make recommendations regarding: the dose to take forward to the second part and the continuation of the trial overall. 

At interim analysis, if a molecular signature permits to identify a subpopulation of patients who respond better to the treatment, and this subpopulation needs enrichment the signature will become part of the inclusion criteria fora third cohort in the second stage of the trial, and the treatment effect will be estimated in the corresponding subgroup in the second and third cohort (Freidlin and Simon, 2005).  

Further, the sample size and events will be re-estimated for the selected dose to ensure that the power is well maintained given the estimated treatment effect at the interim analysis using the promising zone design (Mehta and Pocock, 2011).  

The poster will give details on all steps and how they are combined for evidence generation and what is done to protect type-1-error and the scientific integrity of the trial.

Conclusion : 
The adaptive trial design and statistical simulations are novel approaches to provide solutions to complex clinical development questions/scenarios and are presented to further scientific understanding in the clinical trials community.

The overall drug development plan and specifically the study design for Phase IIB presented in the poster recognizes that the European Commission has awarded a Horizon 2020 project grant to support the execution of this particular study in a stipulated timeframe and according to mutually-agreed specific conditions and procedures.

Progression directly to the Phase IIB study after promising preliminary findings in a Phase I study allows for a fast drug development, and through the adaptive elements provides additional important information regarding dose of 2-OHOA and a possible signature subpopulation in relation to efficacy for future clinical studies.

The nature of this disease and the available population of trial patients suggests this approach is more ethical and practical than to conduct two or more separate studies. The benefit/risk assessment is considered favourable. The proposed study design is subject to regulatory approval under the relevant clinical trial authorizations applicable for the sites chosen.

Literature

Freidlin, B., & Simon, R. (2005). Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients. Clinical cancer research, 11(21), 7872-7878.
Mehta, C. R., & Pocock, S. J. (2011). Adaptive increase in sample size when interim results are promising: a practical guide with examples. Statistics in medicine, 30(28), 3267-3284

Adaptive trial design with dose-selection and enrichment for assessing 2-OHOA for treatment of glioblastoma

DIA Europe 2019

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