Community Research and Development Information Service - CORDIS

H2020

RETHRIM Report Summary

Project ID: 643580
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - RETHRIM (Restoring tissue regeneration in patients with visceral Graft versus Host Disease.)

Reporting period: 2015-01-01 to 2016-06-30

Summary of the context and overall objectives of the project

Allogeneic stem cell transplantation is a potentially curative treatment for a variety of haematological disorders. While offering the potential for cure, one of the major complications after transplantation is the occurrence of acute Graft-versus-Host Disease (aGvHD), which in its severe form (grade III-IV with organ involvement) caries a mortality risk of up to 75%. The consortium partners have been involved in a number of phase I/II trials that indicated that the use of third-party Mesenchymal Stromal Cells (MSC) might be an effective therapy for visceral (organ involvement) GvHD. However, no definitive proof of effectiveness through double-blind placebo controlled multicentre studies has been obtained. The current phase III clinical trial is aimed at setting a new standard for the treatment of visceral GvHD. MSC regenerative therapy will be employed to determine its potential to improve the rates of remission and overall survival and to improve quality of life.

The underlying hypothesis of the project is that outcome of MSC treatment is determined by the interplay between the MSC product and the inflammatory environment in the patient. To this end, patient samples obtained from the clinical trial and the MSC products produced to treat patients will be extensively studied to provide insight into the mechanisms of response to MSC therapy. Ideally this will provide insight for diagnostic and therapeutic development of MSC potency assays and biomarker assays to predict response to therapy.

In addition to the clinical trial, quality of life and health technology assessments will be performed as well as ethical studies regarding patient access to care. Output from these studies will allow the consortium to formulate a set of measures to convince health authorities, regulatory bodies and insurance companies on the usefulness of MSC therapy and provide suggestions and recommendations for changes in clinical practise, legislation and regulation of MSC regenerative therapy.

Within RETHRIM, clinical work is the central part of the project. The three main objectives are all closely linked to the clinical trial. In short the objective can be characterised as Treat, Design and Recommend:

- Objective 1, Treat patients to establish therapy effectiveness;
- Objective 2, Design potency signatures for MSC and biomarker assays to predict therapy outcome; -
- Objective 3, Provide recommendations to initiate changes in clinical practice and to allow the implementation of better regulatory requirements for regenerative therapies.

Figure 1 is a graphical representation of the work packages within the project showing their integration which starts with production of the drug product for the treatment of patients to development of assays and evaluation of clinical data. The expected impact is that the consortium will be able to create awareness of the study results among all stakeholders through dissemination and communication to achieve changes in clinical practice and deliver a business plan to exploit the study results.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Central to the RETHRIM project is a phase III clinical trial to which all the work packages in this study are linked.

Figure 1 is a graphical representation of the work packages within the project showing their integration which starts with production of the drug product for the treatment of patients to development of assays and evaluation of clinical data. The expected impact is that the consortium will be able to create awareness of the study results among all stakeholders through dissemination and communication to achieve changes in clinical practice and deliver a business plan to exploit the study results.

WP1, PROJECT MANAGEMENT, deals with overall management of the consortium and so far 3 consortium meetings and over 10 teleconferences have been organised to discuss the progress of the project.

WP2, MSC PRODUCTION, deals with the production and characterisation of the drug product used in the clinical trial. In this reporting period the consortium generated a completely adjusted production protocol including revisions requested by NCAs that assures full harmonisation of MSC production in all production centres. Furthermore a flow cytometry-based potency test was developed, which is now ready for validation. MSC batches produced for the study and historical samples were analysed for product heterogeneity both within one MSC product and between MSC products derived from different patients.

WP3, CLINICAL TRIAL, has been initiated in 3 of the 6 participating member states and so far 10 patients have been included in the study. Furthermore electronic systems were established to optimize data collection and data quality control.

WP4, IMMUNOLOGICAL PROFILE DEVELOPMENT, uses samples from the clinical study and the MSC products to establish an immune profile and define a predictive biomarker signature. During this reporting period a small patient cohort was used to validate the planned antibody array-based screening approach for which interesting candidate proteins were successfully identified that can be used to predict and monitor the response to MSC-mediated immunotherapy. Futhermore, new proteins have been produced for the generation of antibodies that can be used for biomarker finding using the antibody array and CyTOF/flow cytometry approach.

WP5, AUALITY OF LIFE, uses data obtained in the clinical trial. For this a number of assessment forms is used and the specific order in which these forms are handed to the patients has been established.

WP6, HEALTH TECHNOLOGY ASSESSMENT, studies the cost effectiveness of using MSC therapy for the treatment of Graft versus Host Disease. A number of study models have been set up.

WP7, ETHICAL ISSUES, deals with questions related to the study. In this reporting period arguments were presented that the placebo control design used in RETHRIM trial meets the requirements set forth in the contemporary ethics guidelines and that placebo control design can be applied on the basis that no proven intervention exists for the studied condition, that the trial has compelling methodological reasons to employ the placebo control design because a placebo controlled trial is more likely to achieve its goals and that the trial does not involve the risk of additional serious and/or irreversible harm for the placebo group as long as add-on trial design is used and as long as the placebo group receives the second-line therapy which they would otherwise receive, had they not participated in the trial.

WP8, COMMUNICATION, DISSEMINATION AND EXPLOITATION, deals with informing and communicating all relevant stackholders about the results of the project and their potential impact and the utilisation of the project results. To this end a file and data sharing platform has been created, a website is up and running a scientific meeting, EU-MSC2 was organised and a communication plan was drafted.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

"The overall ambition of the project is to set a new standard for the treatment of severe and steroid resistant acute GvHD following allogeneic stem cell transplantation, thereby improving the rates of remission and overall survival and improving quality of life. Within the consortium clinical centres collaborate with with diagnostic and biomarker companies, to identify a signature of biomarkers that will help to predict response enabling the selection of only those patients that benefit from the treatment. These studies may be considered as part of a pre-commercial development and will allow our partners from biotech to further commercialise these diagnostic tools. Next to performing the clinical trial and providing signature profiles for commercialisation, the consortium will provide recommendation to competent authorities and demonstrate the cost effectiveness of MSC regenerative therapy for GvHD to be able to provide a convincing health management plan to policy makers and health insurance companies. Finally, we aim to facilitate future clinical trials involving cellular therapies by identifying the legal and ethical hurdles involved in obtaining Europe-wide ethical approval. We equally aim to contribute to the ongoing ethical debates by investigating the conditions that would justify withholding a potential successful treatment benefit in randomized placebo controlled trials, in particular in cases where the benefit of the potentially successful experimental treatment amounts to potentially life-saving therapy and where the efficacy of the existing "best proven" therapy is poor and by examining the criteria for (non)involvement of children in such trials."

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