Treatment Of Steroid-Refractory Acute Graft-versus-host Disease With Mesenchymal Stromal Cells Versus Best Available Therapy

Study Overview
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Brief Summary
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The primary purpose of this trial is to demonstrate the superiority of MC0518 compared to the first used best available therapy (BAT) with respect to overall response rate (ORR) at Day 28 and/or overall survival (OS) until Visit Month 24 in adult and adolescent subjects with steroid-refractory acute graft-versus-host disease (SR-aGvHD).

Official Title
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A Randomised, Open-label, Multicentre, Phase 3 Trial of First-line Treatment With Mesenchymal Stromal Cells MC0518 Versus Best Available Therapy in Adult and Adolescent Subjects With Steroid-refractory Acute Graft-versus-host Disease After Allogeneic Haematopoietic Stem Cell Transplantation (IDUNN Trial)

Conditions
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Steroid-refractory Acute Graft-versus-host Disease

Intervention / Treatment
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* Biological: MC0518
* Biological: BAT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant had a previous allogeneic HSCT as indicated for non-malignant (including inborn errors of metabolism, primary immunodeficiencies, haemoglobinopathies, and bone marrow failure syndromes) or haematological malignant disease, irrespective of human leukocyte antigen match Participant has been clinically diagnosed with Grade II to IV aGvHD at the Screening Visit Participant has experienced failure of previous first-line aGvHD treatment (ie, SR-aGvHD), defined as: a) aGvHD progression within 3 to 5 days of therapy onset with >= 2 mg/kg/day of prednisone equivalent or b) failure to improve within 5 to 7 days of treatment initiation with >= 2 mg/kg/day of prednisone equivalent or c) incomplete response after > 28 days of immunosuppressive treatment including at least 5 days with >= 2 mg/kg/day of prednisone equivalent Participant has an estimated life expectancy > 28 days at the Screening Visit Male or female participant who is >= 12 years of age at the Screening Visit Exclusion Criteria: Participant has overt relapse or progression or persistence of the underlying disease at the Screening Visit Participant has received the last HSCT for a solid tumour disease Participant has GvHD overlap syndrome at the Screening Visit Participant has received systemic first line treatment for aGvHD other than steroids and a prophylaxis with other than calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, anti-thymocyte globulin (ATG), mycophenolate mofetil (MMF), methotrexate (MTX), and / or cyclophosphamide before the Screening Visit Participant has a known pregnancy (as confirmed by a positive pregnancy test at the Screening Visit) and or is breastfeeding at the Screening Visit Participant has received treatment with any other investigational agent within 30 days or 5 half-lives (whichever is longer) before the Screening Visit (compliance to be confirmed for the period between the Screening Visit and the Baseline Visit at the Baseline Visit).

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MC0518<br>Participants will receive MC0518 1-2 million cells/ kilogram infusions (based on body weight at the Screening Visit) once a week for 4 weeks (Visit Day 1, 8, 15, and 22). Participants with partial response (PR) on Day 28 will have 2 additional MC0518 infusions administered on Day 29 and 36. | Biological: MC0518<br>* MC0518 will be intravenously infused immediately after thawing.<br>|
| Active Comparator: Best Available Therapy (BAT)<br>Participants will receive any one of the following systemic BATs based on the Investigator's decision: mycophenolate mofetil (MMF), extracorporeal photopheresis (ECP), anti-thymocyte globulin (ATG), everolimus, and ruxolitinib (RUX). | Biological: BAT<br>* BAT including MMF, ECP, ATG, everolimus, and RUX will be administered based on Investigator's decision.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response (OR) | OR is defined as complete response (CR) or partial response (PR) at Day 28 relative to aGvHD status at baseline. CR is defined as resolution of aGvHD in all involved organs. PR is defined as improvement in 1 stage in 1 or more organs involved with aGvHD symptoms without progression in others. Number of participants with OR will be reported. | Day 28 | 
| Overall Survival | Overall survival is defined as the time from randomization to the date of death due to any cause. | Up to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from Treatment Failure (FFTF) | FFTF is defined as death, relapse or progression of the underlying disease, or addition or change to any further systemic immunosuppressive aGvHD therapy. Number of participants with FFTF will be reported. | Up to 6 months | 
| Acute Graft-versus-host Disease (aGvHD) Response | Number of participants with aGvHD response will be reported. aGvHD response will be categorized as OR (CR + PR), CR, PR, and NR. NR is defined as the absence of CR or PR. | Days 28, 60, 100 and 180 | 
| Change from Baseline in aGvHD Grades | aGvHD grades: Grade 0- no organ involvement (ie, Stage 0 skin, Stage 0 liver, and Stage 0 GI); Grade I-Stage 1 - 2 skin without liver/GI involvement; Grade II- Stage 3 skin and / or Stage 1 liver and / or Stage 1 GI; Grade III- Stage 2 - 3 liver and / or Stage 2 - 3 GI; Grade IV- Stage 4 skin and / or Stage 4 liver and/or Stage 4 GI. | Baseline and Days 8, 15, 22, 28, 60, 100 and 180 | 
| Time to Response | Time to response is defined as the time from the date of the first treatment administration to the date of response. | Up to Month 24 | 
| Duration of Response | Duration is calculated from time from the first OR (CR or PR) until the time point of no aGvHD response in comparison to baseline. | Up to Month 24 | 
| Best Overall Response (OR) | Best OR is defined as the achievement of an OR at any time point up to and including Day 28. Number of participants with best OR will be reported. | Up to Day 28 | 
| Cumulative Dose of Steroids for SR-aGvHD per Kilogram (kg) of Body Weight | The cumulative dose of steroids given for SR-aGvHD per kg of body weight from baseline until Day 60 and until Visit Month 24 will be analyzed. | Up to Day 60 and Month 24 | 
| Number of Participants with Chronic Graft-versus-host Disease (cGvHD) | Number of participants with cGvHD will be reported. | Day 60 to Month 24 | 
| Time to Chronic Graft-versus-host Disease (cGvHD) | Time to cGvHD is defined as the time between the last day of haematopoietic stem cell transplantation (HSCT) to the first episode of cGvHD. | Day 60 to Month 24 | 
| Number of Participants with Graft Failure (GF) | Number of participants with GF will be reported. | Up to Month 24 | 
| Number of Participants with Relapse or Progression in Participants with Underlying Malignant Disease | Number of participants with relapse or progression in participants with underlying malignant disease will be reported. | Up to Month 24 | 
| Time to Relapse or Progression in Participants with Underlying Malignant Disease | Time to relapse or progression in participants with underlying malignant disease will be reported. | Up to Month 24 | 
| Event-free survival (EFS) | EFS is defined as the time from the date of randomization to the date of the event. An event is defined as GF, relapse or progression of the underlying disease, or death due to any cause. | Up to Month 24 | 
| Non-relapse Mortality (NRM) | NRM is defined as the time from the date of randomisation to the date of the event. An event is defined as death without previous relapse or progression of the underlying disease. | Up to Month 24 | 
| Number of Participants with Adverse Events (AEs) and Adverse Reactions (ARs) |  | Until Day 60 or until 30 days after last administration of trial treatment, whichever is later (Up to Month 24) | 
| Number of Participants with Adverse Events (AEs) and Adverse Reactions (ARs) by Severity | Severity will be graded based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe; Grade 4- Life-threatening consequences; urgent intervention indicated; Grade 4- Death related to the AE. | Until Day 60 or until 30 days after last administration of trial treatment, whichever is later (Up to Month 24) | 
| Change from Baseline in Performance score based on Karnofsky scale (recipient age >= 16 years) | The Karnofsky performance score (KPS), which is reported on an ordinal scale from 0 to 100, provides a rough measure of the participant's well-being, including their ability to conduct activities of daily living and functional capacity. Higher score indicates normal, no complaints and no evidence of disease. | Baseline, Days 8, 15, 22, 28, 60 and 100 | 
| Change from Baseline in Performance score based on Lansky Scale | A Lansky score (recipient age greater than or equal to [>=] 1 years and less than [<] 16 years) will be recorded pre-treatment and measured serially at regular intervals after treatment. The score is a standard performance score that measures overall function of the child with a scale range from 0 to 100. Higher score indicates full activeness. | Baseline, Days 8, 15, 22, 28, 60 and 100 | 
| Change from Baseline in EuroQol-5D-5L (EQ-5D-5L): Health Status Index (HSI) | EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. EQ-5D-5L descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health TODAY. Responses were used to generate a HSI. HSI ranges from 0 (dead) to 1.00 (full health). | Baseline, Days 28, 60, 100 and 180 | 
| Change from Baseline in EuroQol-5D-5L (EQ-5D-5L): Visual Analogue Scale (VAS) | EQ-5D-5L is a 2-part instrument for use as a measure of health outcome, designed for self-completion by respondents. It consists of EQ-5D-5L descriptive system and EQ VAS. The EQ VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 (the worst health you can imagine) to 100 (the best health you can imagine). | Baseline, Days 28, 60, 100 and 180 | 
| Change from Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) Score | The FACT-BMT questionnaire was designed to measure the quality of life in subjects undergoing bone marrow (BM) transplantation. It consists of the following categories of assessment: physical well-being, social / family well-being, emotional well-being, functional well-being, and additional miscellaneous concerns that the subject may have concerning their healthcare, persons involved in their life, and other emotions and incapabilities. Score ranges from 0-164, with higher score indicating better quality of life. | Baseline, Days 28, 60, 100 and 180 |