Trial of efficacy and safety of MC0518 versus best available therapy in patients with steroid-refractory acute graft versus host disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

13 Nov 2023 → ongoing

Decision date (initial)

2023-09-12

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-503952-28-00

WHO UTN

U1111-1290-6434

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Others

Comparative evaluation of the overall response rate in paediatric participants with steroid-refractory acute graft-versus-host disease (SR aGvHD) at Visit Day 28 after treatment with MC0518 or first used best available therapy (BAT)

Secondary objectives 4

1. Comparative evaluation of freedom from treatment failure defined by the absence of death, malignancy relapse or progression, or addition of or change to any further systemic acute graft-versus-host disease (aGvHD) therapy within 6 months after randomisation and prior to diagnosis of chronic graft versus-host disease (cGvHD)
2. Comparative evaluation of further secondary efficacy endpoints with respect to overall survival (OS) and response to treatment
3. Comparative evaluation of the safety
4. Comparative evaluation of health-related quality of life (HRQoL)

Conditions and MedDRA coding

Steroid refractory Acute Graft versus host Disease

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002706-PIP01-19

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 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 or neuroblastoma.
2. Participant has been clinically diagnosed with Grade II to IV aGvHD according to Harris et al. A biopsy of the involved organs with aGvHD is encouraged but not required.
3. Participant has experienced failure of previous first line aGvHD treatment (ie, SR aGvHD), defined as: - aGvHD progression within 3 to 5 days of therapy onset with ≥ 2 mg/kg/day of prednisone equivalent or - failure to improve within 5 to 7 days of treatment initiation with ≥ 2 mg/kg/day of prednisone equivalent or - incomplete response after > 28 days of immunosuppressive treatment including at least 5 days with ≥ 2 mg/kg/day of prednisone equivalent.
4. Male or female participant who is ≥ 28 days and < 18 years of age and has a minimum BW of 3.2 kg at the Screening Visit.
5. Participant has an estimated life expectancy of > 28 days.
6. Participant, if female and of childbearing potential, agrees to use a highly effective contraceptive measure starting at the Screening Visit and continuing throughout the entire trial period. The definition of women of childbearing potential and a complete list of highly effective contraceptive measures are included in an appendix to the protocol.
7. Participant, if a fertile male, agrees to sexual abstinence or to use a condom during sexual activity with their female partner of childbearing potential or pregnant partner. Additionally, if their partner is a woman of childbearing potential, then their partner must use an additional highly effective contraceptive method during sexual activity starting at the Screening Visit and continuing throughout the entire trial period. The definition of fertile men and a complete list of highly effective contraceptive measures are included in an appendix to the protocol.
8. A written informed consent of the participant’s parent(s) / legal guardian(s) (and participant’s assent, when applicable) has been obtained according to national regulations.

Exclusion criteria 11

1. Participant has overt relapse or progression or persistence of the underlying disease.
2. Participant has received the last HSCT for a solid tumour disease other than neuroblastoma.
3. Participant has graft-versus-host disease overlap syndrome as defined by Jagasia et al.
4. Participant has received systemic first line treatment for aGvHD other than steroids and a prophylaxis with other than calcineurin inhibitors, mammalian target of rapamycin inhibitors, anti thymocyte globulin, mycophenolate mofetil, methotrexate, abatacept, or cyclophosphamide. Please Note: In vitro or in vivo graft manipulation to prevent graft-versus-host disease (eg, T cell depletion) during HSCT is permitted. Restart of initial prophylaxis with calcineurin inhibitors, mammalian target of rapamycin inhibitors, or mycophenolate mofetil after aGvHD onset is permitted.
5. Participant has received prior mesenchymal stromal cell (MSC) treatment, including MC0518/Obnitix®.
6. Participant has a known pregnancy (as confirmed by a positive pregnancy test result at the Screening Visit) and / or is breastfeeding.
7. Participant has a known hypersensitivity to MC0518 and / or its excipients (dimethyl sulfoxide, human serum albumin, isotonic sodium chloride solution).
8. Participant has a known hypersensitivity or any contraindication to the Investigator’s choice BAT (extracorporeal photopheresis, anti thymocyte globulin, etanercept, infliximab, or ruxolitinib) and / or its excipients. For a list of excipients please refer to the respective Summary of Product Characteristics.
9. Participant has an underlying or current medical or psychiatric condition that, in the opinion of the Investigator, would interfere with the evaluation of the participant.
10. Participant has an uncontrolled infection (eg, sepsis or multi-organ failure) including significant bacterial, fungal, viral, or parasitic infection requiring treatment.
11. Participant has received treatment with any other investigational agent within 30 days or 5 half lives (whichever is longer) before the Screening Visit

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall response (OR), defined as complete response (CR) or partial response (PR) at Visit Day 28 relative to the aGvHD status at baseline (Visit Day 1 prior to the first treatment).

Secondary endpoints 16

1. Freedom from treatment failure until 6 months (Visit Day 180), defined as the time from the date of randomisation to the date of the event. An event is defined as death, relapse or progression of the underlying disease, or addition of or change to any further systemic aGvHD therapy (except changes in steroid treatment). The diagnosis of cGvHD is a competing event
2. OS until Visit Month 24, defined as the time from the date of randomisation to the date of death due to any cause
3. aGvHD response at Visit Day 28 assessed by CR, PR, and NR and at Visit Day 60, Visit Day 100, and Visit Day 180 assessed by OR, CR, PR, and NR relative to baseline
4. Change of aGvHD grade at Visit Day 8, Visit Day 15, Visit Day 22, Visit Day 28, Visit Day 60, Visit Day 100, and Visit Day 180 relative to baseline
5. Time to response, defined as the time from the date of the first treatment administration to the date of the first response (CR or PR)
6. Duration of response until Visit Month 24, defined as the time from the date of the first OR (CR or PR) to the date of aGvHD assessed as NR compared to the baseline assessment, or the date of addition of or change to any further systemic aGvHD therapy (except changes in steroid treatment), in responders
7. Best OR until Visit Day 28, defined as the achievement of an OR at any time point up to and including Visit Day 28
8. Cumulative dose of steroids given for SR-aGvHD per kg body weight (BW) from the date of the first treatment administration until Visit Day 28, Visit Day 60, and until Visit Month 24
9. Incidence of and time to cGvHD from Visit Day 60 until Visit Month 24
10. Incidence of graft failure (GF) from baseline until Visit Month 24
11. Incidence of and time to relapse or progression of the underlying disease in participants with underlying malignant disease from randomisation until Visit Month 24
12. Event free survival until Visit Month 24, defined as the time from the date of randomisation 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
13. Non-relapse mortality until Visit Month 24, 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. Relapse or progression are competing events
14. The incidence and severity of all adverse events (AEs), including viral, bacterial, and fungal infections until Visit Day 60, and of adverse reactions (ARs) until Visit Month 24
15. Performance score (Karnofsky / Lansky scale) at Visit Day 8, Visit Day 15, Visit Day 22, Visit Day 28, Visit Day 60, and Visit Day 100 compared to baseline
16. HRQoL measures: Paediatric Quality of Life InventoryTM (PedsQL™) 4.0 Generic Core Scales with the PedsQL™ Stem Cell Transplant Module at Visit Day 28, Visit Day 60, Visit Day 100, and Visit Day 180 compared to baseline

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Sponsor organisation

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Address

Theaterstrasse 6

City

Wedel

Postcode

22880

Country

Germany

Scientific contact point

Organisation

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Contact name

Clinical Trial Information

Public contact point

Organisation

Medac Gesellschaft fuer klinische Spezialprapaerate mbH

Contact name

Clinical Trial Information

Third parties 6

Locations

5 EU/EEA countries · 36 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 87 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications