Study comparing thymoglobulin to grafalon, two treatments used to prevent graft versus host disease in elderly patients with acute myeloid leukemia or myelodysplastic syndrome and receiving an allogeneic stem cell transplantation with an unrelated matched donor after a reduced intensity conditioning regimen

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

28 Nov 2023 → ongoing

Decision date (initial)

2023-09-29

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

MEDAC SAS · NEOVII Pharmaceuticals AG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To compare the incidence of grade II-IV acute GVHD at day 100 post-transplantation in MDS or AML patients transplanted with a 10/10 matched unrelated donor (MUD) following a reduced intensity conditioning with fludarabine-treosulfan between patients receiving a GVHD prophylaxis with ATG-thymoglobulin versus ATLG-grafalon

Secondary objectives 15

1. To evaluate the effect of the 2 GVHD prophylaxis on the engraftment and graft failure
2. To evaluate the effect of the 2 GVHD prophylaxis on the incidence of grade I acute GVHD and of chronic GvHD
3. To evaluate the effect of the 2 GVHD prophylaxis on incidence of infections
4. To evaluate the effect of the 2 GVHD prophylaxis on progression free survival
5. To evaluate the effect of the 2 GVHD prophylaxis on relapse incidence
6. To evaluate the effect of the 2 GVHD prophylaxis on non-relapse mortality
7. To evaluate the effect of the 2 GVHD prophylaxis on overall survival
8. To evaluate the effect of the 2 GVHD prophylaxis on GVHD and relapse free survival (GRFS)
9. To evaluate the effect of the 2 GVHD prophylaxis on health-related Quality of life (FACT BMT)
10. To evaluate the effect of the 2 GVHD prophylaxis on chimerism
11. To evaluate the effect of the 2 GVHD prophylaxis on immune reconstitution (T, B, NK, regulatory T cell levels in the peripheral blood)
12. To evaluate the effect of the 2 GVHD prophylaxis on days of hospitalization during the first 12 months post-transplantation
13. To evaluate the effect of the 2 GVHD prophylaxis on incidence and severity of VOD
14. To identify prognostic factors associated with the primary endpoint for each prophylaxis arm: search for treatment-by-covariate interactions on the primary endpoint
15. To evaluate the effect of the 2 GVHD prophylaxis on the incidence of late acute GvHD (after day 100), overlap syndromes and chronic GvHD.

Conditions and MedDRA coding

Myelodysplastic syndrome (MDS)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age ≥ 50 and ≤ 70 years
2. Patient between 50 and 55 years should be unfit for a myeloblative conditioning
3. AML requiring allogeneic stem cell transplantation (intermediate or high risk AML) in complete cytologic response (CR1 or above) or MDS requiring allogeneic stem cell transplantation (IPSS≥ 1.5 or IPSS-R > 4.5 or IPSS-R > 3-4.5 with risk features [rapid blast increase, life-threatening neutropenia (<0.3 G/L) or thrombopenia (<30G/L) or high transfusion needs (>2/month for 6 months)]
4. Without an HLA matched related donor
5. Having an identified matched HLA 10/10 unrelated donor
6. With usual criteria for HSCT: a) ECOG performans status ≤ 2 ; b) No severe and uncontrolled infection ; c) Cardiac left ventricular ejection fraction ≥50% ; d) Lung DLCO > 40% ; e) Adequate organ function: ASAT and ALAT ≤ 3N, total bilirubin ≤ 2N, creatinine clearance ≥ 50 mL/min (except if those abnormalities are linked to the hematological disease)
7. With health insurance coverage
8. Having signed a written informed consent
9. Contraception methods must be prescribed during all the duration of the research. NB: The authorized contraceptive methods are: For women of childbearing age and in absence of permanent sterilization: oral, intravaginal or transdermal combined hormonal contraception; oral, injectable or implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormonal releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence (only if this is the preferred and usual lifestyle of the participants). For men in absence of permanent sterilization: sexual abstinence, condoms

Exclusion criteria 16

1. Carcinoma in the last 5 years (except basal cell carcinoma of the skin or “in situ” carcinoma of the cervix)
2. Patients with any debilitating medical or psychiatric illness, which would preclude the realization of the SCT or the understanding of the protocol
3. Patient under state medical aid
4. Patient under legal protection (protection of the court, or in curatorship or guardianship)
5. For Grafalon : Any contraindications mentioned in the SmPC of GRAFALON
6. For Thymoglobulin : Hypersensitivity to rabbit proteins or to any of the excipients
7. Participation in other clinical trials on medicinal products for human use or being in the exclusion period at the end of a previous study
8. Uncontrolled infection
9. Seropositivity for HIV or HTLV-1 or active hepatitis B or C
10. Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation
11. Heart failure according to NYHA (II or more) or Left ventricular ejection fraction < 50%.
12. Lung DLCO ≤ 40%
13. Preexisting acute hemorrhagic cystitis
14. Renal failure with creatinine clearance < 50ml / min
15. Pregnancy (β-HCG positive) or breast-feeding
16. Any contraindications mentioned in the SmPC of all auxiliary medicinal products planned to be used in the trial: cyclosporine, mycophenolate mofetil, fludarabine, treosulfan

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence of grade II-IV acute GVHD according to the MAGIC classification (Appendix 19.9 section 1) at day 100 post-transplantation.

Secondary endpoints 17

1. Hematopoietic recoveries: at least 7 consecutive days with neutrophils > 0.5 G/L, with platelets > 20 G/L
2. Immune reconstitution by analyzing T, B, NK, regulatory T cell and gammaglobulin levels in the peripheral blood at M1, D+100, M6, M12 and M24 post-transplantation
3. Chimerism at M1, D+100, M6, M12
4. Grade I acute GVHD incidence (Appendix 19.9 section 1) and acute GvHD treatments: first line treatment, response to steroids, treatment courses for refractory acute GVHD
5. Chronic GvHD incidence (date and grading) at M12 and M24 (NIH classification, Appendix 19.9 section 4)
6. Relapse incidence at M12 and M24 (relapse will be defined by the reappearance of leukemic cells or MDS features after allo-HSCT in the bonne marrow (cytology +/- cytogenetic analysis from bone marrow aspiration) or extra-medullary sites (proven by a biopsy).
7. Progression free survival at M12 and M24
8. Severe infections (CTAE grade 3-4) at D+100 and M12 will be fully described
9. Incidences of CMV and EBV reactivations at D+100, M6 and M12
10. Non-relapse mortality at M6, M12 and M24
11. Overall survival at M12 and M24
12. GVHD and relapse free survival (GRFS) defined by being alive without disease relapse and without having developed acute grade III-IV or severe chronic GVHD
13. Health-related Quality of life, assessed by using theFACT-BMT-v4 questionnaire at inclusion and at D+100, M6, M12 post-transplantation
14. Number of days of hospitalization for the transplant and after the hospitalization for transplantation related complications until M12
15. Incidence and severity of VOD at D+100
16. Lymphocyte counts on standard blood counts before conditioning (D-7)
17. Late acute GvHD, overlap syndromes and chronic GvHD at D+120.

Investigational products

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

Test 2

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Régis PEFFAULT DE LATOUR

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Marine CAMUS

Locations

1 EU/EEA country · 28 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 10 files

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

Application history

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