Phase III Study Comparing GVHD Prophylaxis With ATG-thymoglobulin to ATLG-grafalon in Elderly Patients With Acute Myeloid Leukemia or Myelodysplasic Syndrome and Receiving an Allogeneic Hematopoietic Stem Cell Transplantation With a 10/10 HLA Matched Unrelated Donor

NCT ID: NCT06083129

Last Updated: 2023-10-13

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 324 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-11-01
• Study Completion Date: 2028-11-01

Brief Summary

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Most of the patients requiring an allo-HSCT are above 50 years of age and are transplanted with a reduced intensity conditioning (RIC) regimen. The optimal RIC and Graft Versus Host Disease (GVHD) prophylaxis regimen allowing a good control of the disease while preventing GVHD remains to be determined for elderly patients. A phase III trial comparing the conventional RIC fludarabine-busulfan 2 days to fludarabine-treosulfan demonstrated an advantage for the flu-treosulfan arm in terms of event free survival (EFS), that should therefore be considered as the new standard of RIC regimen for AML and MDS. GVHD prevention has a crucial role in post-transplant outcomes by potentially interfering with the graft-versus-leukemia (GVL) effect and immune reconstitution. Anti-thymocyte globulins (ATG) are recommended to reduce the risk of acute and chronic GVHD in transplants performed with matched unrelated donors. However, the optimal type of ATG between the 2 approved brands (ATG-thymoglobulin and ATLG-grafalon) displaying distinct characteristics and the optimal dose of ATG are still unknown. In a retrospective study of patients transplanted mainly with RIC with matched related and unrelated donors for haematological malignancies, we observed that Anti-T lymphocyte globulin (ATLG) was associated with a reduction of grade II-IV acute GVHD in comparison to ATG without increasing the incidence of relapse.

In this phase III randomised study, we propose to compare GVHD prevention with ATG versus ATLG in AML and MDS patients above 50 years of age transplanted with a matched unrelated donor following a fludarabine-treosulfan RIC, with the hypothesis that ATLG would better control GVHD in this population of patients thus limiting the risk of morbidity and mortality of the procedure.

Conditions

GVHD

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Anti-T lymphocyte globulin (ATLG)

Group Type: ACTIVE_COMPARATOR

Grafalon

Intervention Type: DRUG

10 mg/Kg/day IV for 3 consecutive days (day-3 to -1 before transplantation)

Anti Thymocyte Globulins (ATG)

Group Type: ACTIVE_COMPARATOR

Thymoglobulin

Intervention Type: DRUG

2.5 mg/Kg/day IV for 2 consecutive days (day-3 and -2 before transplantation)

Interventions

Grafalon

10 mg/Kg/day IV for 3 consecutive days (day-3 to -1 before transplantation)

Intervention Type: DRUG

Thymoglobulin

2.5 mg/Kg/day IV for 2 consecutive days (day-3 and -2 before transplantation)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 50 and ≤ 70 years

2. Patient between 50 and 55 years should be unfit for a myeloblative conditioning (SORROR score ≥2)

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 [rapide 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:

1. ECOG performans status ≤ 2

2. No severe and uncontrolled infection

3. Cardiac left ventricular ejection fraction ≥50%

4. Lung DLCO > 40%

5. 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 transdermal progestogen-only hormonal contraception, intrauterine hormonal releasing system (IUS), sexual abstinence (only if this the preferred and usual lifestyle of the participants).
• For man in absence of permanent sterilization: sexual abstinence, condoms

Exclusion Criteria

1. Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)

2. Uncontrolled infection

3. Seropositivity for HIV or HTLV-1 or active hepatitis B or C

4. Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation

5. Heart failure according to NYHA (II or more) or Left ventricular ejection fraction < 50%.

6. Lung DLCO ≤ 40%

7. Preexisting acute hemorrhagic cystitis

8. Renal failure with creatinine clearance < 50ml / min

9. Pregnancy (β-HCG positive) or breast-feeding

10. Patients with any debilitating medical or psychiatric illness, which would preclude the realization of the SCT or the understanding of the protocol

11. Patient under state medical aid

12. Patient under legal protection (protection of the court, or in curatorship or guardianship).

13. For Grafalon: Hypersensitivity to the active substance or to any of the excipients

14. For Thymoglobulin: Hypersensitivity to rabbit proteins or to any of the excipients

15. Participation in other interventional clinical trials

16. Any contraindication mentioned in the SmPC of all auxiliary medicinal products planned to be used in the trial: cyclosporine, mycophenolate mofetil, fludarabine, treosulfan

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Régis Peffault de Latour, Pr

Role: CONTACT

regis.peffaultdelatour@aphp.fr

+33142385073

Jérôme Lambert, Dr

Role: CONTACT

jerome.lambert@u-paris.fr

+33142499742

Other Identifiers

APHP230276

Identifier Type: -

Identifier Source: org_study_id