GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide

NCT ID: NCT04622956

Last Updated: 2021-09-14

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-07
• Study Completion Date: 2025-12-31

Brief Summary

Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic strategy for many malignant and benign hematologic diseases. Haploidentical HCT has been increasingly used in patients lacking a HLA-matched donor due to its prompt availability, possibly lower cost and results comparable with other donor types. Graft-versus-host disease (GVHD) is the main cause of morbidity and mortality after HSCT, and prophylactic strategies are routinely used. In the context of haploidentical HCT, posttransplant cyclophosphamide plus cyclosporine and mycophenolate mofetil (MMF) is the most common platform used in Brazil. Data comparing MMF and methotrexate (MTX) as GVHD prophylaxes have proved controversial in other donor types, yet some large studies have showed that MTX is associated with lower risk of GVHD and improved long-term outcomes. Moreover, it is known that MMF is a potent inhibitor of natural killer (NK) cells, possibly interfering with the graft-versus-leukemia effect in haploidentical HCT. Given the possible advantages and the absence of consistent evidence regarding safety, efficacy and ideal dosage of MTX as GVHD prophylaxis in this setting, we propose a phase I / II study evaluating this drug in adult patients with hematologic malignancies undergoing haploidentical HCT with posttransplant cyclophosphamide.

Conditions

Graft Vs Host Disease; Hematopoietic Neoplasm

Study Design

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

Study Groups

Experimental

GVHD prophylaxis will consist of high-dose PTCy (50 mg/kg i.v. on days +3 and +4) with mesna, cyclosporine (initiated on day +5) and methotrexate i.v (see doses on the right). Cyclosporine will be dosed with a target trough of 200 to 250 ng/mL and discontinued without taper at D+60 (if bone marrow graft) or until D+90 (is peripheral blood graft), unless acute GVHD is present. Filgrastim will be administered from day +5 until neutrophil recovery to ≥ 1,000/mcL for 3 days.

Group Type: EXPERIMENTAL

Methotrexate Injectable Solution

Intervention Type: DRUG

Phase 1:

• Level -1: Methotrexate 7.5 mg/m2 on D+6 and D+9*. Level -1 will be explored only if the starting dose is too toxic (reduced dose).
• Level 0 [Starting Dose]: Methotrexate 10 mg/m2 on D+6 and 7.5 mg/m2 on D+9
• Level +1: Methotrexate 10 mg/m2 on D+6 and D+9
• Level +2: Methotrexate 15 mg/m2 on D+6 and 10 mg/m2 on D+9

Phase 2: dose determined in the phase 1 trial

Control Group

GVHD prophylaxis will consist of high-dose PTCy (50 mg/kg i.v. on days +3 and +4) with mesna, cyclosporine (initiated on day +5) and mycophenolate mofetil (15 mg/kg/dose p.o. t.i.d. initiated on day +5). Cyclosporine will be dosed with a target trough of 200 to 250 ng/mL and discontinued without taper at D+60 (if bone marrow graft) or until D+90 (is peripheral blood graft), unless acute GVHD is present.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Methotrexate Injectable Solution

Phase 1:

• Level -1: Methotrexate 7.5 mg/m2 on D+6 and D+9*. Level -1 will be explored only if the starting dose is too toxic (reduced dose).
• Level 0 [Starting Dose]: Methotrexate 10 mg/m2 on D+6 and 7.5 mg/m2 on D+9
• Level +1: Methotrexate 10 mg/m2 on D+6 and D+9
• Level +2: Methotrexate 15 mg/m2 on D+6 and 10 mg/m2 on D+9

Phase 2: dose determined in the phase 1 trial

Intervention Type: DRUG

Other Intervention Names

Fauldmetro [Libbs]

Eligibility Criteria

Inclusion Criteria

• Diagnosis of acute myeloid leukemia and chronic myeloid leukemia in complete morphologic remission, myelodysplastic syndrome with less than 10% in bone marrow or peripheral blood, Ph-negative acute lymphoblastic leukemia in complete morphologic remission, chemosensitive Hodgkin lymphoma or non-Hodgkin lymphoma in at least partial remission
• Donor type: haploidentical related donor
• Graft source: bone marrow or peripheral blood
• Recipients of non-myeloblative or myeloablative intensity conditioning
• Left Ventricle Ejection fraction > 40%
• Estimated creatinine clearance > 40 mL/min
• Adjusted DLCO ≥ 40% and FEV1 ≥ 40%
• Total bilirubin < 2x ULN e ALT/AST < 2.5x ULN

Exclusion Criteria

• Prior allogeneic transplant
• Ex-vivo graft manipulation (T-cell-depleted or CD34-selected grafts)
• Use of alemtuzumab or anti-thymocyte globulin
• KPS < 70%
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
• Pregnant or lactating women
• Patients seropositive for human immunodeficiency virus (HIV) or active hepatitis B or C infection by PCR
• Presence of fluid collection (ascites, pleural or pericardial effusion) that may interfere with methotrexate clearance or make methotrexate use contraindicated
• Patients with a serious medical or psychiatric illness likely to interfere with participation in this study

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Libbs Farmacêutica LTDA

INDUSTRY

Sponsor Role: collaborator

University of Sao Paulo General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Giancarlo Fatobene, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital das Clínicas da Universidade de São Paulo

Locations

Instituto Nacional de Câncer José Alencar Gomes Da Silva - Inca

Rio de Janeiro, Rio de Janeiro, Brazil

Site Status: RECRUITING

Centro de Hematologia e Hemoterapia - HEMOCENTRO

Campinas, São Paulo, Brazil

Site Status: RECRUITING

Hospital Amaral Carvalho / Fundação Dr. Amaral Carvalho

Jaú, São Paulo, Brazil

Site Status: RECRUITING

Hospital das Clinicas da Universidade de Sao Paulo

São Paulo, , Brazil

Site Status: RECRUITING

Countries

Brazil

Central Contacts

Giancarlo Fatobene, MD

Role: CONTACT

gian_fatobene@hotmail.com

+551126617575

Facility Contacts

Maria Claudia R Moreira, MD

Role: primary

mclaudiarm@gmail.com

Afonso Vigorito, MD, PhD

Role: primary

afonso@unicamp.br

Iago Colturato, MD

Role: primary

iago_colt@hotmail.com

Giancarlo Fatobene, MD

Role: primary

gian_fatobene@hotmail.com

+551126617575

Bruna Carvalho

Role: backup

bruna.carvalho@hc.fm.usp.br

+551126617575

Other Identifiers

30802020.7.1001.0068

Identifier Type: -

Identifier Source: org_study_id