Clinical trial NCT04622956: GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide
Official title: GVHD Prophylaxis With Methotrexate and Cyclosporine in Haploidentical Stem Cell Transplantation Using Posttransplant Cyclophosphamide in Hematologic Malignancies: Phase I/II Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Graft Vs Host Disease
Hematopoietic Neoplasm
Keywords: Methotrexate
Post-transplant cyclophosphamide
Cyclosporine
Haploidentical
Hematopoietic cell transplantation
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
Collaborators: name: Libbs Farmacêutica LTDA
First posted: 2020-11-10
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase I / II multicenter open-label clinical trial with prospective nonrandomized arm and historical control group
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: Methotrexate dose to be used in the phase 2 (Phase 1)
timeFrame: Day 30
measure: GVHD-free, relapse-free survival (Phase 2)
timeFrame: Day 365
Secondary outcomes:
measure: Overall survival
timeFrame: Day 365
measure: Cumulative incidence of neutrophil and platelet engraftment
timeFrame: Day 30
measure: Cumulative incidence of graft failure
timeFrame: Day 30
measure: Cumulative incidence of grade II-IV acute GVHD
timeFrame: Day 100
measure: Cumulative incidence of grade III-IV acute GVHD
timeFrame: Day 100
measure: Cumulative incidence of non-relapse/progression related mortality
timeFrame: Day 365
measure: Cumulative incidence of Chronic GVHD
timeFrame: Day 365
measure: Change in 36-Item Short Form Health Survey (SF-36)
timeFrame: Baseline, Days 30, 90, 180, and 365
measure: Change in the Functional Assessment of Cancer Therapy (FACT)-Bone Marrow Transplantation (BMT) Survey
timeFrame: Baseline, Days 30, 90, 180, and 365
measure: Frequency of Grade 3-5 adverse events
timeFrame: Day 30
measure: Change in Natural Killer cell function [% activity]
timeFrame: Days 30, 90, and 180
measure: Change in lymphocyte subsets [absolute number/mcL]
timeFrame: Days 30, 90, and 180
measure: Cumulative incidence of CMV and EBV reactivation
timeFrame: Day 100
measure: Change in bone marrow or peripheral blood donor chimerism [%]
timeFrame: Days 30, 90, and 180
measure: Change in mean free mycophenolic acid and mycophenolic acid glucuronide level [mcg/mL] on peripheral blood (controls only)
timeFrame: Days 12 and 19
Other outcomes:
Locations:
city: Rio De Janeiro
country: Brazil
facility: Instituto Nacional de Câncer José Alencar Gomes Da Silva - Inca
state: RJ
city: Campinas
country: Brazil
facility: Centro de Hematologia e Hemoterapia - HEMOCENTRO
state: São Paulo
city: Jaú
country: Brazil
facility: Hospital Amaral Carvalho / Fundação Dr. Amaral Carvalho
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas da Universidade de Sao Paulo
Study officials:
affiliation: Hospital das Clínicas da Universidade de São Paulo
name: Giancarlo Fatobene, MD
role: PRINCIPAL_INVESTIGATOR
References: