GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide

NCT04622956 | Unknown Phase 1 DMC

• 1 other identifier: 30802020.7.1001.0068
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 4

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

Keywords

Methotrexate; Post-transplant cyclophosphamide; Cyclosporine; Haploidentical; Hematopoietic cell transplantation

Outcome Measures

Primary Outcomes (2)

• Methotrexate dose to be used in the phase 2 (Phase 1)

  The methotrexate dose to be used in the subsequent phase 2 will be equal to or lower than the maximum tolerated dose (MTD). MTD will be considered exceeded if at least 2 out of 6 subjects on a certain dosing level develop dose-limiting toxicity (DLT). DLT consists of gastrointestinal tract perforation, mediastinitis, airway obstruction requiring orotracheal intubation, severe gastrointestinal bleeding (without evidence of GVHD), graft failure, or hyperbilirubinemia or increase in alanine transaminase \[ALT\] / aspartate transaminase \[AST\] levels \> 5x the upper limit of normal.

  Day 30

• GVHD-free, relapse-free survival (Phase 2)

  Relapse, grade 3-4 GVHD and 2014 NIH Chronic GVHD will be considered events, and non-relapse related mortality will be a competing event.

  Day 365

Secondary Outcomes (15)

• Overall survival

  Day 365

• Cumulative incidence of neutrophil and platelet engraftment

  Day 30

• Cumulative incidence of graft failure

  Day 30

• Cumulative incidence of grade II-IV acute GVHD

  Day 100

• Cumulative incidence of grade III-IV acute GVHD

  Day 100

Study Arms (2)

Experimental

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.

Drug: Methotrexate Injectable Solution

Control Group

NO INTERVENTION

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.

Interventions

Methotrexate Injectable Solution 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

Also known as: Fauldmetro [Libbs]

Experimental

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead
• Libbs Farmacêutica LTDA: collaborator

Study Sites (4)

Instituto Nacional de Câncer José Alencar Gomes Da Silva - Inca

Rio de Janeiro, Rio de Janeiro, Brazil

RECRUITING

Centro de Hematologia e Hemoterapia - HEMOCENTRO

Campinas, São Paulo, Brazil

RECRUITING

Hospital Amaral Carvalho / Fundação Dr. Amaral Carvalho

Jaú, São Paulo, Brazil

RECRUITING

Hospital das Clinicas da Universidade de Sao Paulo

São Paulo, 05403-000, Brazil

RECRUITING

MeSH Terms

Conditions

Graft vs Host Disease; Hematologic Neoplasms

Condition Hierarchy (Ancestors)

Immune System Diseases; Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Giancarlo Fatobene, MD

  Hospital das Clínicas da Universidade de São Paulo

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giancarlo Fatobene, MD

CONTACT

+551126617575; gian_fatobene@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase I / II multicenter open-label clinical trial with prospective nonrandomized arm and historical control group

Study Record Dates

• First Submitted: October 29, 2020
• First Posted: November 10, 2020
• Study Start: October 7, 2020
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2025
• Last Updated: September 14, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

BR (4)