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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
47
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
Instituto Nacional de Câncer José Alencar Gomes Da Silva - Inca
Rio de Janeiro, Rio de Janeiro, Brazil
RECRUITINGCentro de Hematologia e Hemoterapia - HEMOCENTRO
Campinas, São Paulo, Brazil
RECRUITINGHospital Amaral Carvalho / Fundação Dr. Amaral Carvalho
Jaú, São Paulo, Brazil
RECRUITINGHospital das Clinicas da Universidade de Sao Paulo
São Paulo, Brazil
RECRUITINGMethotrexate 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.
Time frame: 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.
Time frame: Day 365
Overall survival
Time to death
Time frame: Day 365
Cumulative incidence of neutrophil and platelet engraftment
Neutrophil engraftment will be the first of three consecutive daily absolute neutrophil counts \> 500 / mcL after transplantation. Disease relapse will be a competitive event. Platelet engraftment will be considered as the first of seven daily consecutive platelet counts \> 20,000 / mcL without transfusion support. Disease relapse will be a competitive event.
Time frame: Day 30
Cumulative incidence of graft failure
Time to primary or secondary graft failure. Primary graft failure will be defined as failure to reach neutrophils \> 500 / mcL for three consecutive days or donor chimerism \<5% in any hematopoietic compartment (lymphocyte chimerism or total bone marrow / peripheral blood chimerism) and requiring additional hematopoietic cells. Secondary graft failure will be defined as the need for additional hematopoietic cells due to declining hematopoietic recovery in a patient with previous neutrophil engraftment.
Time frame: Day 30
Cumulative incidence of grade II-IV acute GVHD
Time to onset of grade II-IV acute GVHD according to the MAGIC criteria. Death without previous acute GVHD will be a competing event.
Time frame: Day 100
Cumulative incidence of grade III-IV acute GVHD
Time to onset of grade III-IV acute GVHD according to the MAGIC criteria. Death without previous acute GVHD will be a competing event.
Time frame: Day 100
Cumulative incidence of non-relapse/progression related mortality
Time to onset of disease relapse or progression (imaging, morphologic or molecular). Non-relapse related mortality will be a competing event.
Time frame: Day 365
Cumulative incidence of Chronic GVHD
Time to onset of 2014 NIH Chronic GVHD. Non-relapse related mortality will be a competing event.
Time frame: Day 365
Change in 36-Item Short Form Health Survey (SF-36)
Change in mean subscale response of the SF-36 Survey version 2.0 (Physical functioning, Role limitations due to physical health, Role limitations due to emotional problems, Energy/fatigue, Emotional well-being, Social
Time frame: Baseline, Days 30, 90, 180, and 365
Change in the Functional Assessment of Cancer Therapy (FACT)-Bone Marrow Transplantation (BMT) Survey
Change in mean subscale response of the FACT-BMT survey
Time frame: Baseline, Days 30, 90, 180, and 365
Frequency of Grade 3-5 adverse events
Adverse events will be classified according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 5.0
Time frame: Day 30
Change in Natural Killer cell function [% activity]
Time frame: Days 30, 90, and 180
Change in lymphocyte subsets [absolute number/mcL]
Time frame: Days 30, 90, and 180
Cumulative incidence of CMV and EBV reactivation
Time frame: Day 100
Change in bone marrow or peripheral blood donor chimerism [%]
Time frame: Days 30, 90, and 180
Change in mean free mycophenolic acid and mycophenolic acid glucuronide level [mcg/mL] on peripheral blood (controls only)
Time frame: Days 12 and 19
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