Back to resultsGVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide
Primary Purpose
Graft Vs Host Disease, Hematopoietic Neoplasm
Status
Recruiting
Phase
Phase 1
Locations
Brazil
Study Type
Interventional
Intervention
Methotrexate Injectable Solution
Sponsored by
About this trial
This is an interventional prevention trial for Graft Vs Host Disease focused on measuring Methotrexate, Post-transplant cyclophosphamide, Cyclosporine, Haploidentical, Hematopoietic cell transplantation
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
Sites / Locations
- Instituto Nacional de Câncer José Alencar Gomes Da Silva - IncaRecruiting
- Centro de Hematologia e Hemoterapia - HEMOCENTRORecruiting
- Hospital Amaral Carvalho / Fundação Dr. Amaral CarvalhoRecruiting
- Hospital das Clinicas da Universidade de Sao PauloRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Experimental
Control Group
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
Overall survival
Time to death
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.
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.
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.
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.
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.
Cumulative incidence of Chronic GVHD
Time to onset of 2014 NIH Chronic GVHD. Non-relapse related mortality will be a competing event.
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
Change in the Functional Assessment of Cancer Therapy (FACT)-Bone Marrow Transplantation (BMT) Survey
Change in mean subscale response of the FACT-BMT survey
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
Change in Natural Killer cell function [% activity]
Change in lymphocyte subsets [absolute number/mcL]
Cumulative incidence of CMV and EBV reactivation
Change in bone marrow or peripheral blood donor chimerism [%]
Change in mean free mycophenolic acid and mycophenolic acid glucuronide level [mcg/mL] on peripheral blood (controls only)
Full Information
NCT ID
NCT04622956
First Posted
October 29, 2020
Last Updated
September 10, 2021
Sponsor
University of Sao Paulo General Hospital
Collaborators
Libbs Farmacêutica LTDA
1. Study Identification
Unique Protocol Identification Number
NCT04622956
Brief Title
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
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Recruiting
Study Start Date
October 7, 2020 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Sao Paulo General Hospital
Collaborators
Libbs Farmacêutica LTDA
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Vs Host Disease, Hematopoietic Neoplasm
Keywords
Methotrexate, Post-transplant cyclophosphamide, Cyclosporine, Haploidentical, Hematopoietic cell transplantation
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Phase I / II multicenter open-label clinical trial with prospective nonrandomized arm and historical control group
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
47 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Experimental
Arm Type
Experimental
Arm Description
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.
Arm Title
Control Group
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Methotrexate Injectable Solution
Other Intervention Name(s)
Fauldmetro [Libbs]
Intervention Description
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
Primary Outcome Measure Information:
Title
Methotrexate dose to be used in the phase 2 (Phase 1)
Description
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
Title
GVHD-free, relapse-free survival (Phase 2)
Description
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
Secondary Outcome Measure Information:
Title
Overall survival
Description
Time to death
Time Frame
Day 365
Title
Cumulative incidence of neutrophil and platelet engraftment
Description
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
Title
Cumulative incidence of graft failure
Description
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
Title
Cumulative incidence of grade II-IV acute GVHD
Description
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
Title
Cumulative incidence of grade III-IV acute GVHD
Description
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
Title
Cumulative incidence of non-relapse/progression related mortality
Description
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
Title
Cumulative incidence of Chronic GVHD
Description
Time to onset of 2014 NIH Chronic GVHD. Non-relapse related mortality will be a competing event.
Time Frame
Day 365
Title
Change in 36-Item Short Form Health Survey (SF-36)
Description
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
Title
Change in the Functional Assessment of Cancer Therapy (FACT)-Bone Marrow Transplantation (BMT) Survey
Description
Change in mean subscale response of the FACT-BMT survey
Time Frame
Baseline, Days 30, 90, 180, and 365
Title
Frequency of Grade 3-5 adverse events
Description
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
Title
Change in Natural Killer cell function [% activity]
Time Frame
Days 30, 90, and 180
Title
Change in lymphocyte subsets [absolute number/mcL]
Time Frame
Days 30, 90, and 180
Title
Cumulative incidence of CMV and EBV reactivation
Time Frame
Day 100
Title
Change in bone marrow or peripheral blood donor chimerism [%]
Time Frame
Days 30, 90, and 180
Title
Change in mean free mycophenolic acid and mycophenolic acid glucuronide level [mcg/mL] on peripheral blood (controls only)
Time Frame
Days 12 and 19
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Giancarlo Fatobene, MD
Phone
+551126617575
Email
gian_fatobene@hotmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Giancarlo Fatobene, MD
Organizational Affiliation
Hospital das Clínicas da Universidade de São Paulo
Official's Role
Principal Investigator
Facility Information:
Facility Name
Instituto Nacional de Câncer José Alencar Gomes Da Silva - Inca
City
Rio De Janeiro
State/Province
RJ
Country
Brazil
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Claudia R Moreira, MD
Email
mclaudiarm@gmail.com
Facility Name
Centro de Hematologia e Hemoterapia - HEMOCENTRO
City
Campinas
State/Province
São Paulo
Country
Brazil
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Afonso Vigorito, MD, PhD
Email
afonso@unicamp.br
Facility Name
Hospital Amaral Carvalho / Fundação Dr. Amaral Carvalho
City
Jaú
State/Province
São Paulo
Country
Brazil
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Iago Colturato, MD
Email
iago_colt@hotmail.com
Facility Name
Hospital das Clinicas da Universidade de Sao Paulo
City
Sao Paulo
ZIP/Postal Code
05403-000
Country
Brazil
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giancarlo Fatobene, MD
Phone
+551126617575
Email
gian_fatobene@hotmail.com
First Name & Middle Initial & Last Name & Degree
Bruna Carvalho
Phone
+551126617575
Email
bruna.carvalho@hc.fm.usp.br
First Name & Middle Initial & Last Name & Degree
Giancarlo Fatobene, MD
First Name & Middle Initial & Last Name & Degree
Vanderson Rocha, MD, PhD
12. IPD Sharing Statement
Plan to Share IPD
No
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GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide
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