Graft Vs Host DiseasePhase 1/2NCT04622956
GVHD Prophylaxis With Methotrexate in Haploidentical HCT Using Posttransplant Cyclophosphamide
A Phase 1/2 study testing Methotrexate Injectable Solution in people with Graft Vs Host Disease and Hematopoietic Neoplasm, run by University of Sao Paulo General Hospital at 4 sites in Brazil.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Graft Vs Host Disease, Hematopoietic Neoplasm
- What is being tested?
- Methotrexate Injectable Solution
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 47 participants
- Where
- 4 sitesBrazil
- Study dates
- 7 Oct 2020to Dec 2025
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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
Trial locations and contacts
4 sites in 1 country.
Brazil4 sites, 4 recruiting
- Recruiting
Centro de Hematologia e Hemoterapia - HEMOCENTRO
Campinas, São Paulo
Afonso Vigorito, MD, PhD, afonso@unicamp.br
- Recruiting
Hospital Amaral Carvalho / Fundação Dr. Amaral Carvalho
Jaú, São Paulo
Iago Colturato, MD, iago_colt@hotmail.com
- Recruiting
Instituto Nacional de Câncer José Alencar Gomes Da Silva - Inca
Rio de Janeiro, Rio de Janeiro
Maria Claudia R Moreira, MD, mclaudiarm@gmail.com
- Recruiting
Hospital das Clinicas da Universidade de Sao Paulo
São Paulo, 05403-000
Giancarlo Fatobene, MD, +551126617575, gian_fatobene@hotmail.com
Bruna Carvalho, +551126617575, bruna.carvalho@hc.fm.usp.br
About this study
Official title: GVHD Prophylaxis With Methotrexate and Cyclosporine in Haploidentical Stem Cell Transplantation Using Posttransplant Cyclophosphamide in Hematologic Malignancies: Phase I/II Trial
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
- Being tested
- Methotrexate Injectable Solution
- Keywords
- Methotrexate, Post-transplant cyclophosphamide, Cyclosporine, Haploidentical, Hematopoietic cell transplantation
- Medical subject headings
- Graft vs Host Disease, Hematologic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Methotrexate Injectable SolutionDrug
Also called Fauldmetro [Libbs]
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
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Day 365
Secondary outcomes (15)
Overall survival
Time to death
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 365
Cumulative incidence of Chronic GVHD
Time to onset of 2014 NIH Chronic GVHD. Non-relapse related mortality will be a competing event.
Measured: 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
Measured: 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
Measured: 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
Measured: Day 30
Change in Natural Killer cell function [% activity]
Measured: Days 30, 90, and 180
Change in lymphocyte subsets [absolute number/mcL]
Measured: Days 30, 90, and 180
Cumulative incidence of CMV and EBV reactivation
Measured: Day 100
Change in bone marrow or peripheral blood donor chimerism [%]
Measured: Days 30, 90, and 180
Change in mean free mycophenolic acid and mycophenolic acid glucuronide level [mcg/mL] on peripheral blood (controls only)
Measured: Days 12 and 19
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Nov 2020
- Study start7 Oct 2020
- Primary completionDec 2023 (estimated)
- Study completionDec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Graft Vs Host DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Phase I / II multicenter open-label clinical trial with prospective nonrandomized arm and historical control group
- Masking
- None (open label)
- Enrolment
- 47 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Libbs Farmacêutica LTDA
- Responsible party
- Sponsor
- Investigators
- Giancarlo Fatobene, MD, Principal investigator, Hospital das Clínicas da Universidade de São Paulo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04622956
- Sponsor's protocol ID
- 30802020.7.1001.0068
- Status last verified
- Sep 2021
- First submitted
- 29 Oct 2020
- Last updated
- 14 Sep 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- GVHD Prophylaxis With Methotrexate and Cyclosporine in Haploidentical Stem Cell Transplantation Using Posttransplant Cyclophosphamide in Hematologic Malignancies: Phase I/II Trial
- ClinicalTrials.gov ID
- NCT04622956
- Acronym / sponsor ID
- 30802020.7.1001.0068
- Conditions
- Graft Vs Host Disease, Hematopoietic Neoplasm
- Keywords
- Methotrexate, Post-transplant cyclophosphamide, Cyclosporine, Haploidentical, Hematopoietic cell transplantation
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 47 participants (estimated)
- Lead sponsor
- University of Sao Paulo General HospitalUniversity, hospital or other
- Collaborators
- Libbs Farmacêutica LTDA
- Study start
- 7 Oct 2020 (actual)
- Primary completion
- Dec 2023 (estimated)
- Study completion
- Dec 2025 (estimated)
- First posted
- 10 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Phase I / II multicenter open-label clinical trial with prospective nonrandomized arm and historical control group
| Arm | Type | Receives |
|---|---|---|
| Experimental | Experimental | Drug: Methotrexate Injectable SolutionGVHD 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. |
| 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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%
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Methotrexate Injectable SolutionAlso: Fauldmetro [Libbs]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 | Drug | Experimental |
Primary outcome
Methotrexate dose to be used in the phase 2 (Phase 1)
Time frame: Day 30
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)
Time frame: Day 365
Relapse, grade 3-4 GVHD and 2014 NIH Chronic GVHD will be considered events, and non-relapse related mortality will be a competing event.
15 secondary outcomes
Overall survival
Time frame: Day 365
Cumulative incidence of neutrophil and platelet engraftment
Time frame: Day 30
Cumulative incidence of graft failure
Time frame: Day 30
Cumulative incidence of grade II-IV acute GVHD
Time frame: Day 100
Cumulative incidence of grade III-IV acute GVHD
Time frame: Day 100
Cumulative incidence of non-relapse/progression related mortality
Time frame: Day 365
Cumulative incidence of Chronic GVHD
Time frame: Day 365
Change in 36-Item Short Form Health Survey (SF-36)
Time frame: Baseline, Days 30, 90, 180, and 365
Change in the Functional Assessment of Cancer Therapy (FACT)-Bone Marrow Transplantation (BMT) Survey
Time frame: Baseline, Days 30, 90, 180, and 365
Frequency of Grade 3-5 adverse events
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
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Sep 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Giancarlo Fatobene, MD principal investigator
Hospital das Clínicas da Universidade de São Paulo
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Methotrexate Injectable Solution in people with Graft Vs Host Disease and Hematopoietic Neoplasm, run by University of Sao Paulo General Hospital at 4 sites in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Giancarlo Fatobene, MD (+551126617575, gian_fatobene@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Methotrexate dose to be used in the phase 2 (Phase 1) (time frame: Day 30). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Sep 2021.