Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease (BMT CTN 1301)
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|ClinicalTrials.gov Identifier: NCT02345850|
Recruitment Status : Recruiting
First Posted : January 26, 2015
Last Update Posted : January 31, 2018
|Condition or disease||Intervention/treatment||Phase|
|Acute Leukemia Myelodysplasia||Procedure: Unmanipulated Bone Marrow Graft with Tacrolimus/Methotrexate Procedure: Mobilized CD34-selected Peripheral Blood Stem Cell graft Procedure: Unmanipulated Bone Marrow Graft with Cyclophosphamide Drug: Cyclophosphamide Drug: Tacrolimus Drug: Methotrexate||Phase 3|
Chronic Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) survivors; it occurs when the new cells from a transplant attack the recipient's body. The current standard GVHD prophylaxis regimen for patients with hematologic malignancies undergoing HSCT involves a combination of immunosuppressive agents given for the first 6 months after transplant. Often, patients develop GVHD and continue on these agents for much longer periods. The combination of calcineurin inhibitors (tacrolimus and cyclosporine A) with methotrexate (MTX) is the most common GVHD prophylaxis used worldwide in the context of myeloablative conditioning transplants. This regimen demonstrates better control of acute GVHD, but is less effective against chronic GVHD. Management of chronic GVHD remains a challenge and it has become a significant health problem in transplant survivors with more frequent use of mobilized peripheral blood stem cells. Additionally, several issues arise with the standard approach including various toxicity symptoms and side effects, increased risk of thrombotic microangiopathy due to CNI, no prevention of other infectious diseases, and no prevention for disease relapse.
This standard strategy of Tac/MTX will be used as a control in comparison to two other treatment plans both utilizing CNI-free methods: CD34 selected T-cell depletion in peripheral blood stem cell (PBSC) grafts, and infusion of bone marrow (BM) grafts followed by post-transplant Cyclophosphamide (PTCy). Study participants will be randomized to one of these three treatment arms.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||345 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease (BMT CTN #1301; Progress II)|
|Actual Study Start Date :||August 2015|
|Estimated Primary Completion Date :||September 2020|
|Estimated Study Completion Date :||September 2021|
Active Comparator: Tacrolimus/Methotrexate Control Arm
Unmanipulated bone marrow graft with Tacrolimus/Methotrexate GVHD prophylaxis. Tacrolimus will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant.
Cyclosporine may be substituted for tacrolimus if the patient is intolerant of tacrolimus or per institutional practice.
Procedure: Unmanipulated Bone Marrow Graft with Tacrolimus/Methotrexate
Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.Drug: Tacrolimus
Tacrolimus will be given orally or intravenously per institutional standards starting Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of tacrolimus (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD.
Other Names:Drug: Methotrexate
Methotrexate will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. Leucovorin rescue is allowed according to institutional practices.
Other Name: MTX
Experimental: CD34 Selection Arm
Mobilized CD34-selected Peripheral Blood Stem Cell graft
Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date.
Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD).
Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products.
Procedure: Mobilized CD34-selected Peripheral Blood Stem Cell graft
Mobilized CD34-selected PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.
Experimental: Post Transplant Cyclophosphamide
Unmanipulated Bone Marrow Graft with Cyclophosphamide
Procedure: Unmanipulated Bone Marrow Graft with Cyclophosphamide
Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.Drug: Cyclophosphamide
Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide.
Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).
Other Name: Cytoxan®
- Chronic GVHD-free, relapse-free survival (CRFS) probability [ Time Frame: 2 years ]Intention-to-treating CRFS as a time to event variable.
- Incidence of Acute GVHD [ Time Frame: Day 100 ]Cumulative incidences of grade II-IV and III-IV acute GVHD will be determined. Acute GVHD will be graded according to the BMT CTN Manual of Procedures (MOP).
- Immunosuppression-free Survival [ Time Frame: 1 Year ]Patients who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post HSCT are considered successes for this endpoint. Immune suppression is defined as any systemic agents used to control or suppress GVHD.
- Incidence of Neutrophil Engraftment [ Time Frame: Day 28 ]Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 500/mm^3 for three consecutive measurements on three different days.
- Incidence of Platelet Recovery [ Time Frame: Day 60 ]Platelet recovery is defined as the first day of a sustained platelet count >20,000/mm^3 with no platelet transfusion in the preceding seven days.
- Incidence of Disease Relapse [ Time Frame: 2 Years ]Relapse is defined by either morphological evidence of acute leukemia or MDS consistent with pre-transplant features, documented or not by biopsy. The event is defined as increase in size of prior sites of disease or evidence of new sites of disease, documented or not by biopsy.
- Treatment-related Mortality [ Time Frame: 2 Years ]An event for this endpoint is death without evidence of disease recurrence. Disease recurrence will be considered a competing event.
- Incidence of Grade ≥ 3 Toxicity [ Time Frame: 2 Years ]All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention arm.
- Incidence of Infections [ Time Frame: 2 Years ]The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm.
- Immune Reconstitution [ Time Frame: Days 35, 100, 180, and 365 ]Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19 and CD56 positive lymphocytes will be tabulated according to time from transplant.
- Health-Related Quality of Life (HQL) [ Time Frame: Days 100, 180, 365, and 730 ]HQL will be measured post-transplant using patient-reported surveys.
- Overall Survival (OS) [ Time Frame: 2 Years ]OS is defined as the time interval between date of transplant and death from any cause or for surviving patients, to last follow-up. The event for this endpoint is death from any cause.
- Relapse-free Survival [ Time Frame: 2 Years ]Relapse-free survival is the time from date of transplant to death or relapse, whichever comes first. The event for this endpoint is relapse or death. Patients alive and free from disease relapse will be censored at last follow-up.
- Chronic GVHD-free Survival [ Time Frame: 2 Years ]The event for this endpoint includes moderate to severe chronic GVHD according to NIH consensus criteria global score, or death by any cause.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02345850
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|Study Director:||Mary Horowitz, MD||Center for International Blood and Marrow Transplant Research|