TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801)

Study Overview
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Brief Summary
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1703: The study is designed as a randomized, phase III, multicenter trial comparing two acute graft-versus-host disease (aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX) versus post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in the setting of reduced intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation. 1801: The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Detailed Description
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1703: Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; 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. The standard strategy of Tacrolimus/Methotrexate will be used as a control arm in comparison to one other treatment plan utilizing Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide. Study participants will receive an infusion of mobilized peripheral blood stem cell grafts on both arms. Study participants will be randomized to one of these two treatment arms. 1801: A relationship between the intestinal microbiota and graft-versus-host disease (GVHD) has long been appreciated but is still not well understood. Mice transplanted in germ-free conditions or treated with gut-decontaminating antibiotics developed less severe GVHD. Clinical studies initially suggested a benefit from near-total bacterial decontamination, but later showed no clear benefit and this approach was discontinued in the early 1990s. Partial gut decontamination continues to be practiced at many centers. More recently, the advent of next-generation sequencing (NGS) has resulted in cheaper and easier characterization of complex microbial mixtures. This has led to a renewed interest in evaluating the relationship between the microbiota and human health and disease, including recipients of hematopoietic cell transplantation (HCT). Similarly, NGS has also contributed to significant advancements in the investigator's understanding of immune reconstitution in HCT patients and how this may impact clinica outcomes. The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Official Title
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A Randomized, Multicenter, Phase III Trial of Tacrolimus/Methotrexate Versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation (BMT CTN 1703; Progress III); Companion Study: Microbiome and Immune Reconstitution in Cellular Therapies and Hematopoietic Stem Cell Transplantation (BMT CTN 1801; Mi-Immune)

Conditions
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Acute Leukemia, Chronic Myelogenous Leukemia (CML), Myelodysplasia, Lymphoma

Intervention / Treatment
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* Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate
* Drug: Tacrolimus
* Drug: Methotrexate
* Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18.0 years or older at the time of enrollment on Segment A Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 5% blasts in the bone marrow Patients with myelodysplasia/chronic myelomonocytic leukemia with no circulating blasts and with less than 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with <5% vs. 5-10% blasts in this disease) Patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma with chemosensitive disease at time of transplantation Patients with lymphoma [follicular lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma] with chemosensitive disease at the time of transplantation Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a) Patients must have a related or unrelated peripheral blood stem cell donor as follows: Sibling donor must be a 6/6 match for Human Leukocyte Antigen-A (HLA)-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells and meet National Marrow Donor Program (NMDP) criteria for donation. Cardiac function: Left ventricular ejection fraction at least 45% Estimated creatinine clearance acceptable per institutional guidelines Pulmonary function: Diffusing capacity of lung for carbon monoxide (DLCO) corrected for hemoglobin at least 40% and forced expiratory volume at one second (FEV1) predicted at least 50% Liver function acceptable per institutional guidelines Karnofsky Performance Score at least 60% Female patients (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two (2) effective methods of contraception at the same time, or agree to completely abstain from heterosexual intercourse, from the time of signing the informed consent through 12 months post-transplant (see Section 2.6.4 for definition of postmenopausal) Male patients (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception (see Section 2.6.4 for list of barrier methods), or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant Plans for the use of post-transplant maintenance therapy must be disclosed upon enrollment and must be used irrespective of the outcome of the randomization. Please note that THIS DOES NOT INCLUDE INVESTIGATIONAL AGENTS and maintenance therapy with investigational treatment requires approval by the study chairs. Voluntary written consent obtained prior to the performance of any study-related procedure that is not a part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. Exclusion Criteria: Prior allogeneic transplant Active central nervous system (CNS) involvement by malignant cells Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including chronic myelomonocytic leukemia (CMML) Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment. Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated Patients seropositive for human immunodeficiency virus (HIV) with detectable viral load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia. Female patients who are pregnant (as per institutional practice) or lactating Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study Patients with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously must be reviewed and approved by the Protocol Officer or Chairs. Planned use of antithymocyte globulin (ATG) or alemtuzumab in conditioning regimen

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks of random sizes.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tacrolimus/Methotrexate<br>Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate | Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate<br>* Mobilized 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.<br>* Other names: HSCT;Drug: Tacrolimus<br>* Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting on 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 per institutional guidelines with a suggested range of 5-15. If patients are on medications which alter the metabolism of tacrolimus (e.g.concurrent CYP3A4 inhibitors), 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 HCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices and patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD.<br>* Other names: FK506;Drug: Methotrexate<br>* Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. Methotrexate should be dose reduced, given with leucovorin rescue, or held for complications such as severe mucositis per institutional guidelines.<br>* Other names: MTX;|
| Experimental: Tacrolimus/MMF/PTCY<br>Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide | Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide<br>* Mobilized 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.<br>* Other names: HSCT;Drug: Tacrolimus<br>* Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting Day +5. Starting tacrolimus dose can be modified to account for possible drug interactions (e.g. concurrent CYP3A4 inhibitor use) according to institutional guides. Serum levels of tacrolimus will be measured at Day +7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD<br>* Other names: FK506;Drug: Mycophenolate Mofetil<br>* MMF will be given at a dose of 15 mg/kg/dose ter in die (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day +5 and discontinue after the last dose on Day +35, or may be continued if active GVHD is present.<br>* Other names: MMF;Drug: Cyclophosphamide<br>* Cyclophosphamide [50 mg/kg ideal body weight (IBW); if actual body weight (ABW) < IBW, use ABW] will be given on Day +3 (between 60 and 72 hours after the start of the PBSC 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).<br>* Other names: Cytoxan®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GVHD-free, Relapse-free survival (GRFS) probability | The primary endpoint is GRFS as a time to event endpoint from the time of randomization. All transplanted patients will be followed for the primary endpoint for one year; however the primary endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the intent-to-treat principle. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute GVHD | Incidence of acute GVHD grade II-IV and grade III-IV at Days 100, 180 and 1 year will be estimated with 95% confidence intervals for each treatment group - using the cumulative incidence estimate, treating death prior to aGVHD as a competing event. | Days 100, 180, and 1 year | 
| Chronic GVHD | Incidence of chronic GVHD at 1 year will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death prior to chronic GVHD as a competing event. | 1 year | 
| Immunosuppression-free Survival | Proportions of patients alive, relapse free, and off immune suppression at 1 year will be described for each treatment group, along with 95% confidence intervals. | 1 year | 
| Hematologic Recovery | Probabilities of neutrophil recovery by Day 28 and Day 100 will be described with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death as a competing event. | Days 28 and 100 | 
| Donor Cell Engraftment | Donor chimerism at Day 28 and Day 100 after transplantation in each of the randomized treatment arms will be described numerically as median and range for those evaluable as well as according to proportions with full (>95% donor cell), mixed (5.0-94.9% donor cells), graft rejection (<5%), or death prior to assessment of donor chimerism. | Days 28 and 100 | 
| Disease Relapse or Progression | Incidence of disease relapse or progression at 1 year will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death prior to disease relapse as a competing event. | 1 year | 
| Transplant-related Mortality | Incidence of transplant-related mortality (TRM) at Days 100, 180 and 1 year will be estimated for each treatment group using the cumulative incidence estimate, treating disease relapse or progression as a competing event. | Days 100, 180 and 1 year | 
| Toxicity grade over time | All Grade 3-5 toxicities will be tabulated by grade for each randomized treatment arm, by type of toxicity as well as the peak grade overall. Toxicity frequencies up to 1 year will be described for each time interval as well as cumulative over time. | 1 year | 
| Infections | The number of infections and the number of patients experiencing infections will be tabulated for each randomized treatment arm by type of infection, severity, and time period after transplant. | 1 year | 
| Disease-free Survival | Kaplan-Meier curves will be constructed to estimate 1 year disease free survival probabilities for each treatment group. | 1 year | 
| Overall Survival | Kaplan-Meier curves will be constructed to estimate 1 year overall survival probabilities for each treatment group. | 1 year | 
| Post-Transplant Lymphoproliferative Disease (PTLD) | Probabilities of PTLD at 1-year post transplant will be described with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death as a competing event. | 1 year | 
| Patient-Reported Outcomes (PRO) | Patient-Reported Outcomes will be measured at baseline then at Days 100, 180 and one year post HCT. Using a repeated measures model, we will compute PRO composite scores and compare treatments after adjustment for baseline characteristics as described for the primary endpoint. | Days 100, 180 and 1 year | 
| Diversity of Immune Repertoire | To study the diversity of the immune repertoire post-transplant and correlate with clinical outcomes, as well as study the impact on immune recovery of the method of GVHD prophylaxis and other patient and transplant factors. | 3, 6, 12, and 24 Months | 
| Diversity and Composition of the Gut Microbiome | To study the diversity and composition of the gut microbiome post-transplant and correlate with clinical outcomes, as well as study the impact on the microbiome of the method of GVHD prophylaxis and other patient and transplant factors. | 3, 6, 12, and 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Leukemia, Chronic Myelogenous Leukemia (CML), Myelodysplasia (MDS), Lymphoma, GVHD prophylaxis, Acute GVHD