Clinical trial NCT03959241: TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Leukemia
Chronic Myelogenous Leukemia (CML)
Myelodysplasia
Lymphoma
Keywords: Acute Leukemia
Chronic Myelogenous Leukemia (CML)
Myelodysplasia (MDS)
Lymphoma
GVHD prophylaxis
Acute GVHD
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
name: National Marrow Donor Program
First posted: 2019-05-22
Enrollment: 431
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks of random sizes.
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age 18.0 years or older at the time of enrollment on Segment A
2. Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 5% blasts in the bone marrow
3. 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)
4. Patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma with chemosensitive disease at time of transplantation
5. 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
6. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)
7. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

   1. 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.
   2. 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.
8. Cardiac function: Left ventricular ejection fraction at least 45%
9. Estimated creatinine clearance acceptable per institutional guidelines
10. 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%
11. Liver function acceptable per institutional guidelines
12. Karnofsky Performance Score at least 60%
13. 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)
14. 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
15. 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.
16. 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:

1. Prior allogeneic transplant
2. Active central nervous system (CNS) involvement by malignant cells
3. Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including chronic myelomonocytic leukemia (CMML)
4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
5. Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
6. Patients seropositive for human immunodeficiency virus (HIV) with detectable viral load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible.
7. 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.
8. Female patients who are pregnant (as per institutional practice) or lactating
9. Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
10. 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.
11. Planned use of antithymocyte globulin (ATG) or alemtuzumab in conditioning regimen

Primary outcomes:
measure: Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) at One Year
timeFrame: 1 year post randomization
Secondary outcomes:
measure: Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant
timeFrame: Days 100 post-transplant
measure: Participants With Maximum Acute GVHD at One Year Post-transplant
timeFrame: One year post-transplant
measure: Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant
timeFrame: Day 100 post-transplant
measure: Participants With Maximum Stage of Upper GI at Day 100 Post-transplant
timeFrame: Day 100 post-transplant
measure: Percentage of Participants With Chronic GVHD Post-transplant
timeFrame: 6, 12 months post-transplant
measure: Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant
timeFrame: 12 months post-transplant
measure: Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant
timeFrame: 1 year post-transplant
measure: Percentage of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant
timeFrame: 1 year post-transplant
measure: Percentage of Participants With Neutrophil Recovery Post-transplant
timeFrame: Days 28 and day 100 post-transplant
measure: Percentage of Participants With Platelet Recovery Post-transplant
timeFrame: Day 60 and Day 100 post-transplant
measure: Percentage of Participants With Lymphocyte Recovery Post-transplant
timeFrame: Day 60, Day 100, 6 Months, and 1 year post-transplant
measure: Number of Participants With Each Level of Donor Cell Engraftment Post-transplant
timeFrame: Day 28 and Day 100 post-transplant
measure: Summary Statistics for Donor Chimerism
timeFrame: Day 28 and Day 100 post-transplant
measure: Percentage of Participants With Disease Relapse at 1 Year Post-transplant
timeFrame: 1 year post-transplant
measure: Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant
timeFrame: Days 100, 180 and 1 year post-transplant
measure: Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant
timeFrame: 1 year post-transplant
measure: Frequencies of Infections Categorized by Infection Type
timeFrame: 1 year post-transplant
measure: Number of Participants With Grade 2 and 3 Infections
timeFrame: 1 year post-transplant
measure: Percentage of Participants With Grade 2 and 3 Infections
timeFrame: 6 months and 1 year post-transplant
measure: Percentage of Participants With CMV at Day 100 Post-transplant
timeFrame: Day 100 post-transplant
measure: Percentage of Participants With Disease-Free Survival (DFS) at 1 Year Post-transplant
timeFrame: 1 year post-transplant
measure: Percentage of Participants With Overall Survival (OS) at 1 Year Post-transplant
timeFrame: 1 year post-transplant
measure: Percentage of Participants With Lymphoproliferative Disease (PTLD) at 1 Year Post-Transplant
timeFrame: 1 year Post-Transplant
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Blood & Marrow Transplant Program at Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Indiana BMT - St. Francis Hospital
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute/Brigham & Women's
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute/Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute, Children's Hospital of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University/Barnes Jewish Hospital
state: Missouri
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland/Case Western
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State/Arthur G. James Cancer Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: Baylor College of Medicine/The Methodist Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Research Center
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University, MCV Hospital
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital & Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD, MS
role: STUDY_DIRECTOR
References:
citation: Bolanos-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, Elmariah H, Rezvani AR, Gooptu M, Larkin KT, Shaffer BC, El Jurdi N, Loren AW, Solh M, Hall AC, Alousi AM, Jamy OH, Perales MA, Yao JM, Applegate K, Bhatt AS, Kean LS, Efebera YA, Reshef R, Clark W, DiFronzo NL, Leifer E, Horowitz MM, Jones RJ, Holtan SG; BMT CTN 1703 Investigators. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. doi: 10.1056/NEJMoa2215943.