Clinical trial NCT02345850: Calcineurin Inhibitor-Free Interventions BMT CTN 1301 for Prevention of Graft-versus-Host Disease (BMT CTN 1301)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Leukemia
Myelodysplasia
Keywords: Acute Leukemia
Myelodysplasia
GVHD Prophylaxis
Chronic GVHD
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
Collaborators: name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
First posted: 2015-01-26
Enrollment: 346
Sex: ALL
Minimum age (years): 1
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The study is designed as a three arm randomized Phase III, multicenter trial comparing two calcineurin inhibitor (CNI)-free strategies for Graft-versus-Host Disease (GVHD) prophylaxis to standard tacrolimus and methotrexate (Tac/Mtx) in patients with hematologic malignancies undergoing myeloablative conditioning hematopoietic stem cell transplantation.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Males and females aged ≥ 1.0 year and \< 66.0 years
2. Patients with acute leukemia in morphologic complete remission with or without hematologic recovery or with myelodysplasia (MDS) with no circulating blasts and with less than 5% blasts in the bone marrow. Patients with CMML must have a WBC count ≤ 10,000 cells/µL and \< 5% blasts in the marrow. Patients with ≥ 5% blasts due to a regenerating marrow must contact the protocol chairs for review.
3. Planned myeloablative conditioning regimen
4. Patients must have a related or unrelated donor as follows:

   1. Related donor must be an 8/8 match for human leukocyte antigen (HLA)-A, -B, and -C at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing. Pediatric related donors must weigh ≥ 25.0 kg., must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter, must be willing to (1) donate bone marrow and (2) receive G-CSF followed by donation of peripheral blood stem cells (product to be determined by randomization post enrollment) and must meet institutional criteria for donation.
   2. Unrelated donor must be an 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be medically eligible to donate according to National Marrow Donor Program (NMDP) (or equivalent donor search organization) criteria. At time of enrollment, the donor should not have any known preferences or contraindications to donate bone marrow or peripheral blood stem cells. (Selection of unrelated donors is to be performed according to institutional practice. It is recommended that the time from collection to initiation of the cell processing be considered when prioritizing donors, as data shows better results for CD34 selection when cell processing begins within 36 hours of the end of collection)
5. Cardiac function: Ejection fraction at rest ≥ 45.0% or shortening fraction of ≥ 27.0% by echocardiogram or radionuclide scan (MUGA).
6. Estimated creatinine clearance (for patients \> 12 years) greater than 50.0 mL/minute (using the Cockcroft-Gault formula and actual body weight); for pediatric patients (\> 1 year to 12 years), Glomerular Filtration Rate (GFR) estimated by the updated Schwartz formula ≥ 90.0 mL/min/1.73 m\^2. If the estimated creatinine clearance is \< 90 mL/min/1.73 m\^2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be \> 70.0 mL/min/1.73 m\^2.
7. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 50% (adjusted for hemoglobin), and forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) ≥ 50%; for children who are unable to perform for Pulmonary Function Tests (PFTs) due to age or developmental ability, there must be no evidence of dyspnea and no need for supplemental oxygen, as evidenced by O2 saturation ≥ 92% on room air.
8. Liver function: total bilirubin \< 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) \< 2.5x the upper limit of normal.
9. Signed informed consent.

Exclusion Criteria:

1. Prior autologous or allogeneic hematopoietic stem cell transplant
2. Karnofsky or Lansky Performance Score \< 70%
3. Active central nervous system (CNS) involvement by malignant cells
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 fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
6. Patients seropositive for HIV-1 or -2
7. Patients seropositive for Human T-Lymphotrophic Virus (HTLV)-I or -II
8. Patients with active Hepatitis B or C viral replication by polymerase chain reaction (PCR)
9. Documented allergy to iron dextran or murine proteins
10. Women who are pregnant (positive serum or urine βHCG) or breastfeeding
11. Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use 2 effective forms of birth control or abstinence for one year after transplantation
12. History of uncontrolled autoimmune disease or on active treatment
13. Patients with prior malignancies, except resected non-melanoma 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 will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
14. Patient unable to comply with the treatment protocol including appropriate supportive care, follow-up and research tests
15. Planned post-transplant maintenance therapy except for FLT3 inhibitors or TKIs must be declared prior to randomization.
16. If it is known prior to enrollment that the hematopoietic stem cell product will need to be cryopreserved, the patient should not be enrolled.
17. German centers only: Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or participation in any other interventional clinical study.

Primary outcomes:
measure: Chronic GVHD-free, Relapse-free Survival (CRFS) Probability
timeFrame: 2 years
Secondary outcomes:
measure: Percentage of Participants With Overall Survival (OS)
timeFrame: 2 Years
measure: Percentage of Participants With Relapse-free Survival
timeFrame: 2 Years
measure: Percentage of Participants With Treatment-related Mortality
timeFrame: 2 Years
measure: Participants With Immunosuppression-free Survival
timeFrame: 1 Year
measure: Percentage of Participants With Disease Relapse
timeFrame: 2 Years
measure: Percentage of Participants With Neutrophil Engraftment
timeFrame: Day 28
measure: Percentage of Participants With Platelet Recovery
timeFrame: Day 60
measure: Participants With Primary Graft Failure
timeFrame: Day 28
measure: Percentage of Participants With Secondary Graft Failure
timeFrame: 2 Years
measure: Percentage of Participants With Acute GVHD
timeFrame: Day 100
measure: Participants With Maximum Acute GVHD
timeFrame: Day 100
measure: Percentage of Participants With Chronic GVHD
timeFrame: 2 Years
measure: Percentage of Participants With Chronic GVHD-free Survival
timeFrame: 2 Years
measure: Participants With Grade ≥ 3 Toxicity
timeFrame: 2 Years
measure: Participants Infected Post Transplant
timeFrame: 2 Years
measure: Incidence of Infections
timeFrame: 2 years
measure: Health-Related Quality of Life (HQL) - Medical Outcomes Study Short Form 36 (SF36)
timeFrame: Baseline, Day 100, Day 180, 1 year, 2 years
measure: Health-Related Quality of Life (HQL) - Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT)
timeFrame: Baseline, Day 100, Day 180, 1 year, 2 years
measure: Health-Related Quality of Life (HQL) - MDASI
timeFrame: Baseline, Day 100, Day 180, 1 year, 2 years
measure: Health-Related Quality of Life (HQL) - PedsQL
timeFrame: Baseline, Day 100, Day 180, 1 year, 2 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
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
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Blood & Marrow Transplant Program at Northside Hospital
state: Georgia
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: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins/SKCCC
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: 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: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center/New York Presbyterian
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: Columbus
country: United States
facility: Ohio State/Arthur G. James Cancer Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and 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: Richmond
country: United States
facility: Virginia Commonwealth University/MCV Hospitals
state: Virginia
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
role: STUDY_DIRECTOR
References:
citation: Luznik L, Pasquini MC, Logan B, Soiffer RJ, Wu J, Devine SM, Geller N, Giralt S, Heslop HE, Horowitz MM, Jones RJ, Litzow MR, Mendizabal A, Muffly L, Nemecek ER, O'Donnell L, O'Reilly RJ, Palencia R, Schetelig J, Shune L, Solomon SR, Vasu S, Ho VT, Perales MA. Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies. J Clin Oncol. 2022 Feb 1;40(4):356-368. doi: 10.1200/JCO.21.02293. Epub 2021 Dec 2.
citation: Del Pozo Martin Y. 47th Annual Meeting of the EBMT. Lancet Haematol. 2021 May;8(5):e317-e318. doi: 10.1016/S2352-3026(21)00104-6. Epub 2021 Mar 31. No abstract available.