Protocol Summary

Protocol No.: OCR13948

Sponsor Protocol No.: CTN 1301

Study Title
A Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus Host-Disease

Principal Investigator(s)
Wingard, John

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.

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.

Phase: Phase III

Age Group: Both

Scope: National

Active Comparator: Tacrolimus/Methotrexate Control Arm
Unmanipulated bone marrow graft with Tacrolimus/Methotrexate GVHD prophylaxis. Tac will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m2 for a maximum of 4 doses post-transplant.

Experimental: CD34 Selection Arm
Mobilized CD34-selected Peripheral Blood Stem Cell graft

Experimental: CD34 Selection Arm
Mobilized CD34-selected Peripheral Blood Stem Cell graft

Experimental: Post Transplant Cyclophosphamide
Unmanipulated Bone Marrow Graft with Cyclophosphamide

Detailed Eligibility
Males and females aged > 1.0 year and
Patients must have a related or unrelated donor as follows:
- 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. Related donor 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 donation1.
- 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 todonate bone marrow or peripheral blood stem cells .

Planned myeloablative conditioning regimen (see eligible regimens in Table 2.4)

Patients must have a related or unrelated that meets protocol eligibility criteria.

Organ function and lab values within protocol-defined limits.

Prior autologous or allogeneic hematopoietic stem cell transplant

Karnofsky or Lansky Performance Score
Active central nervous system (CNS) involvement by malignant cells

Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment

Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated

Patients seropositive for HIV-1 or -2

Patients seropositive for Human T-Lymphotrophic Virus (HTLV)-I or -II

Patients with active Hepatitis B or C viral replication by polymerase chain reaction (PCR)

Documented allergy to iron dextran or murine proteins

Women who are pregnant (positive serum or urine βHCG) or breastfeeding

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

History of uncontrolled autoimmune disease or on active treatment

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
Patient unable to comply with the treatment protocol including appropriate supportive care, follow-up and research tests

Applicable Disease Sites
Stem Cell Transplant

Participating Institutions
UF Gainesville : Meghan Vazquez

Meghan Vazquez, RN
Phone: +1 352-273-6843


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