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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
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Heart, Lung, and Blood Institute (NHLBI)

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.

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

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 345 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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


Arm Intervention/treatment
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:
  • Prograf®
  • FK506

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®




Primary Outcome Measures :
  1. Chronic GVHD-free, relapse-free survival (CRFS) probability [ Time Frame: 2 years ]
    Intention-to-treating CRFS as a time to event variable.


Secondary Outcome Measures :
  1. 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).

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Health-Related Quality of Life (HQL) [ Time Frame: Days 100, 180, 365, and 730 ]
    HQL will be measured post-transplant using patient-reported surveys.

  11. 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.

  12. 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.

  13. 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.



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Ages Eligible for Study:   1 Year to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. If it is known prior to enrollment that the hematopoietic stem cell product will need to be cryopreserved, the patient should not be enrolled.
  16. 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.

Information from the National Library of Medicine

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


Contacts
Contact: Dylan Maawby dmawby@emmes.com
Contact: Adam Mendizabal amendizabal@emmes.com

  Show 31 Study Locations
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
Investigators
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT02345850     History of Changes
Other Study ID Numbers: BMTCTN1301
U01HL069294 ( U.S. NIH Grant/Contract )
First Posted: January 26, 2015    Key Record Dates
Last Update Posted: January 31, 2018
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public
URL: https://biolincc.nhlbi.nih.gov/home/

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):
Acute Leukemia
Myelodysplasia
GVHD Prophylaxis
Chronic GVHD

Additional relevant MeSH terms:
Graft vs Host Disease
Myelodysplastic Syndromes
Preleukemia
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Cyclophosphamide
Methotrexate
Tacrolimus
Calcineurin Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors