Overview

This trial is active, not recruiting.

Conditions acute leukemia, chronic myelogenous leukemia, myelodysplasia, chronic lymphocytic leukemia, small lymphocytic lymphoma, lymphoma, b-cell, lymphoma, follicular, lymphoma, large b-cell, diffuse, hodgkin's lymphoma
Treatments tacrolimus (arm with methotrexate), tacrolimus (arm with mmf and cyclophosphamide), methotrexate (arm with maraviroc), methotrexate (arm with bortezomib), maraviroc, bortezomib, mycophenolate mofetil, cyclophosphamide
Phase phase 2
Target proteasome
Sponsor National Heart, Lung, and Blood Institute (NHLBI)
Collaborator Blood and Marrow Transplant Clinical Trials Network
Start date August 2014
End date August 2018
Trial size 279 participants
Trial identifier NCT02208037, BMTCTN1203, U01HL069294

Summary

Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free survival at one year after transplant compared to the current standard prophylaxis regimen.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose prevention
Arm
(Experimental)
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
tacrolimus (arm with methotrexate) Prograf®
Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg 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. The dose should be adjusted accordingly to maintain a suggested level 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.
methotrexate (arm with bortezomib) MTX
Methotrexate will be administered, per institutional practices, 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. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of bortezomib. 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.
bortezomib Velcade®
Bortezomib will be administered at the dose of 1.3 mg/m2 based upon actual body weight (ABW) as an approximately 3-5 second IV push on Days +1, +4, and +7 after hematopoietic stem cell infusion. There must be at least 72 hours between each dose of bortezomib. Subcutaneous administration of bortezomib is not allowed on this protocol.
(Experimental)
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
tacrolimus (arm with methotrexate) Prograf®
Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg 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. The dose should be adjusted accordingly to maintain a suggested level 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.
methotrexate (arm with maraviroc) MTX
Methotrexate will be administered, per institutional practices, 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. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of maraviroc. 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.
maraviroc Selzentry®
Maraviroc will be dosed at 300 mg orally twice a day and will start on Day -3 prior to hematopoietic stem cell infusion, and continue until Day 30 post HSCT. If the patient requires a two-day stem cell infusion, maraviroc treatment will end 30 days after the first infusion day.
(Experimental)
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
tacrolimus (arm with mmf and cyclophosphamide) Prograf®
Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day +5. 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 HSCT 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 HSCT if there is no evidence of active GVHD.
mycophenolate mofetil Cellcept®
MMF will be given at a dose of 15 mg/kg three times a day (TID) based upon ABW 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.
cyclophosphamide Cytoxan®
Hydration prior to cyclophosphamide may be given according to institutional standards. 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 ideal body weight (IBW); if ABW < IBW, use ABW] will be given on Day 3 post-transplant (between 60 and 72 hours after the start of the HSCT) 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).

Primary Outcomes

Measure
GVHD/progression/relapse after Hematopoietic Stem Cell Transplant
time frame: 1 Year

Secondary Outcomes

Measure
Incidence of Acute GVHD Grades II-IV
time frame: Through 180 days post-HSCT
Incidence of Chronic GVHD
time frame: 1 Year
Immunosuppression-free Survival Rate
time frame: 1 Year
Hematologic Recovery (Neutrophils and Platelets)
time frame: Through Day 100 post-HSCT
Donor Cell Engraftment
time frame: Through Day 100 post-HSCT
Immune Reconstitution
time frame: 1 Year
Disease Relapse or Progression
time frame: 1 Year
Cumulative Incidence of Transplant-Related Mortality
time frame: Up to One Year
Frequency of Grade 3 or Greater Toxicities
time frame: 1 Year
Incidence of Grade 2 and 3 Infections
time frame: 1 Year
Overall Survival
time frame: 1 Year
Disease-free Survival
time frame: 1 Year
GVHD Survival
time frame: 1 Year

Eligibility Criteria

Male or female participants from 18 years up to 75 years old.

Inclusion Criteria: 1. Age 18-75 years (patient is older than 18.0 and less than 76.0 years old) 2. Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow. 3. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell, Hodgkin's Lymphoma,or mantle cell lymphoma with chemosensitive disease at time of transplantation 4. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a) 5. Patients must have a related or unrelated peripheral blood stem cell donor as follows: 1. Sibling donor must be a 6/6 match for 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 be medically cleared to donate stem cells according to National Marrow Donor Program (NMDP) criteria. 6. Cardiac function: Ejection fraction at rest ≥ 45% 7. Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight) 8. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50% 9. Liver function: total bilirubin < 1.5 x the upper limit of normal and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5x the upper normal limit. Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value of 1.5x the upper limit of normal. 10. Female subjects (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). 11. Male subjects (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. 12. Signed informed consent Exclusion Criteria: 1. Prior allogeneic transplant 2. Karnofsky 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 with transformed lymphoma (e.g., Richters transformation arising in follicular lymphoma or chronic lymphocytic leukemia) 7. Patients seropositive for the human immunodeficiency virus (HIV) 8. Patient with active Hepatitis B or C determined by serology and/or nucleic acid amplification tests (NAAT) 9. Patients with hypersensitivity to bortezomib, boron or mannitol 10. Patients with ≥ grade 2 sensory peripheral neuropathy 11. Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant. 12. Female patients who are lactating or pregnant 13. Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study 14. Patients with prior malignancies except resected basal cell carcinoma 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. 15. Planned use of anti-thymocyte globulin (ATG) or alemtuzumab in conditioning regimen. 16. Planned post-transplant therapy, including use of tyrosine-kinase inhibitors (TKI). 17. Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes (CYP3A4), or glutathione S-transferases involved in bortezomib and/or busulfan metabolism during day -5 through day +7. It is acceptable to use alternative non-interacting medications during this period, and then resume prior medications. 18. Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including Chronic myelomonocytic leukemia (CMML), with evidence of active myeloproliferative features or myelofibrosis in the background.

Additional Information

Official title A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN #1203; Progress I)
Description GVHD is a complication that can occur after a bone marrow or stem cell transplant. The transplant recipient's body is attacked by the newly introduced cells. Only about 40% of patients with acute GVHD have durable responses when treated with corticosteroid therapy. A strategy that helps fewer people suffer from GVHD, without other adverse effects, would be an effective approach to improve survival after allogeneic transplantation. GVHD incidence can be decreased with various treatment plans. Early transplants were done using post-transplant methotrexate to prevent GVHD. Another drug, cyclosporine, was later shown to work better than methotrexate. Then doctors discovered that the combined use of cyclosporine and methotrexate worked even better than either agent alone. More recently, other calcineurin-inhibitors, such as tacrolimus have been developed as GVHD prophylactic agents due to favorable toxicity profiles in comparison with cyclosporine. Studies have been conducted to compare available treatment combinations for related and unrelated donors. The combination of tacrolimus/methotrexate remains a standard for GVHD prophylaxis. However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy). This randomized Phase II clinical trial will compare each intervention arm with a Tac/MTX control. This study will enroll people who have a cancer of the blood or lymph glands and a stem cell transplant is a treatment option. The study will take at least two years and will include 270 participants - 90 participants in each of three treatment groups. The purpose of this study is to compare three combinations of medications to see whether one or more of them are better than the current standard of care (Tacrolimus/Methotrexate) to prevent GVHD.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by National Heart, Lung, and Blood Institute (NHLBI).