Trial record 3 of 9 for:    GVHD, John Koreth

A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (1203)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2014 by Medical College of Wisconsin
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
Information provided by (Responsible Party):
Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT02208037
First received: August 1, 2014
Last updated: NA
Last verified: August 2014
History: No changes posted
  Purpose

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.


Condition Intervention Phase
Acute Leukemia, Chronic Myelogenous Leukemia, Myelodysplasia
Chronic Lymphocyte Leukemia/Small Lymphocytic Lymphoma
Lymphoma, B-Cell
Lymphoma, Follicular
Lymphoma, Large B-Cell, Diffuse
Drug: Tacrolimus
Drug: Methotrexate
Drug: Bortezomib
Drug: Maraviroc
Drug: Mycophenolate mofetil
Drug: Cyclophosphamide
Drug: Tacrolimus (a)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN #1203)

Resource links provided by NLM:


Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • GVHD/progression/relapse after Hematopoietic Stem Cell Transplant [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
    Compare one year GVHD/relapse/progression-free survival after HSCT between each of three novel GVHD prophylaxis approaches and a contemporary control.


Secondary Outcome Measures:
  • Incidence of Acute GVHD Grades II-IV [ Time Frame: Through 180 days post-HSCT ] [ Designated as safety issue: Yes ]
  • Incidence of Chronic GVHD [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  • Immunosuppression-free Survival Rate [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  • Hematologic Recovery (Neutrophils and Platelets) [ Time Frame: Through Day 100 post-HSCT ] [ Designated as safety issue: No ]
  • Donor Cell Engraftment [ Time Frame: Through Day 100 post-HSCT ] [ Designated as safety issue: No ]
  • Immune Reconstitution [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  • Disease Relapse or Progression [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  • Cumulative Incidence of Transplant-Related Mortality [ Time Frame: Up to One Year ] [ Designated as safety issue: Yes ]
  • Frequency of Grade 3 or Greater Toxicities [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  • Incidence of Grade 2 and 3 Infections [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  • Overall Survival [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  • Disease-free Survival [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  • GVHD Survival [ Time Frame: 1 Year ] [ Designated as safety issue: No ]

Estimated Enrollment: 270
Study Start Date: August 2014
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tacrolimus/Methotrexate/Bortezomib
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
Drug: Tacrolimus
Tacrolimus will be given per institutional practices, 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.
Drug: Methotrexate
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.
Drug: Bortezomib
Bortezomib will be administered at the dose of 1.3 mg/m2 (based upon actual body weight) 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: Tacrolimus/Methotrexate/Maraviroc
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
Drug: Tacrolimus
Tacrolimus will be given per institutional practices, 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.
Drug: Methotrexate
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.
Drug: Maraviroc
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: Tacrolimus/Mycophenolate Mofetil/Cyclophosphamide
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
Drug: Mycophenolate mofetil
MMF will be given at a dose of 15 mg/kg TID (based upon actual body weight) 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.
Drug: Cyclophosphamide

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 IBW; if ABW < IBW, use ABW] will be given on Day 3 post-transplant (between 60 and 72 hours after the start of the PBSC 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).

Drug: Tacrolimus (a)
Tacrolimus will be given per institutional practices, orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day +5. 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.

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18-75 years
  • Patients with acute leukemia, chronic myelogenous leukemia and myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow
  • Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell or mantle cell lymphoma with chemosensitive disease at time of transplantation
  • Planned reduced intensity conditioning regimen
  • Patients must have a related or unrelated peripheral blood stem cell donor as follows:
  • 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.
  • 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 eligible to donate stem cells according to NMDP criteria.
  • Cardiac function: Ejection fraction at rest >45%
  • Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
  • Pulmonary function: DLCO ≥40% (adjusted for hemoglobin) and FEV1≥50%
  • Liver function: total bilirubin < 1.5 x the upper limit of normal and ALT/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.
  • 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.
  • Male subjects (even if surgically sterilized), of partners of women of childbearing potential must agree to one of the following: practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post transplant.
  • Signed informed consent

Exclusion Criteria:

  • Prior allogeneic transplant
  • Karnofsky Performance Score < 70%
  • Active 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 with transformed lymphoma (e.g., Richters transformation arising in follicular lymphoma or chronic lymphocytic leukemia).
  • Patients seropositive for the human immunodeficiency virus (HIV).
  • Patient with active Hepatitis B or C determined by serology and/or NAAT.
  • Patients with hypersensitivity to bortezomib, boron or mannitol.
  • Patients with >/= grade 2 sensory peripheral neuropathy.
  • 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 or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant
  • Female patients who are lactating or pregnant
  • Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • 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.
  • Planned use of ATG or alemtuzumab in conditioning regimen.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02208037

  Show 29 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
Blood and Marrow Transplant Clinical Trials Network
Investigators
Study Chair: Javier Bolaños -Meade, MD Johns Hopkins University
Study Chair: John Koreth, MBBS Dana-Farber Cancer Institute
Study Chair: Ran Reshef, MD University of Pennsylvania
  More Information

No publications provided

Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT02208037     History of Changes
Other Study ID Numbers: BMTCTN1203
Study First Received: August 1, 2014
Last Updated: August 1, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Medical College of Wisconsin:
Acute Lymphoblastic Leukemia/Lymphoma
Acute Myelogenous Leukemia
Mantel-Cell Lymphoma
Hematopoietic Transplant
GVHD Prophylaxis

Additional relevant MeSH terms:
Graft vs Host Disease
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma
Leukemia
Lymphoma, B-Cell
Myelodysplastic Syndromes
Preleukemia
Lymphoma, Follicular
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Leukemia, B-Cell
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Precancerous Conditions
Cyclophosphamide
Methotrexate
Tacrolimus
Mycophenolate mofetil
Bortezomib
Mycophenolic Acid

ClinicalTrials.gov processed this record on October 01, 2014