Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)

Phase 2

Completed

• Conditions: Acute Leukemia; Chronic Myelogenous Leukemia; Myelodysplasia; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, B-Cell; Lymphoma, Follicular; Hodgkin's Lymphoma
• Interventions: Drug: Tacrolimus (ARM with Methotrexate); Drug: Tacrolimus (ARM with MMF and Cyclophosphamide); Drug: Methotrexate (ARM with Maraviroc); Drug: Methotrexate (ARM with Bortezomib); Drug: Mycophenolate mofetil; Drug: Bortezomib; Drug: Maraviroc; Drug: Cyclophosphamide

• Registration Number: NCT02208037
• Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Brief 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.

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.

Study Timeline

• Study Start: 2014-08
• Study First Submitted: 2014-08-01
• Study First Submitted QC: 2014-08-01
• Study First Posted: 2014-08-04
• Primary Completion: 2017-10
• Study Completion: 2017-10
• Status Verified: 2017-12
• Results First Submitted: 2018-12-04
• Results First Submitted QC: 2019-01-02
• Last Update Submitted: 2019-01-02
• Results First Posted: 2019-01-23
• Last Update Posted: 2019-01-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 279

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tacrolimus/Methotrexate/Maraviroc	Tacrolimus (ARM with Methotrexate)	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
Tacrolimus/Methotrexate/Bortezomib	Tacrolimus (ARM with Methotrexate)	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
Tacrolimus/Methotrexate/Maraviroc	Methotrexate (ARM with Maraviroc)	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
Tacrolimus/Methotrexate/Bortezomib	Methotrexate (ARM with Bortezomib)	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
Tacrolimus/MMF/Cyclophosphamide	Tacrolimus (ARM with MMF and Cyclophosphamide)	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
Tacrolimus/Methotrexate/Bortezomib	Bortezomib	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
Tacrolimus/Methotrexate/Maraviroc	Maraviroc	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
Tacrolimus/MMF/Cyclophosphamide	Mycophenolate mofetil	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
Tacrolimus/MMF/Cyclophosphamide	Cyclophosphamide	Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS)	1 Year Post-transplant	GRFS is defined as being free of grade III-IV acute GVHD onset, chronic GVHD onset requiring systemic immunosuppressive therapy, disease relapse or progression, and death from any cause.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Grade II-IV Acute GVHD	Day 180 Post-transplant	Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash; 1. Rash \<25% of body surface area; 2. Rash on 25-50% of body surface area; 3. Rash on \> 50% of body surface area; 4. Generalized erythroderma with bullous formation; Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL; 1. 2-3 mg/dL; 2. 3.01-6 mg/dL; 3. 6.01-15.0 mg/dL; 4. \>15 mg/dL; GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day; 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD; 2. Diarrhea 1000-1499 mL/day; 3. Diarrhea \>1500 mL/day; 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.; GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
Percentage of Participants With Grade III-IV Acute GVHD	Day 180 Post-transplant	Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash; 1. Rash \<25% of body surface area; 2. Rash on 25-50% of body surface area; 3. Rash on \> 50% of body surface area; 4. Generalized erythroderma with bullous formation; Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1.2-3 mg/dL 2.3.01-6 mg/dL 3.6.01-15.0 mg/dL 4.\>15 mg/dL; GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day; 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD; 2. Diarrhea 1000-1499 mL/day; 3. Diarrhea \>1500 mL/day; 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.; GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
Percentage of Participants With Chronic GVHD	1 Year Post-transplant	Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification.
Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy	1 Year Post-transplant	Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. This endpoint considers the occurrence of chronic GVHD that necessitated initiation of immunosuppressive therapy for treatment.
Percentage of Participants With Disease Relapse or Progression	1 Year Post-transplant	Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS consistent with pretransplant features, or radiologic evidence of lymphoma. Progression of disease applies to patients with lymphoproliferative diseases (lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation and is defined as increase in size of prior sites of disease or evidence of new sites of disease.
Percentage of Participants With Transplant-Related Mortality (TRM)	1 Year Post-transplant	TRM is defined as death without prior disease relapse or progression.
Percentage of Participants With Disease-free Survival	1 Year Post-transplant	Disease-free survival is defined as being alive and free of disease relapse or progression.
Percentage of Participants With GVHD-free Survival	1 Year Post-transplant	GVHD-free survival is defined as being alive without previous onset of Grade III-IV acute GVHD or chronic GVHD requiring immunosuppressive therapy.
Percentage of Participants With Overall Survival	1 Year Post-transplant
Percentage of Participants With Neutrophil Recovery	Days 28 and 100 Post-transplant	Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 500/mm\^3 for three consecutive measurements on three different days.
Percentage of Participants With Platelet Recovery	Days 60 and 100 Post-transplant	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.
Donor Cell Engraftment	Days 28 and 100 Post-transplant	Donor cell engraftment will be assessed with donor/recipient chimerism. Chimerism may be evaluated in bone marrow, whole blood, or CD3 fractions. Full donor chimerism is defined as the presence of ≥ 95% of donor cells as a proportion of total cells. Mixed chimerism is defined as the presence of donor cells, as a proportion of total cells, of \< 95% but \> 5% in the bone marrow or peripheral blood. Full and mixed chimerism will be evidence of donor cell engraftment. Donor cells of ≤ 5% will be considered as graft rejection.
Primary Cause of Death	1 Year Post-transplant

Trial Locations

Locations (30)

University of Florida College of Medicine (Shands); 🇺🇸 Gainesville, Florida, United States

Virginia Commonwealth University MCV Hospitals; 🇺🇸 Richmond, Virginia, United States

University of North Carolina Hospital at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

University of Iowa Hospitals and Clinics; 🇺🇸 Iowa City, Iowa, United States

Stanford Hospital and Clinics; 🇺🇸 Stanford, California, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

Ohio State/Arthur G. James Cancer Hospital; 🇺🇸 Columbus, Ohio, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

BMT Program at Northside Hospital; 🇺🇸 Atlanta, Georgia, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

University of Kansas Hospital; 🇺🇸 Westwood, Kansas, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Dana Farber Cancer Institute/Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

University Hospitals of Cleveland/Case Western; 🇺🇸 Cleveland, Ohio, United States

University of Pennsylvania Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Memorial Sloan-Kettering Cancer Center; 🇺🇸 Manhattan, New York, United States

Washington University/Barnes Jewish Hospital; 🇺🇸 Saint Louis, Missouri, United States

Dana Farber Cancer Institute/Brigham & Women's; 🇺🇸 Boston, Massachusetts, United States

H. Lee Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

Karmanos Cancer Institute/BMT; 🇺🇸 Detroit, Michigan, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

University of Texas/MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Texas Transplant Institute; 🇺🇸 San Antonio, Texas, United States

University of Utah Med School; 🇺🇸 Salt Lake City, Utah, United States