Tacrolimus, Bortezomib, & Thymoglobulin in Preventing Low Toxicity GVHD in Donor Blood Stem Cell Transplant Patients

Study Overview
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Brief Summary
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This phase II trial studies how well tacrolimus, bortezomib, and anti-thymocyte globulin (thymoglobulin) work in preventing low toxicity graft versus host disease (GVHD) in patients with blood cancer who are undergoing donor stem cell transplant. Tacrolimus and anti-thymocyte globulin may reduce the risk of the recipient's body rejecting the transplant by suppressing the recipient's immune system. Giving bortezomib after the transplant may help prevent GVHD by stopping the donor's cells from attacking the recipient. Giving tacrolimus, bortezomib, and anti-thymocyte globulin may be a better way to prevent low toxicity GVHD in patients with blood cancer undergoing donor stem cell transplant.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine a composite end point of alive and severe acute GVHD free at 6 months following human leukocyte antigen (HLA) matched related or unrelated donor hematopoietic peripheral blood transplant in patients with hematologic malignancies who receive the immunosuppressive combination tacrolimus, bortezomib, anti-thymocyte globulin (TBT) as GVHD prophylaxis. II. To determine the safety of this combination in the first six months post-transplant. SECONDARY OBJECTIVES: I. To determine the cumulative incidence of grade III-IV aGVHD. II. To determine incidence and severity of chronic GVHD. III. To determine disease relapse or progression overall and disease free survival at one year. OUTLINE: Patients receive tacrolimus intravenously (IV) on day -3 through day 180. Patients may receive tacrolimus orally (PO) later at the doctor's discretion. Patients receive anti-thymocyte globulin IV on days -3, -2, and -1 and bortezomib IV on day 0 and day 3. Patients undergo allogeneic bone marrow transplant on day 0. After completion of study treatment, patients are followed up for 6 months and then periodically for up to 2 years.

Official Title
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Phase II Trial of Low Toxicity GVHD Prevention and Enhanced Immune Recovery With Tacrolimus, Bortezomib and Thymoglobulin® TBT

Conditions
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Acute Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Graft Versus Host Disease, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Myelodysplastic Syndrome, Myelofibrosis, Myeloproliferative Neoplasm, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Biological: Thymoglobulin
* Drug: Bortezomib
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with acute leukemia, chronic myelogenous leukemia, myeloproliferative disorder and myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow within 4 weeks of the start of transplant conditioning regimen Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma; follicular, marginal zone, diffuse large B-cell or mantle cell lymphoma with chemo-sensitive disease at time of transplant Patients must have a related or unrelated peripheral blood stem cell donor; sibling donor must be a 6/6 match for human leukocyte antigen (HLA)-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using deoxyribonucleic acid (DNA)-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation; unrelated donor must be 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 National Marrow Donor Program (NMDP) criteria Cardiac function: ejection fraction > 40% Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight) Pulmonary function: carbon monoxide diffusing capability test (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in 1 second (FEV1) ≥ 50% Total bilirubin < 1.5 x the upper limit of normal; patients who have been diagnosed with Gilbert's disease are allowed to exceed the defined bilirubin value of 1.5 x the upper limit of normal Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x the upper normal limit Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two effective methods of contraception 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 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 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 Patients with transformed lymphoma (e.g., Richter's transformation arising in follicular lymphoma or chronic lymphocytic leukemia) Patients seropositive for the human immunodeficiency virus (HIV) Patient with active hepatitis B or C 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 electrocardiography (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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus, bortezomib, thymoglobulin<br>Patients receive tacrolimus IV on day -3 through day 180. Patients may receive tacrolimus PO later at the doctor's discretion. Patients receive thymoglobulin IV on days -3, -2, and -1 and bortezomib IV on day 0 and day 3. Patients undergo allogeneic bone marrow transplant on day 0. | Biological: Thymoglobulin<br>* Given IV<br>* Other names: Anti-Thymocyte Globulin;Drug: Bortezomib<br>* Given IV<br>* Other names: Velcade;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Serious Adverse Events and Adverse Events Related to This Immunosuppressive Regimen | An adverse event (AE) is defined as any untoward medical experience or change of an existing condition that occurs during or after treatment. All AEs occurring during this study, whether observed by the physician, nurse, or reported by the patient, will be graded per NCI CTCAE version 4.0 and recorded on protocol-specific case report forms. A serious adverse event (SAE) is defined as any expected or unexpected adverse event (AE, generally equivalent to CTCAE grades 3, 4 or 5) that results in any of the following outcomes: Death Life-threatening event In-patient hospitalization (not required as part of the treatment) or prolongation of existing hospitalization Persistent or significant disability/incapacity Congenital anomaly/birth defect Cancer Overdose | Up to 6 months post-transplant | 
| Number of Patients Alive and Free of Severe Acute GVHD Following HLA Matched Related or Unrelated Donor Hematopoietic Peripheral Blood Transplant | Will use patient counts for the number of patients alive and free of severe acute graft versus host disease (GVHD) following human leukocyte antigen (HLA) matched related or unrelated donor hematopoietic peripheral blood transplant. | At 6 months post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Grade III-IV aGVHD | Will be summarized as percentage and 95% confidence level will be also constructed. | Up to 2 years post-transplant | 
| Incidence of Chronic GVHD | Will be summarized as percentage and 95% confidence level will be also constructed. | Up to 2 years post-transplant | 
| Overall Survival | Will be analyzed with Kaplan Meier method and Logrank test. | At 1 year post-transplant |