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
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALThymoglobulin
Given IV
DRUGBortezomib
Given IV
DRUGTacrolimus
Given IV and PO
Sponsors
Emory University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Serious Adverse Events and Adverse Events Related to This Immunosuppressive Regimen | Up to 6 months post-transplant | 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 |
| Number of Patients Alive and Free of Severe Acute GVHD Following HLA Matched Related or Unrelated Donor Hematopoietic Peripheral Blood Transplant | At 6 months post-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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Grade III-IV aGVHD | Up to 2 years post-transplant | Will be summarized as percentage and 95% confidence level will be also constructed. |
| Incidence of Chronic GVHD | Up to 2 years post-transplant | Will be summarized as percentage and 95% confidence level will be also constructed. |
| Overall Survival | At 1 year post-transplant | Will be analyzed with Kaplan Meier method and Logrank test. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from 9/9/2016 to 7/11/2017 at Winship Cancer Institute of Emory University.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus, Bortezomib, Thymoglobulin 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.
Thymoglobulin: Given IV
Bortezomib: Given IV
Tacrolimus: Given IV and PO | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Trial was closed early | 5 |
Baseline characteristics
| Characteristic | Tacrolimus, Bortezomib, Thymoglobulin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 5 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 5 |
| other Total, other adverse events | 0 / 5 |
| serious Total, serious adverse events | 4 / 5 |
Outcome results
Primary
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.
Time frame: At 6 months post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tacrolimus, Bortezomib, Thymoglobulin | Number of Patients Alive and Free of Severe Acute GVHD Following HLA Matched Related or Unrelated Donor Hematopoietic Peripheral Blood Transplant | 1 Participants |
Primary
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
Time frame: Up to 6 months post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus, Bortezomib, Thymoglobulin | Total Number of Serious Adverse Events and Adverse Events Related to This Immunosuppressive Regimen | 9 events |
Secondary
Cumulative Incidence of Grade III-IV aGVHD
Will be summarized as percentage and 95% confidence level will be also constructed.
Time frame: Up to 2 years post-transplant
Population: Data were not collected because trial closed early.
Secondary
Incidence of Chronic GVHD
Will be summarized as percentage and 95% confidence level will be also constructed.
Time frame: Up to 2 years post-transplant
Population: Data were not collected because trial closed early.
Secondary
Overall Survival
Will be analyzed with Kaplan Meier method and Logrank test.
Time frame: At 1 year post-transplant
Population: Data were not collected because trial closed early.