Graft-versus-host-disease, GVHD
Conditions
Brief summary
Bone marrow transplant (BMT) patients can develop graft-versus-host disease (GVHD), a serious and potentially fatal complication. The researchers have developed a blood test to identify patients most at risk for developing severe GVHD. Patients who consent to this study will have their blood tested up to two times after BMT to determine if they are at high risk for severe GVHD. The tests will be performed one week and two weeks after BMT. Patients who are high risk will be treated with a drug called alpha-1-antitrypsin (AAT) to see if it prevents the development of severe GVHD. Patients will receive 16 doses of AAT through a catheter placed into a blood vessel over eight weeks. AAT will be given either in the hospital or the outpatient clinic two times per week. Patients will be followed for the development of severe GVHD for up to four months from the BMT and will continue to be followed at routine clinic visits for up to one year after BMT.
Interventions
AAT will be given either in the hospital or the outpatient clinic two times per week.
Sponsors
National Cancer Institute (NCI)
John Levine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Open label single arm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* High risk prediction score as determined by the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm at either day 7 or day 14 post Hematopoietic cell transplant (HCT). * Any donor type (e.g., related, unrelated) or stem cell source (bone marrow, peripheral blood, cord blood). * Donor and recipient match each other for at least 7/8 HLA-loci (HLA-A, B, C, and DR) * Any conditioning regimen (non-myeloablative, myeloablative, or reduced intensity) is acceptable. * GVHD prophylaxis must include a calcineurin inhibitor combined with methotrexate or mycophenolate. * The use of serotherapy to prevent GVHD (e.g., antithymocyte globulin) prior to day 3 post-HCT is permitted * Direct bilirubin must be \<2 mg/dL unless the elevation is known to be due to Gilbert syndrome within 3 days prior to enrollment. * ALT/SGPT and AST/SGOT must be \<5 x the upper limit of the normal range within 3 days prior to enrollment. * Signed and dated written informed consent obtained from patient or legal representative.
Exclusion criteria
* Patients who develop acute GVHD prior to start of study drug * Patients at very high risk for relapse post HCT as defined by very high disease risk index * Patients participating in a clinical trial where prevention of GVHD is the primary endpoint * Uncontrolled active infection (i.e., progressive symptoms related to infection despite treatment or persistently positive microbiological cultures despite treatment or any other evidence of severe sepsis) * Patients who are pregnant * Patients on dialysis within 7 days of enrollment * Patients requiring ventilator support or oxygen supplementation exceeding 40% FiO2 within 14 days of enrollment. * Patients receiving investigational agent within 30 days of enrollment. However, the Principal Investigator (PI) may approve prior use of an investigational agent if the agent is not expected to interfere with the safety or the efficacy of alpha-1-antitrypsin. * History of allergic reaction to alpha-1-antitrypsin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of High Risk Patients Who Develop Steroid Refractory GVHD | Day 100 post HCT. | Number of High Risk patients who develop steroid refractory GVHD by day 100 post Hematopoietic cell transplant (HCT) . Steroid refractory GVHD defined as patients who did not achieve Complete Response (CR) or Partial Response (PR) by day 28 of systemic steroid treatment OR if additional immunosuppression beyond steroids was given for treatment of GVHD prior to 28 days of steroid treatment. * CR: All evaluable organs (skin, liver, GI tract) stage 0. For a response to be scored as CR on day 28, the patient must be in CR on that day and have had no intervening additional GVHD therapy. * PR: An improvement in one or more organ involved with GVHD symptoms without worsening in others. For a response to be scored as PR on day 28, the patient must be in PR on that day and have had no intervening additional GVHD therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Non-relapse Mortality (NRM) | 6 months and 1 year | Number of participants with NRM - deaths which could not be attributed to disease relapse or progression. Non-relapse mortality defined as death without prior relapse. |
| Number of Participants With Relapse | 1 year | Number of participants with relapse at one year. Relapse defined as recurrence of disease that required transplant. |
| Number of Participants With Clinically Relevant GVHD States Grade II-IV GVHD | 100 days | Number of participants with clinically relevant GVHD states grade II-IV GVHD requiring systemic treatment. GVHD grades II-IV are defined as * Rash covering more than 50% of the body surface area, AND/OR * Total bilirubin \> 2 mg/dl AND/OR * Persistent nausea or vomiting, AND/OR * Diarrhea \> 500 ml/day AND/OR * Severe abdominal pain requiring treatment or blood present in the diarrhea |
| Number of Participants Alive at 6 Months and 1 Year | 6 months and 1 year | Overall survival - The number of that patients are still alive from the start of treatment at 6 months and 1 year |
| Number of Participants With Severe GI GVHD Stage 3 or 4 | By day 100 post-HCT | Number of participants with severe GI GVHD stage 3 or 4. GI GVHD stage 3 or 4 is defined as diarrhea \>1000 ml/day OR severe abdominal pain requiring treatment OR blood present in the diarrhea. |
| Number of Participants With Chronic GVHD Requiring Systemic Steroid Treatment | 1 year | Number of participants with chronic GVHD requiring systemic steroid treatment. Chronic GVHD Requiring Systemic Steroid Treatment: defined as the development of symptoms of chronic GVHD according to NIH Consensus Criteria that require treatment with oral or intravenous corticosteroids. |
| Number of Participants With Serious Infections | 1 year | Number of participants with serious infections (defined as grade 3 by the Blood and Marrow Transplant Clinical Trials Network). Serious Infection: Defined as bacterial, fungal, viral or parasitic infections that required oral or intravenous treatments such as antibiotics. |
| Number of Participants Achieving Overall Response | Day 28 | For patients who develop GVHD prior to day 100 post-HCT, the number of participants achieving overall response. The overall response rate = complete remission and partial remission (CR + PR) 28 days after initiation of systemic steroid treatment. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited and enrolled between August 2018 and July 2019.
Participants by arm
| Arm | Count |
|---|---|
| Alpha-1-antitrypsin (AAT) AAT was administered intravenously at a loading dose of 90 mg/kg (study day 0), followed by twice weekly doses of 45 mg/kg for 15 more doses (totaling 16 doses over 8 weeks). | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 8 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Alpha-1-antitrypsin (AAT) |
|---|---|
| Age, Continuous | 51 years |
| Diagnosis Acute lymphoblastic leukemia | 5 Participants |
| Diagnosis Acute myelogenous leukemia | 9 Participants |
| Diagnosis Myelodysplastic syndrome | 13 Participants |
| Diagnosis Non-Hodgkin's lymphoma | 1 Participants |
| Diagnosis Nonmalignant disease | 2 Participants |
| Donor Matched related | 3 Participants |
| Donor Matched unrelated | 26 Participants |
| Donor Mismatched related | 0 Participants |
| Donor Mismatched unrelated | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| GVHD Prophylaxis calcineurin inhibitor/sirolimus | 15 Participants |
| GVHD Prophylaxis CNI/MMF -Calcineurin inhibitors/mycophenolate mofetil | 0 Participants |
| GVHD Prophylaxis CNI/MTX - calcineurin inhibitor/methotrexate | 14 Participants |
| GVHD Prophylaxis Cyclophosphamide based | 0 Participants |
| GVHD Prophylaxis Other | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 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 | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 30 |
| other Total, other adverse events | 9 / 30 |
| serious Total, serious adverse events | 14 / 30 |
Outcome results
Primary
Number of High Risk Patients Who Develop Steroid Refractory GVHD
Number of High Risk patients who develop steroid refractory GVHD by day 100 post Hematopoietic cell transplant (HCT) . Steroid refractory GVHD defined as patients who did not achieve Complete Response (CR) or Partial Response (PR) by day 28 of systemic steroid treatment OR if additional immunosuppression beyond steroids was given for treatment of GVHD prior to 28 days of steroid treatment. * CR: All evaluable organs (skin, liver, GI tract) stage 0. For a response to be scored as CR on day 28, the patient must be in CR on that day and have had no intervening additional GVHD therapy. * PR: An improvement in one or more organ involved with GVHD symptoms without worsening in others. For a response to be scored as PR on day 28, the patient must be in PR on that day and have had no intervening additional GVHD therapy.
Time frame: Day 100 post HCT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of High Risk Patients Who Develop Steroid Refractory GVHD | 6 Participants |
Secondary
Number of Participants Achieving Overall Response
For patients who develop GVHD prior to day 100 post-HCT, the number of participants achieving overall response. The overall response rate = complete remission and partial remission (CR + PR) 28 days after initiation of systemic steroid treatment.
Time frame: Day 28
Population: This is the number of patients who developed GVHD and were systemically treated (not all patients on study developed GVHD and of those that did develop GVHD, not all received systemic treatment).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants Achieving Overall Response | 10 Participants |
Secondary
Number of Participants Alive at 6 Months and 1 Year
Overall survival - The number of that patients are still alive from the start of treatment at 6 months and 1 year
Time frame: 6 months and 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants Alive at 6 Months and 1 Year | 1 year | 22 Participants |
| Alpha-1-antitrypsin (AAT) | Number of Participants Alive at 6 Months and 1 Year | 6 months | 26 Participants |
Secondary
Number of Participants With Chronic GVHD Requiring Systemic Steroid Treatment
Number of participants with chronic GVHD requiring systemic steroid treatment. Chronic GVHD Requiring Systemic Steroid Treatment: defined as the development of symptoms of chronic GVHD according to NIH Consensus Criteria that require treatment with oral or intravenous corticosteroids.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants With Chronic GVHD Requiring Systemic Steroid Treatment | 8 Participants |
Secondary
Number of Participants With Clinically Relevant GVHD States Grade II-IV GVHD
Number of participants with clinically relevant GVHD states grade II-IV GVHD requiring systemic treatment. GVHD grades II-IV are defined as * Rash covering more than 50% of the body surface area, AND/OR * Total bilirubin \> 2 mg/dl AND/OR * Persistent nausea or vomiting, AND/OR * Diarrhea \> 500 ml/day AND/OR * Severe abdominal pain requiring treatment or blood present in the diarrhea
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants With Clinically Relevant GVHD States Grade II-IV GVHD | 12 Participants |
Secondary
Number of Participants With Non-relapse Mortality (NRM)
Number of participants with NRM - deaths which could not be attributed to disease relapse or progression. Non-relapse mortality defined as death without prior relapse.
Time frame: 6 months and 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants With Non-relapse Mortality (NRM) | 6 months | 3 Participants |
| Alpha-1-antitrypsin (AAT) | Number of Participants With Non-relapse Mortality (NRM) | 1 year | 6 Participants |
Secondary
Number of Participants With Relapse
Number of participants with relapse at one year. Relapse defined as recurrence of disease that required transplant.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants With Relapse | 3 Participants |
Secondary
Number of Participants With Serious Infections
Number of participants with serious infections (defined as grade 3 by the Blood and Marrow Transplant Clinical Trials Network). Serious Infection: Defined as bacterial, fungal, viral or parasitic infections that required oral or intravenous treatments such as antibiotics.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants With Serious Infections | 2 Participants |
Secondary
Number of Participants With Severe GI GVHD Stage 3 or 4
Number of participants with severe GI GVHD stage 3 or 4. GI GVHD stage 3 or 4 is defined as diarrhea \>1000 ml/day OR severe abdominal pain requiring treatment OR blood present in the diarrhea.
Time frame: By day 100 post-HCT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alpha-1-antitrypsin (AAT) | Number of Participants With Severe GI GVHD Stage 3 or 4 | 4 Participants |