A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD

Study Overview
=================
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.

Official Title
-----------------
A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD

Conditions
-----------------
Graft-versus-host-disease, GVHD

Intervention / Treatment
-----------------
* Drug: Alpha 1-Antitrypsin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: Open label single arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: alpha-1-antitrypsin (AAT)<br>16 doses of AAT through a catheter placed into a blood vessel over eight weeks. | Drug: Alpha 1-Antitrypsin<br>* AAT will be given either in the hospital or the outpatient clinic two times per week.<br>* Other names: AAT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 100 post HCT. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 6 months and 1 year | 
| 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. | 6 months and 1 year | 
| Number of Participants With Relapse | Number of participants with relapse at one year. Relapse defined as recurrence of disease that required transplant. | 1 year | 
| 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 | 100 days | 
| 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. | Day 28 | 
| 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. | By day 100 post-HCT | 
| 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. | 1 year | 
| 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. | 1 year |