Clinical trial NCT03459040: A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD
Official title: A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft-versus-host-disease
GVHD
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2018-03-08
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label single arm
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: Number of High Risk Patients Who Develop Steroid Refractory GVHD
timeFrame: Day 100 post HCT.
Secondary outcomes:
measure: Number of Participants Alive at 6 Months and 1 Year
timeFrame: 6 months and 1 year
measure: Number of Participants With Non-relapse Mortality (NRM)
timeFrame: 6 months and 1 year
measure: Number of Participants With Relapse
timeFrame: 1 year
measure: Number of Participants With Clinically Relevant GVHD States Grade II-IV GVHD
timeFrame: 100 days
measure: Number of Participants Achieving Overall Response
timeFrame: Day 28
measure: Number of Participants With Severe GI GVHD Stage 3 or 4
timeFrame: By day 100 post-HCT
measure: Number of Participants With Chronic GVHD Requiring Systemic Steroid Treatment
timeFrame: 1 year
measure: Number of Participants With Serious Infections
timeFrame: 1 year
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: John Levine, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gergoudis SC, DeFilipp Z, Ozbek U, Sandhu KS, Etra AM, Choe HK, Kitko CL, Ayuk F, Aziz M, Baez J, Ben-David K, Bunworasate U, Gandhi I, Hexner EO, Hogan WJ, Holler E, Kasikis S, Kowalyk SM, Lin JY, Merli P, Morales G, Nakamura R, Reshef R, Rosler W, Srinagesh H, Young R, Chen YB, Ferrara JLM, Levine JE. Biomarker-guided preemption of steroid-refractory graft-versus-host disease with alpha-1-antitrypsin. Blood Adv. 2020 Dec 22;4(24):6098-6105. doi: 10.1182/bloodadvances.2020003336.