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

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ClinicalTrials.gov Identifier: NCT03459040
Recruitment Status : Active, not recruiting
First Posted : March 8, 2018
Last Update Posted : November 5, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
John Levine, Icahn School of Medicine at Mount Sinai

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.

Condition or disease Intervention/treatment Phase
Graft-versus-host-disease GVHD Drug: Alpha 1-Antitrypsin Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Open label single arm
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of Steroid-Refractory Acute GVHD
Actual Study Start Date : August 17, 2018
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020


Arm Intervention/treatment
Experimental: alpha-1-antitrypsin (AAT)
16 doses of AAT through a catheter placed into a blood vessel over eight weeks.
Drug: Alpha 1-Antitrypsin
AAT will be given either in the hospital or the outpatient clinic two times per week.
Other Name: AAT




Primary Outcome Measures :
  1. Proportion of High Risk patients who develop steroid refractory GVHD by day 100 post HCT. [ Time Frame: Day 100 post HCT. ]

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 1 year ]
    The length of time from the start of treatment that patients are still alive at 1 year

  2. Non-relapse mortality (NRM) rate [ Time Frame: 1 year ]
    Cumulative incidence of NRM - deaths which could not be attributed to disease relapse or progression

  3. Relapse rate [ Time Frame: 1 year ]
    Cumulative incidence of relapse at one year

  4. Incidence of clinically relevant GVHD states [ Time Frame: 100 days ]
    including steroid-refractory moderate and severe GVHD, grade II-IV GVHD.

  5. Overall Response Rate [ Time Frame: Day 28 ]
    For patients who develop GVHD prior to day 100 post-HCT, the overall response rate = complete remission and partial remission (CR + PR) 28 days after initiation of systemic steroid treatment. PR is defined as improvement in one or more organs involved with GVHD symptoms without progression in others. For a response to be scored as PR on day 28, the patient must be in PR on day 28 and have had no intervening systemic therapy for acute GVHD other than steroids.

  6. Cumulative incidence of severe GI GVHD stage 3 or 4 [ Time Frame: By day 100 post-HCT ]
  7. Cumulative incidence of chronic GVHD requiring systemic steroid treatment [ Time Frame: By one year ]
  8. Number of serious infections [ Time Frame: 1 year ]
    Number of serious infections (defined as grade 3 by the Blood and Marrow Transplant Clinical Trials Network)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • High risk prediction score as determined by the MAGIC algorithm at either day 7 or day 14 post 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03459040


Locations
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United States, California
City of Hope
Duarte, California, United States, 91010
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
John Levine
National Cancer Institute (NCI)
Investigators
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Principal Investigator: John Levine, MD Icahn School of Medicine at Mount Sinai

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Responsible Party: John Levine, Professor of Internal Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT03459040     History of Changes
Other Study ID Numbers: GCO 17-2666
P01CA039542 ( U.S. NIH Grant/Contract )
First Posted: March 8, 2018    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action