search
Back to results

Alpha 1 Anti-Trypsin (AAT) in Treating Patients With Acute Graft-Versus-Host Disease GVHD)

Primary Purpose

Graft-Versus-Host Disease (GVHD) Acute on Chronic

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft-Versus-Host Disease (GVHD) Acute on Chronic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients transplanted from related or unrelated, human leukocyte antigen (HLA) matched or mismatched donors
  • Patients transplanted with hematopoietic stem cells from any source
  • Patients receiving calcineurin inhibitors as part of graft versus host disease (GVHD) prophylaxis
  • Patients with acute GVHD grades II-IV developing despite GVHD prophylaxis
  • Patients who have not shown a satisfactory response to methylprednisolone-equivalent doses at 2 mg/kg/day, based on adjusted body weight
  • Signed and dated informed consent

Exclusion Criteria:

  • Patients who have received any systemic agents in addition to steroids for treatment of GVHD
  • Patients unable to give informed consent
  • Patients with manifestations of classic chronic GVHD
  • Patients with evidence of recurrent malignancy
  • Patients with acute/chronic GVHD overlap syndrome
  • Patients whose GVHD developed after donor lymphocyte infusion (DLI)

  • Patients with severe organ dysfunction, defined as

    • On dialysis
    • Requiring oxygen (O2) at more than 2 l/min
    • Uncontrolled arrhythmia or heart failure
    • Veno-occlusive disease (sinusoidal obstruction syndrome)
  • Patients with uncontrolled infections

Sites / Locations

  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Other

Other

Arm Label

Cohort 1 (30 mg/kg)

Cohort 2 (60 mg/kg)

Cohort 3 (90 mg/kg)

Arm Description

Alpha 1 anti-trypsin (AAT) will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) every other day (QOD) on days 3, 5, 7, 9, 11, 13 & 15.

AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15.

AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15.

Outcomes

Primary Outcome Measures

Number (Percentage) of Patients at Each Dosing Cohort Who Experience no Toxicity and in Whom Graft Versus Host Disease (GVHD) is Stable or Improved
Toxicity and adverse events were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All adverse events were reported regardless of attribution to alpha 1 anti-trypsin (AAT). GVHD response was defined per standard criteria for improvement, no change or progression of signs/symptoms in skin rash (% body surface area), GI (nausea, vomiting, anorexia, diarrhea, GI bleeding, abdominal cramping) and hepatic function (serum bilirubin levels). For this outcome measure, the requirement for additional GVHD treatment beyond AAT was not included in the criteria for response (i.e patients who may have required additional GVHD treatment before study day 28 were not automatically categorized as non-responders or as having progressive GVHD).

Secondary Outcome Measures

Number (Percentage) of Patients at Each Dosing Cohort Experiencing an Unexpected Serious Adverse Event (SAE)
Serious adverse events included death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or congenital anomaly/birth defect. Significant events that do not meet these criteria may be considered serious if they jeopardize the patient and require a medical intervention to prevent one of the outcomes above. An "unexpected" adverse event is defined as an event that is not identified in nature, severity or frequency in the current investigator brochure/package insert/product information.
Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Suspected Serious Adverse Reactions (Infusion Related Reactions)
Serious adverse reactions were assessed by the NCI CTCAE v4.0.
Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Thrombotic or Thrombo-embolic Events
Events were assessed using the NCI CTCAE v4.0.
Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections
Infections were assessed using NCI CTCAE v4.0.
Number (Percentage) of Patients at Each Dosing Cohort With Progression of GVHD
GVHD responses were assessed using criteria established by the Center for International Blood and Marrow Transplant Research and criteria from the Acute GVHD Activity Index. Patients who required additional systemic GVHD treatment beyond AAT before study day 28 were defined as having progressive GVHD.

Full Information

First Posted
January 23, 2012
Last Updated
October 29, 2018
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
search

1. Study Identification

Unique Protocol Identification Number
NCT01523821
Brief Title
Alpha 1 Anti-Trypsin (AAT) in Treating Patients With Acute Graft-Versus-Host Disease GVHD)
Official Title
Treatment of Steroid Non-responsive Acute GVHD With Alpha 1 Antitrypsin (AAT). A Phase I/II Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
October 11, 2013 (Actual)
Primary Completion Date
January 15, 2017 (Actual)
Study Completion Date
January 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I/II trial evaluates the efficacy and adverse effects of alpha 1 anti-trypsin (AAT) for the treatment of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the safety and tolerability of AAT in patients with steroid non-responsive acute GVHD. II. Characterize pharmacodynamic effects of AAT on pro-inflammatory cytokines, heparan sulfate, and the spectrum of peripheral blood T cells. III. Determine clinical responses of GVHD to AAT in patients with steroid non-responsive acute GVHD. OUTLINE: This is a phase I/II dose-escalation study of AAT. Patients will receive AAT intravenously (IV) on study days 1, 3, 5, and 7. Patients who experience no toxicity and in whom GVHD is stable or improved after the day 7 dose can continue therapy with AAT on days 9, 11, 13 and 15 for a total of 8 doses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft-Versus-Host Disease (GVHD) Acute on Chronic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
The study will have three escalating alpha 1 anti-trypsin (AAT) dose cohorts with six patients in each cohort (Phase I). Based on response and toxicity, an additional six patients will be enrolled in the optimal dose (Phase II).
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1 (30 mg/kg)
Arm Type
Other
Arm Description
Alpha 1 anti-trypsin (AAT) will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) every other day (QOD) on days 3, 5, 7, 9, 11, 13 & 15.
Arm Title
Cohort 2 (60 mg/kg)
Arm Type
Other
Arm Description
AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15.
Arm Title
Cohort 3 (90 mg/kg)
Arm Type
Other
Arm Description
AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15.
Intervention Type
Drug
Intervention Name(s)
Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]
Intervention Description
Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days
Primary Outcome Measure Information:
Title
Number (Percentage) of Patients at Each Dosing Cohort Who Experience no Toxicity and in Whom Graft Versus Host Disease (GVHD) is Stable or Improved
Description
Toxicity and adverse events were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All adverse events were reported regardless of attribution to alpha 1 anti-trypsin (AAT). GVHD response was defined per standard criteria for improvement, no change or progression of signs/symptoms in skin rash (% body surface area), GI (nausea, vomiting, anorexia, diarrhea, GI bleeding, abdominal cramping) and hepatic function (serum bilirubin levels). For this outcome measure, the requirement for additional GVHD treatment beyond AAT was not included in the criteria for response (i.e patients who may have required additional GVHD treatment before study day 28 were not automatically categorized as non-responders or as having progressive GVHD).
Time Frame
Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28.
Secondary Outcome Measure Information:
Title
Number (Percentage) of Patients at Each Dosing Cohort Experiencing an Unexpected Serious Adverse Event (SAE)
Description
Serious adverse events included death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or congenital anomaly/birth defect. Significant events that do not meet these criteria may be considered serious if they jeopardize the patient and require a medical intervention to prevent one of the outcomes above. An "unexpected" adverse event is defined as an event that is not identified in nature, severity or frequency in the current investigator brochure/package insert/product information.
Time Frame
SAEs were reported through 30 days after the last dose of alpha 1 anti-trypsin (AAT).
Title
Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Suspected Serious Adverse Reactions (Infusion Related Reactions)
Description
Serious adverse reactions were assessed by the NCI CTCAE v4.0.
Time Frame
Within 48 hours after each infusion
Title
Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Thrombotic or Thrombo-embolic Events
Description
Events were assessed using the NCI CTCAE v4.0.
Time Frame
Events were reported through 15 days after the last dose of AAT.
Title
Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections
Description
Infections were assessed using NCI CTCAE v4.0.
Time Frame
Infections were reported through 15 days after the last dose of AAT.
Title
Number (Percentage) of Patients at Each Dosing Cohort With Progression of GVHD
Description
GVHD responses were assessed using criteria established by the Center for International Blood and Marrow Transplant Research and criteria from the Acute GVHD Activity Index. Patients who required additional systemic GVHD treatment beyond AAT before study day 28 were defined as having progressive GVHD.
Time Frame
GVHD responses were assessed on day 28 after starting AAT therapy or at time of death if patient died before study day 28.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients transplanted from related or unrelated, human leukocyte antigen (HLA) matched or mismatched donors Patients transplanted with hematopoietic stem cells from any source Patients receiving calcineurin inhibitors as part of graft versus host disease (GVHD) prophylaxis Patients with acute GVHD grades II-IV developing despite GVHD prophylaxis Patients who have not shown a satisfactory response to methylprednisolone-equivalent doses at 2 mg/kg/day, based on adjusted body weight Signed and dated informed consent Exclusion Criteria: Patients who have received any systemic agents in addition to steroids for treatment of GVHD Patients unable to give informed consent Patients with manifestations of classic chronic GVHD Patients with evidence of recurrent malignancy Patients with acute/chronic GVHD overlap syndrome Patients whose GVHD developed after donor lymphocyte infusion (DLI) Patients with severe organ dysfunction, defined as On dialysis Requiring oxygen (O2) at more than 2 l/min Uncontrolled arrhythmia or heart failure Veno-occlusive disease (sinusoidal obstruction syndrome) Patients with uncontrolled infections
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
H. Joachim Deeg
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Alpha 1 Anti-Trypsin (AAT) in Treating Patients With Acute Graft-Versus-Host Disease GVHD)

We'll reach out to this number within 24 hrs