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

Treatment of Steroid Non-responsive Acute GVHD With Alpha 1 Antitrypsin (AAT). A Phase I/II Study

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.

Study Overview

• Status: Completed
• Conditions: Graft-Versus-Host Disease (GVHD) Acute on Chronic
• Intervention / Treatment: Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: Cohort 1 (30 mg/kg); 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.	Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]; Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days
OTHER: Cohort 2 (60 mg/kg); 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.	Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]; Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days
OTHER: Cohort 3 (90 mg/kg); AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15.	Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]; Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	SAEs were reported through 30 days after the last dose of alpha 1 anti-trypsin (AAT).
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.	Within 48 hours after each infusion
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.	Events were reported through 15 days after the last dose of AAT.
Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections	Infections were assessed using NCI CTCAE v4.0.	Infections were reported through 15 days after the last dose of AAT.
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.	GVHD responses were assessed on day 28 after starting AAT therapy or at time of death if patient died before study day 28.

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: H. Joachim Deeg, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 11, 2013
• Primary Completion (ACTUAL): January 15, 2017
• Study Completion (ACTUAL): January 15, 2017

Study Registration Dates

• First Submitted: January 23, 2012
• First Submitted That Met QC Criteria: January 30, 2012
• First Posted (ESTIMATE): February 1, 2012

Study Record Updates

• Last Update Posted (ACTUAL): October 30, 2018
• Last Update Submitted That Met QC Criteria: October 29, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Protease Inhibitors; Alpha 1-Antitrypsin
• Other Study ID Numbers: 2571.00 (OTHER: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2011-03805 (REGISTRY: CTRP (Clinical Trial Reporting Program)); 2571; P01HL036444 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO