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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Graft-Versus-Host Disease (GVHD) Acute on Chronic	Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]	Phase 1; Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	20 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Intervention 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)
Primary Purpose:	Treatment
Official Title:	Treatment of Steroid Non-responsive Acute GVHD With Alpha 1 Antitrypsin (AAT). A Phase I/II Study
Actual Study Start Date :	October 11, 2013
Actual Primary Completion Date :	January 15, 2017
Actual Study Completion Date :	January 15, 2017

Arms and Interventions

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Arm	Intervention/treatment
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
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
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

Outcome Measures

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Primary Outcome Measures :

1. Number (Percentage) of Patients at Each Dosing Cohort Who Experience no Toxicity and in Whom Graft Versus Host Disease (GVHD) is Stable or Improved [ Time Frame: Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28. ]
   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 :

1. Number (Percentage) of Patients at Each Dosing Cohort Experiencing an Unexpected Serious Adverse Event (SAE) [ Time Frame: SAEs were reported through 30 days after the last dose of alpha 1 anti-trypsin (AAT). ]
   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.
2. Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Suspected Serious Adverse Reactions (Infusion Related Reactions) [ Time Frame: Within 48 hours after each infusion ]
   Serious adverse reactions were assessed by the NCI CTCAE v4.0.
3. Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Thrombotic or Thrombo-embolic Events [ Time Frame: Events were reported through 15 days after the last dose of AAT. ]
   Events were assessed using the NCI CTCAE v4.0.
4. Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections [ Time Frame: Infections were reported through 15 days after the last dose of AAT. ]
   Infections were assessed using NCI CTCAE v4.0.
5. Number (Percentage) of Patients at Each Dosing Cohort With Progression of 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. ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Fred Hutchinson Cancer Research Center

National Cancer Institute (NCI)

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:	H. Joachim Deeg	Fred Hutch/University of Washington Cancer Consortium

More Information

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Responsible Party:	Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:	NCT01523821 History of Changes
Other Study ID Numbers:	2571.00; NCI-2011-03805 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2571; 2571.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P01HL036444 ( U.S. NIH Grant/Contract ); P30CA015704 ( U.S. NIH Grant/Contract )
First Posted:	February 1, 2012
Results First Posted:	October 30, 2018
Last Update Posted:	October 30, 2018
Last Verified:	October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases; Protease Inhibitors; Alpha 1-Antitrypsin	Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Trypsin Inhibitors; Serine Proteinase Inhibitors