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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Cohort 1 (30 mg/kg)<br>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]<br>* Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days<br>|
| Other: Cohort 2 (60 mg/kg)<br>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]<br>* Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days<br>|
| Other: Cohort 3 (90 mg/kg)<br>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]<br>* Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days<br>|

What is the study measuring?
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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. |