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.
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Alpha 1-Proteinase Inhibitor, Human 1 MG \[Glassia\] at various levels over different days
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
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).
Time frame: Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28.
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.
Time frame: 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.
Time frame: Within 48 hours after each infusion
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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.
Time frame: 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.
Time frame: 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.
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.