Clinical trial NCT01523821: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Graft-Versus-Host Disease (GVHD) Acute on Chronic
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2012-02-01
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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).
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number (Percentage) of Patients at Each Dosing Cohort Who Experience no Toxicity and in Whom Graft Versus Host Disease (GVHD) is Stable or Improved
timeFrame: Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28.
Secondary outcomes:
measure: Number (Percentage) of Patients at Each Dosing Cohort Experiencing an Unexpected Serious Adverse Event (SAE)
timeFrame: SAEs were reported through 30 days after the last dose of alpha 1 anti-trypsin (AAT).
measure: Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Suspected Serious Adverse Reactions (Infusion Related Reactions)
timeFrame: Within 48 hours after each infusion
measure: Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Thrombotic or Thrombo-embolic Events
timeFrame: Events were reported through 15 days after the last dose of AAT.
measure: Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections
timeFrame: Infections were reported through 15 days after the last dose of AAT.
measure: Number (Percentage) of Patients at Each Dosing Cohort With Progression of GVHD
timeFrame: GVHD responses were assessed on day 28 after starting AAT therapy or at time of death if patient died before study day 28.
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutch/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Fred Hutch/University of Washington Cancer Consortium
name: H. Joachim Deeg
role: PRINCIPAL_INVESTIGATOR
References: