Clinical Trial 20491

• Overview

  Study Title:

  A Randomized, Double-Blind, Placebo-Controlled Multicenter Phase III Trial of Alpha 1 Antitrypsin (AAT) Combined with Corticosteroids vs Corticosteroids Alone for the Treatment of High Risk Acute Graft-versus-Host Disease (GVHD Following Allogeneic Hematopoietic Stem Cell Transplant

  Summary:

  Study CSL964_5001 will investigate the efficacy of AAT with corticosteroids compared with corticosteroids alone as first line therapy for patients with high-risk acute GVHD

  Objective:

  The primary objective of this trial is to compare the rate of complete response (CR) and partial response (PR) on Day 28 post-randomization between AAT and CS versus placebo to match (PTM) and CS in patients with high-risk acute GVHD. Secondary objectives are to assess the following: 1. Duration of response at 6 and 12 months postrandomization. 2. Cumulative incidence of non-relapse mortality (NRM) at 6 and 12 months post-randomization. 3. Overall survival (OS) and progression free survival (PFS) at 6 and 12 months post-randomization. 4. GVHD-free survival at Day 56 post-randomization. 5. Proportions of CR, very good partial response (VGPR), PR, and treatment failure (TF) at Day 7, 14, 21, 28, 56, and 86 post-randomization. 6. Incidence of systemic infections to assess safety. 7. Incidence of Adverse Events (AEs) at 30 days post last dose of drug to assess safety. 8. Incidence of chronic GVHD at 6 and 12 months post randomization and stem cell infusion (Day 0 HCT). 9. Incidence of disease relapse at 6 and 12 months post randomization.

• Treatments

  Medications:

  Alpha 1 - Antitrypsin (); Methylprednisolone (); Placebo (); prednisone ()

• Inclusion Criteria

  • Patients 18 years of age or older
  • Patients experiencing their initial presentation of acute GVHD requiring systemic therapy after allogeneic transplant for any malignant or non-malignant indication
  • The clinical diagnosis of acute GVHD requiring systemic therapy with CS. Patients can be enrolled with only a clinically established diagnosis. Biopsy of involved organs with acute GVHD is encouraged but is not required and should not delay study entry. Enrollment/randomization includes commitment to continue steroids with PTM or AAT as specified in the protocol, as well as the required follow-up observations. If, according to institutional practice, the intention to treat is dependent upon biopsy results, the patient should not complete enrollment on the BMT CTN 1705 study until the biopsy results are available
  • Acute GVHD must meet one of the clinical features per protocol within 72 hours prior to enrollment
  • Acute GVHD developing after allogeneic hematopoietic cell transplantation using any graft or donor source or conditioning intensity
  • Patients should not have received systemic immune suppressive therapy for treatment of active GVHD except for a maximum of 72 hours of prior CS therapy prior to enrollment. Topical skin and GI CS (such as budesonide and oral beclomethasone diproprionate) are allowed
  • Ability to provide written informed consent

• Exclusion Criteria

  • Patients with prior exogenous AAT exposure for GVHD prophylaxis.
  • Relapsed, progressing or persistent malignancy
  • Evidence of minimal residual disease (MRD) requiring withdrawal of systemic immune suppression.
  • Patients with acute GVHD developing after administration of a donor lymphocyte infusion (DLI) for relapse / progression of disease. Patients with acute GVHD after planned donor lymphocyte infusion or planned T cell or NK cell add back are eligible.
  • Patients with uncontrolled infections will be excluded. Infections are considered controlled if appropriate therapy has been instituted and, at the time of enrollment, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
  • A clinical presentation resembling de novo chronic GVHD or overlap syndrome (as defined in Appendix C) developing before or present at the time of enrollment.
  • Patients receiving other drugs for the treatment of GVHD. Note, GVHD prophylaxis agents (e.g., calcineurin inhibitors) may be continued at local Investigator's discretion.
  • Patients receiving systemic CS for any indication within 7 days before the onset of acute GVHD, except the following:
  • CS administered as premedication for supportive care (such as before transfusion of blood products or before intravenous medications to prevent infusion reactions, fever, etc.).
  • If steroid therapy has been administered for treatment of a non-GVHD related condition and tapered to > Treatment of active GVHD with CS is allowed for up to 72 hours prior to enrollment
  • Patients who are pregnant or breastfeeding.
  • Females of childbearing potential (FCBP) or males who can get a FCBP pregnant and have sexual contact with FCBP and are unwilling to use 2 effective forms of birth control or abstinence from the start of study drug treatment through 30 days after the last dose of study drug, Effective forms of birth control are listed in Appendix D.
  • Patients on renal replacement therapy.
  • Patients requiring continuous supplemental oxygen (O2 requirement > 2L/min to maintain peripheral O2 saturation [SpO2] > 90%).
  • Patients with active hepatic sinusoidal obstructive syndrome (SOS) and/or clinical evidence of impaired hepatic function (ascites or encephalopathy related to liver disease) who in the judgment of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment.
  • Patients with a history of hypersensitivity to AAT or any component of the investigational product or PTM (albumin), including congenitally IgA-deficient patients with antibodies to IgA or PTM.
  • Patients unlikely to be adherent to study specific assessments at the transplant center.

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