Partially HLA-matched Third Party Antigen Specific T-cells for Infection Post-stem Cell or Solid Organ Transplantation (R3ACT)

Therapeutic Infusion of Partially HLA-matched Third Party Donor-derived Virus- and Fungus Specific T-lymphocytes in Patients With Active Viral or Fungal Infection Post-allogeneic Stem Cell or Solid Organ Transplantation

To assess the safety and biological efficacy of therapeutically administered most closely HLA-matched third party donor-derived specific cytotoxic T lymphocytes (CTLs) targeting cytomegalovirus (CMV) or Adenovirus (Adv) or Epstein Barr virus (EBV) or fungi including Aspergillus and Candida species for the treatment of viral infection following allogeneic blood or marrow stem cell or solid organ transplantation.

Study Overview

• Status: Unknown
• Conditions: CMV Infection; EBV; Adenovirus
• Intervention / Treatment: Biological: Virus specific CTLs

Detailed Description

The study will analyse the safety and biological efficacy of administering the investigational products (most closely HLA-matched third party donor-derived T cells stimulated with viral or fungal antigen expressing DC), for the treatment of viral reactivation and/or infection or fungal infection following allogeneic blood or marrow or solid organ transplantation. The cells will be given therapeutically after transplantation in patients with active viral reactivation or proven/probably fungal infection despite standard therapy.

Our AIMS are to study the safety of third party donor-derived CTL infusions, their effect on treatment of viral reactivation as well as their effect on reconstitution of virus- and fungus-specific immunity, viral and fungal infection and reactivation rates after transplantation, viral load, and use of antiviral and antifungal pharmacotherapy.

We will evaluate the safety of infusions with respect to the development of adverse events within the first 12 months post-CTL infusion and the dynamics of cell persistence by T-cell chimerism analysis.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: David Gottlieb, MD FRACP; Email: david.gottlieb@sydney.edu.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Recruiting
      • Westmead Hospital
      • Contact: David Gottlieb, MD FRACP; Email: david.gottlieb@sydney.edu.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Recipients of myeloablative or non-myeloablative allogeneic or solid organ transplantation for any indication.

• Presence of viral reactivation or infection with CMV, Adv or EBV or invasive fungal disease must be present at the time of infusion as determined by:

  • For CMV CMV detectable by antigen detection, PCR or culture in peripheral blood or tissue biopsy or by immunohistochemical staining on tissue biopsy specimen
  • For Adv Presence of Adv as detected by PCR, antigen detection or culture in body fluids including blood, stool, urine or nasopharyngeal secretions
  • For EBV Elevated EB virus detectable in peripheral blood by PCR or Presence of documented EBV related PTLD diagnosed by tissue biopsy or Elevated EB virus detectable in the blood by PCR and clinical or imaging findings consistent with EBV lymphoma
  • For invasive fungal disease Proven or probable invasive fungal disease according to De Pauw 2008[114]

• Failure of standard therapy as defined by:

  • For CMV The continued presence of detectable CMV virus or antigen after at least 14 days of antiviral therapy with IV ganciclovir or foscarnet Recurrence of detectable CMV virus or antigen after at least 2 weeks of prior antiviral therapy
  • For Adv A rise or less than 50% reduction in viral load in blood or any site of disease as measured by PCR or any quantitative assay despite use of therapy as determined by the treating physician; Standard therapy may include intravenous cidofovir within the limits of renal function
  • For EBV Increase or less than 50% decrease in the size of EBV lymphoma or

Increase or less than 50% decrease in the EBV viral load in peripheral blood despite use of appropriate therapy as determined by the treating physician which may include:

• Reduction in immunosuppression
• Rituximab 375mg/m2 up to 4 infusions

• Cytotoxic chemotherapy

  o For invasive fungal disease inadequate or incomplete clinical response according to treating physician after at least 5 days of best available therapy

• Adequate hepatic and renal function (< 3 x upper limit of normal for AST (SGOT), ALT (SGPT), < 2 x upper limit of normal for total bilirubin, serum creatinine)
• ECOG status 0 to 3 or Lansky score 30-100
• Patient (or legal representative) has given informed consent

Exclusion Criteria:

• Use of anti-lymphocyte globulin (ALG, ATG, Campath or other broad spectrum lymphocyte antibody) given in the 4 weeks immediately prior to infusion or planned within 4 weeks after infusion.
• Grade II or greater graft versus host disease within 1 week prior to infusion.
• Prednisone or methylprednisolone at a dose of > 1 mg/kg (or equivalent in other steroid preparations) administered within 72 hours prior to cell infusion.
• ECOG status 4 or Lansky score <30
• Privately insured in or outpatients in New South Wales participating centres (see 12.5 Indemnity issues).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 3rd party CTL infusion; Virus specific CTLs	Biological: Virus specific CTLs; Virus specific CTLs will be given to patients with persistent or recurrent viral reactivation after 2 weeks of standard anti-viral therapy; Other Names: T cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infusion related safety	infusion related adverse events	1 week

Collaborators and Investigators

• Sponsor: University of Sydney

Publications and helpful links

General Publications

• Withers B, Blyth E, Clancy LE, Yong A, Fraser C, Burgess J, Simms R, Brown R, Kliman D, Dubosq MC, Bishop D, Sutrave G, Ma CKK, Shaw PJ, Micklethwaite KP, Gottlieb DJ. Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells. Blood Adv. 2017 Nov 2;1(24):2193-2205. doi: 10.1182/bloodadvances.2017010223. eCollection 2017 Nov 14.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): March 1, 2018

Study Registration Dates

• First Submitted: May 18, 2016
• First Submitted That Met QC Criteria: May 18, 2016
• First Posted (Estimate): May 20, 2016

Study Record Updates

• Last Update Posted (Estimate): July 21, 2016
• Last Update Submitted That Met QC Criteria: July 20, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections
• Other Study ID Numbers: R3ACT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No