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Trial registered on ANZCTR


Registration number
ACTRN12618000343202
Ethics application status
Approved
Date submitted
7/12/2017
Date registered
7/03/2018
Date last updated
7/03/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Infusion of virus specific immune cells in patients at the first sign of virus infection after a blood or bone marrow transplant who have received less than 7 days of anti-viral treatment.
Scientific title
Therapeutic infusion of most closely HLA-matched third party donor-derived virus-specific cytotoxic T-lymphocytes in patients with previously untreated viral infection post-allogeneic stem cell transplantation
Secondary ID [1] 293536 0
Nil
Universal Trial Number (UTN)
Trial acronym
R3ACT-QUICKLY
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cytomegalovirus reactivation or infection following allogeneic blood or marrow stem cell transplantation 305732 0
Adenovirus reactivation or infection following allogeneic blood or marrow stem cell transplantation 305733 0
Epstein Barr Virus reactivation or infection following allogeneic blood or marrow stem cell transplantation 305734 0
Condition category
Condition code
Infection 304950 304950 0 0
Studies of infection and infectious agents
Blood 304951 304951 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Up to four doses of (2 x 10^7/m2) most closely HLA matched virus-specific cytotoxic T-Lymphocytes (CTL's), given via intravenous infusion, in patients with active viral replication (cytomegalovirus[CMV], adenovirus or Epstein Barr Virus [EBV]) post allogeneic haematopoietic stem cell transplant no less than 28 days apart. Following the first infusion, patients will be eligible for up to 3 additional CTL infusions (total maximum four infusions) with a minimum of 28 days between each infusion if at the time of subsequent infusion they are not showing at least a partial virological response to the previous infusion (defined as at least 50% reduction in viral copy number in blood compared with the copy number before the previous infusion) or if there is evidence of ongoing tissue infection or EBV lymphoma that has not shown clinical or radiological improvement since the previous infusion. Patients will continue to be eligible subsequent infusions if they have adequate hepatic and renal function (<3 x ULN for AST, ALT, <2 x ULN for bilirubin and serum creatinine), neutrophil count > 1x10^9 without G-CSF support for 3 days. The patient must not have had anti-lymphocyte globulin 4 weeks prior to the infusion or planned 4 weeks after the infusion, grade II or greater GVHD within 1 week prior to the infusion or prednisone/methylprednisone >1mg/kg administered within 72 hours prior to the cell infusion.
The infusions will occur in the hospital outpatient unit where the patient will be observed for 2 hours after the infusion by nursing staff. The infusion will be administered in accordance with BMT policy and procedure by qualified staff such as the treating physician, fellow or nurse practitioner.
Intervention code [1] 299770 0
Treatment: Other
Comparator / control treatment
Historical data of rates/sites of GVHD will be compared with identically treated bone marrow transplant recipients at Westmead Hospital between 2011 and 2016.
Control group
Historical

Outcomes
Primary outcome [1] 304134 0
Short term safety of cytotoxic T-Lymphocyte infusion within 7 days of the infusion. This includes, organ toxicity, death (unrelated to the initial infection) or other adverse events.

Organ toxicity will be measured using blood tests to measure liver function and renal function. The patient will also be reviewed by a transplant clinician to determine any adverse outcomes such as GVHD, fever >38 degrees, rash etc.
Timepoint [1] 304134 0
Short term safety will be assessed one day post-infusion and 7 days post-infusion.
Primary outcome [2] 304552 0
Long term safety of this therapeutic intervention will be established by recording adverse events over a 6 month period of follow up.
Timepoint [2] 304552 0
Long term safety will be assessed at regular intervals, according to the trial protocol, for up to 12 months post-infusion. The follow up will occur weekly for 4 weeks, fortnightly for one month then monthly for 4 months, 3 monthly for 6 months. Thus, the trial specific, follow up will occur a total of 12 months post-infusion. Patients may continue to be followed up according to hospital protocols or doctors discretion after this time.

Long term safety assessment includes reviewing the incidence and nature of chronic GHVD in the trial participants, length and nature of any hospital admissions and survival. Any adverse events or serious adverse events will be reviewed by investigators for causality to the investigational product.
Secondary outcome [1] 341060 0
Viral load, Recurrance of viral reactivation within 6 months of infusion by means of CMV polymerase chain reaction (PCR) testing. A positive PCR testing for CMV, denotes a recurrence of viral reactivation. The PCR will be quantified according to hospital laboratory values.
Timepoint [1] 341060 0
Viral load in peripheral blood will be measured by quantitative PCR immediately prior to and in the weeks following virus-specific CTL infusions. Assays will be performed with a minimum schedule of pre-infusion, one day post-infusion, then weekly for 4 weeks post CTL infusion, monthly up to 6 months then every 3 months until 1 year post CTL infusion. A comparison of pre- and post-infusion viral load will be made to determine the degree of reduction in viral copy number occurring following T cell administration.
Secondary outcome [2] 342373 0
Use of antiviral agents.

The use of anti-viral treatment will be assessed using medical records which contains clinician documentation, medication charts and prescriptions.
Timepoint [2] 342373 0
From first infusion till 12 months after the last infusion of the investigational product.
Secondary outcome [3] 342374 0
Days spent as an in-patient in a hospital ward.
Timepoint [3] 342374 0
Days spent as an in-patient in a hospital ward. will be periodically assessed at 6 months and 12 months post-transplant. This information will be based on hospital records.
Secondary outcome [4] 342375 0
Graft function at 6 and 12 months post-transplant

Evidence of graft function will be determined as appropriate by transplant clinicians caring for patients according to best practice methods for detecting and documenting graft function.
Timepoint [4] 342375 0
At 6 months post-transplant and 12 months post-transplant
Secondary outcome [5] 342376 0
Persistence of infused T cells

Persistence of infused T cells will be assessed by T cell chimerism analysis
Timepoint [5] 342376 0
The persistence of infused T cells will be reviewed weekly for 4 weeks, fortnightly for one month then monthly for 4 months, 3 monthly for 6 months. Thus, the trial specific, follow up will occur a total of 12 months post-infusion.
Secondary outcome [6] 342377 0
Correlation of response with degree of HLA matching
HLA matching will be assessed by determining the number of HLA molecules matched between 3rd party T-cell donor and recipient through which an antiviral response can be shown to be mediated in the T-cell product. The patient’s best viral response at any time after T-cell infusion will be compared with the number of HLA matches mediating anti-viral responses to determine whether HLA matching correlated with better anti-viral responses.
Timepoint [6] 342377 0
The correlation of response with degree of HLA matching will be determined on the blood taken at 3 and 6 months.
Secondary outcome [7] 342378 0
Induction of alloantibodies to infused CTL lines.
Blood taken at 3 and 6 months will be examined for the presence of HLA antibodies directed at HLA molecules not shared between recipients and T-cell product. The presence of HLA antibodies will be correlated with the failure to achieve partial or complete virological response at any time after T-cell infusion.
Timepoint [7] 342378 0
Induction of alloantibodies to infused CTL lines will be determined on the blood samples taken at 3 and 6 months.
Secondary outcome [8] 342379 0
Incidence of acute and chronic graft versus host disease (GVHD)

Clinical evidence of graft versus host disease will be documented at scheduled follow up appointments.
Timepoint [8] 342379 0
Up to 12 months post last CTL infusion.

Eligibility
Key inclusion criteria
1) Recipients of myeloablative or non-myeloablative allogeneic stem cell transplantation for any indication.
2) Reactivation or infection with cytomegalovirus (CMV), Adenovirus (Adv) or Epstein-Barr virus (EBV) or EBV associated post-transplant lymphoproliferative disease (PTLD) must be present at the time of infusion as determined by:
o For CMV
- CMV detectable by antigen detection, Polymerase chain reaction (PCR) or culture in peripheral blood or tissue biopsy or by immunohistochemical staining on tissue biopsy specimen within 7 days of trial inclusion
o For Adv
- AdV detectable by antigen detection, PCR or culture in body fluids including blood, stool, urine or nasopharyngeal secretions or by immunohistochemical staining on tissue biopsy specimen within 7 days of trial inclusion
o For EBV, any of the following within 7 days of trial inclusion
- 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
3) Patients must satisfy criteria for initiation of treatment
o For CMV
- Most recent PCR in peripheral blood greater than or equal to 1,000 viral genome copies/ml OR positive antigen detection, PCR or culture in tissue in association with clinical symptoms and/or signs consistent with CMV tissue infection
o For AdV
- For asymptomatic patients (ie no fever, diarrhoea, respiratory symptoms etc):
Most recent PCR in peripheral blood greater than or equal to 1000 viral genome copies/ml in blood OR 2 positive PCR tests in any organ system that was negative prior to transplant
- For symptomatic patients:
1 positive PCR test from a symptomatic organ or in blood OR 2 positive PCR tests in any organ system that was negative prior to transplant
o For EBV
- Most recent PCR in peripheral blood greater than or equal to 10,000 viral genome copies/ml OR positive antigen detection, PCR or culture in tissue in association with clinical symptoms and/or signs consistent with EBV tissue infection or EBV associated post-transplant lymphoproliferative disease
4) Patients must not have received more than 7 days of prior treatment dose pharmacological anti-viral therapy at the time of T cell infusion. Treatment dose pharmacological therapy is defined as:
o For CMV
- IV ganciclovir or foscarnet at full dose or high dose acyclovir or one of its derivatives or brincidofovir (doses of aciclovir of 800 mg bd or valaciclovir 1 g/day or below will not be considered treatment dose).
o For Adv
- cidofovir or brincidofovir
o For EBV
- rituximab
- cytotoxic chemotherapy
5) 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)
6) ECOG status 0 to 3 or Lansky score 30-100
7) Patient (or legal representative) has given informed consent.
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) 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 unless anti-lymphocyte globulin levels in blood shown to be below the lympholytic threshold prior to infusion.
2) Active grade II or greater graft versus host disease within 1 week prior to infusion.
3) Prednisone or methylprednisolone at a dose of > 1 mg/kg (or equivalent in other steroid preparations) administered within 72 hours prior to cell infusion.
4) Dose of prednisone or methylprednisolone (if administered) not maintained at a stable level for 72 hours prior to T cell infusion
5) ECOG status 4 or Lansky score <30

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Non-randomised, stratified study with historical control group
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Infusion toxicities will be tabulated and presented according to severity and duration. Viral reactivation and infection rates will be plotted using Kaplan-Meier virus-free survival curves. A Cox proportional hazards model will be adjusted for co-variates. Viral load measurements post infusion will be graphed and compared with viral loads in control patients not receiving cell therapy. For parameters of virus-specific immune reconstitution we will plot individual patient profiles and use mixed effects models to model any pattern over time and to examine the effects of other covariates such as drug administration. Use of anti-viral pharmacological agents will be tabulated and presented as type, dose and duration of required therapy. Graft versus host disease incidence will be tabulated according to most severe grade of acute GVHD and site. For chronic GVHD, the extent of disease and sites of involvement will be tabulated. Rates and sites of GVHD will be compared with a historical group of identically treated patients.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 9491 0
Westmead Hospital - Westmead
Recruitment hospital [2] 9492 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 18232 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 298150 0
Charities/Societies/Foundations
Name [1] 298150 0
Leukaemia and Lymphoma Society US
Address [1] 298150 0
The Leukemia & Lymphoma Society
3 International Drive, Suite 200
Rye Brook, NY 10573
Country [1] 298150 0
United States of America
Funding source category [2] 298152 0
Charities/Societies/Foundations
Name [2] 298152 0
Rising Tide Foundation for Clinical Cancer Research
Address [2] 298152 0
Herrenacker 15, CH-8200 Schaffhausen, Switzerland
Country [2] 298152 0
Switzerland
Primary sponsor type
Government body
Name
Western Sydney Local Health District
Address
Cnr Hawkesbury and Darcy Rds
Wesmead
NSW
2145
Country
Australia
Secondary sponsor category [1] 297241 0
None
Name [1] 297241 0
Address [1] 297241 0
Country [1] 297241 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299164 0
Western Sydney Local District
Ethics committee address [1] 299164 0
REN Building
Westmead Hospital
Cnr Hawkesbury and Darcy Roads
Westmead
NSW
2145
Ethics committee country [1] 299164 0
Australia
Date submitted for ethics approval [1] 299164 0
28/09/2016
Approval date [1] 299164 0
09/02/2017
Ethics approval number [1] 299164 0

Summary
Brief summary
This project aims to determine whether infusing virus specific T cells from normal donors and frozen in liquid nitrogen is safe and effective therapy in patients at the first sign of virus infection after blood or bone marrow transplant. During the project a bank of frozen virus specific T cells will be created and if a blood or marrow transplant patient develops a virus infection that needs treatment, cells from the bank will be used early during the infection to see if they can recreate immunity to the infection and avoid the necessity for prolonged used of toxic antiviral drugs.
Trial website
None
Trial related presentations / publications
None
Public notes
There will be no maximum allowable time between infusions but the trial ceases 6 months after T-cell infusion so that effectively 6 months will be the maximum duration between infusions.

Contacts
Principal investigator
Name 79514 0
Prof David Gottlieb
Address 79514 0
Westmead Hospital
Cnr Hawkesbury and Darcy Roads
Westmead
NSW
2145
Country 79514 0
Australia
Phone 79514 0
+61, 02, 88907417
Fax 79514 0
+61, 02, 96893700
Email 79514 0
david.gottlieb@usyd.edu.au
Contact person for public queries
Name 79515 0
Miss Elissa Atkins
Address 79515 0
Haematology Clinical Trials Office
Westmead Hospital
Cnr Hawkesbury and Darcy Roads
Westmead
NSW
2145
Country 79515 0
Australia
Phone 79515 0
+61 02 88909269
Fax 79515 0
+61, 02, 96893700
Email 79515 0
Elissa.Atkins@health.nsw.gov.au
Contact person for scientific queries
Name 79516 0
Prof David Gottlieb
Address 79516 0
Westmead Hospital
Cnr Hawkesbury and Darcy Roads
Westmead
NSW
2145
Country 79516 0
Australia
Phone 79516 0
+61, 02, 88907417
Fax 79516 0
+61, 02, 96893700
Email 79516 0
david.gottlieb@usyd.edu.au

No data has been provided for results reporting
Summary results
Not applicable