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Trial registered on ANZCTR


Registration number
ACTRN12613000603718
Ethics application status
Approved
Date submitted
4/04/2013
Date registered
28/05/2013
Date last updated
10/08/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Phase I/II clinical trial to assess the safety and biological efficacy of treatment with virus-specific, cytotoxic T-lymphocytes from partially matched third-party unrelated donors, in stem cell transplant patients with viral reactivation unresponsive to standard therapy (R3ACT trial)
Scientific title
In allogeneic stem cell transplant patients, with viral reactivation unresponsive to standard antiviral therapy, is therapeutic infusion of most closely HLA-matched, third party, donor-derived, virus-specific cytotoxic T-lymphocytes, safe and efficacious?
Secondary ID [1] 282155 0
Nil known
Universal Trial Number (UTN)
U1111-1140-8324
Trial acronym
R3ACT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Viral reactivation post-allogeneic stem cell transplant 288661 0
Condition category
Condition code
Inflammatory and Immune System 289005 289005 0 0
Other inflammatory or immune system disorders
Blood 289006 289006 0 0
Haematological diseases
Infection 289072 289072 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment will consist of an initial infusion of 2 x 10^7/m^2 partially HLA-matched (minimum 1/6), third party, donor-derived, virus-specific (CMV, EBV, and/or adenovirus) cytotoxic T-lymphocytes. Up to 3 subsequent infusions (with an option of increased dose up to 5 x 10^7/m^2) may be repeated at fortnightly intervals, on the basis of persistent viral reactivation.
Intervention code [1] 286764 0
Treatment: Other
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 289121 0
Safety, as assessed clinically and with routine blood tests on regular follow-up
Timepoint [1] 289121 0
at 24 hrs post infusion, and in the 12 months post-infusion
Secondary outcome [1] 301862 0
Reconstitution of virus-specific immunity will be measured by quantifying virus specific immune cells in the peripheral blood of recipients using flow cytometry and by assessing the functional responses of cells to stimulation with CMV pp65, AdV Hexon, EBV EBNA1, LMP1 and LMP2.
Timepoint [1] 301862 0
In the 12 months post-infusion
Secondary outcome [2] 301863 0
Post-infusion incidence of viral reactivation, viral disease, organ damage, and virus-specific pharmacotherapy, as assessed by clinical assessment, radiological imaging, viral PCR, and/or viral culture
Timepoint [2] 301863 0
Weekly for 4 weeks, monthly until 6 months, and then 3 monthly until 12 months
Secondary outcome [3] 301864 0
Incidence of acute and chronic graft versus host disease as assessed clinically and pathologically (where possible)
Timepoint [3] 301864 0
In the 12 months post-infusion
Secondary outcome [4] 301971 0
Days in hospital post-infusion
Timepoint [4] 301971 0
In the 12 months post-infusion

Eligibility
Key inclusion criteria
1. Recipients of myeloablative or non-myeloablative allogeneic transplantation for any indication.

2. Viral reactivation or infection with CMV, Adv or EBV as determined by:
A) CMV
- CMV detectable by antigen detection, PCR or culture in peripheral blood or tissue biopsy or by immunohistochemical staining on tissue biopsy specimen
B) Adv
- Presence of Adv as detected by PCR, antigen detection or culture in body fluids including blood, stool, urine or nasopharyngeal secretions
C) 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

3. Failure of standard therapy as defined by:
A) 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
B) 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)
C) 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

4. 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)

5. ECOG status 0 to 3

6. Patient (or legal representative) has given informed consent.
Minimum age
No limit
Maximum age
No limit
Sex
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.

2. Grade II or greater graft versus host disease within 1 week prior to infusion.

3. Prednisone or methylprednisone at a dose of > 1 mg/kg (or equivalent in other steroid preparations) administered within 72 hours prior to cell infusion.

4. ECOG status 4

5. Privately insured patients (dependent on site)

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)
Subjects are not randomised
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis
Statistical methodology
1. Sample Size
We anticipate enrolling 30 patients over 4 years. The primary endpoint is CTL safety, and sample size was considered on the basis of the following safety projections. Mortality at 3 months is anticipated to be approximately 10%, and the composite of mortality, graft failure or acute grade 3-4 graft versus host disease, is anticipated to be approximately 25% at 3 months. Based on these projections, 95% confidence intervals were calculated, and estimates of power were provided relating to probability of exceeding thresholds for mortality and composite event rates for sample sizes of 10, 20, 30, 40. A sample size of 30 was felt to offer the best balance of ability to recruit in a timely manner, with reasonable power to assess safety particulary considering mortality and composite mortality/graft failure/GVHD endpoints. The study is highly powered (>80%) to detect a mortality rate greater than 40%, and composite end points at a rate of greater than 50%, and moderately powered (>60%) to detect a mortality rate greater than 30%. Stopping guidelines are in place in the event that the mortality exceeds 10% or the composite endpoint exceeds 25-30%
2. Analysis of feasibility of generation of CTLS
Feasibility of generation of specific CTLs will be determined by analysing the success of cell generation according to pre-established quality control guidelines. All consenting donors will be included on an intention to treat analysis irrespective of subsequent events including virus specific cell infusion.
3. Analysis of feasibility of cell infusion
Patients consenting to participation in the study may become ineligible on the basis of subsequent development of exclusion criteria, voluntary withdrawal, unavailability of a matched virus-specific CTL product or death. To determine what percentage of patients who initially consenting to participation receive treatment as planned, an intention to treat analysis of consenting patients will be performed. Reasons for failure to receive virus specific CTL will be documented on CRFs.
4. Statistical analysis of data
We will illustrate viral reactivation and infection rates by plotting Kaplan-Meier virus-free survival curves. A Cox proportional hazards model will be adjusted for co-variates. Peak viral load measurements post infusion will be graphed and compared with peak 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. Infusion toxicities will be tabulated and presented according to severity and duration. 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 (limited or extensive) 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
11/02/2013
Actual
11/02/2013
Date of last participant enrolment
Anticipated
1/02/2017
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 799 0
Westmead Hospital - Westmead
Recruitment hospital [2] 800 0
Royal Perth Hospital - Perth
Recruitment hospital [3] 801 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [4] 802 0
Royal Children's Hospital - Herston
Recruitment hospital [5] 803 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [6] 804 0
Sydney Children's Hospital - Randwick
Recruitment hospital [7] 805 0
The Alfred - Prahran
Recruitment hospital [8] 806 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [9] 807 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [10] 808 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [11] 4151 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [12] 4152 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [13] 4153 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [14] 4154 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 6620 0
2145 - Westmead
Recruitment postcode(s) [2] 6622 0
6000 - Perth
Recruitment postcode(s) [3] 6623 0
6008 - Subiaco
Recruitment postcode(s) [4] 6624 0
4006 - Herston
Recruitment postcode(s) [5] 6625 0
3052 - Parkville
Recruitment postcode(s) [6] 6626 0
2031 - Randwick
Recruitment postcode(s) [7] 6627 0
3004 - Melbourne
Recruitment postcode(s) [8] 6628 0
3052 - Melbourne University
Recruitment postcode(s) [9] 6629 0
5006 - North Adelaide
Recruitment postcode(s) [10] 6630 0
2145 - Wentworthville
Recruitment postcode(s) [11] 10079 0
2065 - St Leonards
Recruitment postcode(s) [12] 10080 0
2050 - Camperdown
Recruitment postcode(s) [13] 10081 0
2010 - Darlinghurst
Recruitment outside Australia
Country [1] 7086 0
New Zealand
State/province [1] 7086 0
Auckland

Funding & Sponsors
Funding source category [1] 286949 0
Government body
Name [1] 286949 0
National Health and Medical Research Council
Country [1] 286949 0
Australia
Primary sponsor type
Hospital
Name
Western Sydney Local Health Districit
Address
Institute Road, Westmead
Sydney NSW 2145
Country
Australia
Secondary sponsor category [1] 285754 0
None
Name [1] 285754 0
Address [1] 285754 0
Country [1] 285754 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289013 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 289013 0
Ethics committee country [1] 289013 0
Australia
Date submitted for ethics approval [1] 289013 0
Approval date [1] 289013 0
02/04/2012
Ethics approval number [1] 289013 0
HREC2012/2/4.1(3446) AU RED HREC/12/WMEAD/10

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38622 0
Prof David Gottlieb
Address 38622 0
Department of Medicine,
Westmead Hospital,
Hawkesbury Rd, Westmead,
Sydney, NSW 2145
Country 38622 0
Australia
Phone 38622 0
+612-9845-6033
Fax 38622 0
+612-9687-2331
Email 38622 0
david.gottlieb@sydney.edu.au
Contact person for public queries
Name 38623 0
Barbara Withers
Address 38623 0
Westmead Millennium Institute,
Leukaemia Cellular Therapies,
Darcy Rd,
Westmead, NSW 2145
Country 38623 0
Australia
Phone 38623 0
+61 2 9845 9070
Fax 38623 0
Email 38623 0
bwithers@uni.sydney.edu.au
Contact person for scientific queries
Name 38624 0
David Gottlieb
Address 38624 0
Department of Medicine,
Westmead Hospital,
Hawkesbury Rd, Westmead,
Sydney, NSW 2145
Country 38624 0
Australia
Phone 38624 0
+612-9845-6033
Fax 38624 0
+612-9687-2331
Email 38624 0
david.gottlieb@sydney.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Barbara Withers, Emily Blyth, Leighton Clancy, Agn... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AILong-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells2017https://doi.org/10.1182/bloodadvances.2017010223
EmbaseEstablishment and Operation of a Third-Party Virus-Specific T Cell Bank within an Allogeneic Stem Cell Transplant Program.2018https://dx.doi.org/10.1016/j.bbmt.2018.08.024
Dimensions AIMass cytometry reveals immune signatures associated with cytomegalovirus (CMV) control in recipients of allogeneic haemopoietic stem cell transplant and CMV-specific T cells2020https://doi.org/10.1002/cti2.1149
N.B. These documents automatically identified may not have been verified by the study sponsor.