ANZCTR - Registration

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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]

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

Condition category

Condition code

Inflammatory and Immune System

Other inflammatory or immune system disorders

Blood

Haematological diseases

Infection

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]

Treatment: Other

Comparator / control treatment

Uncontrolled

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Safety, as assessed clinically and with routine blood tests on regular follow-up

Timepoint [1]

at 24 hrs post infusion, and in the 12 months post-infusion

Secondary outcome [1]

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]

In the 12 months post-infusion

Secondary outcome [2]

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]

Weekly for 4 weeks, monthly until 6 months, and then 3 monthly until 12 months

Secondary outcome [3]

Incidence of acute and chronic graft versus host disease as assessed clinically and pathologically (where possible)

Timepoint [3]

In the 12 months post-infusion

Secondary outcome [4]

Days in hospital post-infusion

Timepoint [4]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,VIC

Recruitment hospital [1]

Westmead Hospital - Westmead

Recruitment hospital [2]

Royal Perth Hospital - Perth

Recruitment hospital [3]

Princess Margaret Hospital - Subiaco

Recruitment hospital [4]

Royal Children's Hospital - Herston

Recruitment hospital [5]

The Royal Childrens Hospital - Parkville

Recruitment hospital [6]

Sydney Children's Hospital - Randwick

Recruitment hospital [7]

The Alfred - Prahran

Recruitment hospital [8]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [9]

Womens and Childrens Hospital - North Adelaide

Recruitment hospital [10]

The Children's Hospital at Westmead - Westmead

Recruitment hospital [11]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [12]

Royal North Shore Hospital - St Leonards

Recruitment hospital [13]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [14]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment postcode(s) [1]

2145 - Westmead

Recruitment postcode(s) [2]

6000 - Perth

Recruitment postcode(s) [3]

6008 - Subiaco

Recruitment postcode(s) [4]

4006 - Herston

Recruitment postcode(s) [5]

3052 - Parkville

Recruitment postcode(s) [6]

2031 - Randwick

Recruitment postcode(s) [7]

3004 - Melbourne

Recruitment postcode(s) [8]

3052 - Melbourne University

Recruitment postcode(s) [9]

5006 - North Adelaide

Recruitment postcode(s) [10]

2145 - Wentworthville

Recruitment postcode(s) [11]

2065 - St Leonards

Recruitment postcode(s) [12]

2050 - Camperdown

Recruitment postcode(s) [13]

2010 - Darlinghurst

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

Hospital

Name

Western Sydney Local Health Districit

Address

Institute Road, Westmead
Sydney NSW 2145

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Western Sydney Local Health District Human Research Ethics Committee

Ethics committee address [1]

Research Office, Room 1072, Level 1, Education Block
Westmead Hospital, Hawkesbury & Darcy Roads, Westmead NSW 2145

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

02/04/2012

Ethics approval number [1]

HREC2012/2/4.1(3446) AU RED HREC/12/WMEAD/10

Summary

Brief summary

To assess the safety and efficacy of providing partially HLA matched, third party donor-derived, EBV/CMV/adenovirus-specific cytotoxic t-cells, to allogeneic stem cell/marrow transplant patients who have developed post-transplant viral infections unresponsive to standard therapy. It is hypothesised that virus-specific t-cells infusions will improve or restore the virus-specific immunity of the transplant patient in a safe manner without precipitating graft versus host disease.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof David Gottlieb

Address

Department of Medicine,
Westmead Hospital,
Hawkesbury Rd, Westmead,
Sydney, NSW 2145

Country

Australia

Phone

+612-9845-6033

Fax

+612-9687-2331

[email protected]

Contact person for public queries

Name

Barbara Withers

Address

Westmead Millennium Institute,
Leukaemia Cellular Therapies,
Darcy Rd,
Westmead, NSW 2145

Country

Australia

Phone

+61 2 9845 9070

Fax

[email protected]

Contact person for scientific queries

Name

David Gottlieb

Address

Department of Medicine,
Westmead Hospital,
Hawkesbury Rd, Westmead,
Sydney, NSW 2145

Country

Australia

Phone

+612-9845-6033

Fax

+612-9687-2331

[email protected]

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

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Barbara Withers, Emily Blyth, Leighton Clancy, Agn... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells	2017	https://doi.org/10.1182/bloodadvances.2017010223
Embase	Establishment and Operation of a Third-Party Virus-Specific T Cell Bank within an Allogeneic Stem Cell Transplant Program.	2018	https://dx.doi.org/10.1016/j.bbmt.2018.08.024
Dimensions AI	Mass cytometry reveals immune signatures associated with cytomegalovirus (CMV) control in recipients of allogeneic haemopoietic stem cell transplant and CMV-specific T cells	2020	https://doi.org/10.1002/cti2.1149

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically