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Trial registered on ANZCTR


Registration number
ACTRN12615000422527
Ethics application status
Approved
Date submitted
20/04/2015
Date registered
4/05/2015
Date last updated
27/06/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase I clinical trial of autologous Epstein–Barr virus-specific T cell therapy as treatment of progressive multiple sclerosis
Scientific title
Phase I clinical trial to assess feasibility, safety and tolerability of autologous Epstein–Barr virus-specific T cell therapy as treatment of patients with progressive multiple sclerosis
Secondary ID [1] 286315 0
QMS01
Universal Trial Number (UTN)
nil
Trial acronym
Adoptive immunotherapy for multiple sclerosis
Linked study record

Health condition
Health condition(s) or problem(s) studied:
multiple sclerosis 294414 0
Condition category
Condition code
Neurological 294723 294723 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants who meet the trial eligibility criteria following screening and review of blood test results will donate a 200-400 mL blood sample. Peripheral blood mononuclear cells from this sample will be used for laboratory generation of autologous latent membrane protein(LMP1&2)/Epstein-Barr virus nuclear antigen 1 (EBNA1)-specific T cells suspended in clinical grade normal saline.

The investigational product is produced by stimulation with gamma-irradiated autologous peripheral blood mononuclear cells infected with the recombinant adenoviral vector AdE1-LMPpoly. This vector encodes multiple CD8+ T cell epitopes from the EBV latent proteins EBNA1 and LMP1&2. The T cell cultures will be assessed for cell yield, viability and T cell frequency. Approximately 5 weeks will usually pass between collection of the 200-400 mL blood sample and first cell administration.

Patients will receive the T cell therapy intravenously, at fortnightly intervals. Each dose is given once, the initial dose will be 5 × 10^6 T cells, followed by doses of 1 × 10^7, 1.5 × 10^7, and 2 × 10^7 cells. A total of 4 doses will be given over a period of 8 weeks.

The cells will be administered via an intravenous line drip, allowing the slow administration of T cells into the blood, rather than a bolus of cells. The cells will be thawed into 20 mL saline, and will be administered to patients via a normal saline intravenous line over 10–15 min.

Participants will be followed up for 27 weeks from the first cell administration.
Intervention code [1] 291359 0
Treatment: Other
Comparator / control treatment
nil (single arm phase 1 study, no comparator group)
Control group
Uncontrolled

Outcomes
Primary outcome [1] 294483 0
To determine if autologous LMP/EBNA1-specific T cells can be generated to clinical scale from the blood of patients with progressive MS. This will be determined by calculating the proportion of patients for whom the minimum number of two doses of T cells can be generated (ie one vial of 5 x 10^6 cells and one vial of 1 x 10^7 cells).
Timepoint [1] 294483 0
For each patient, the feasibility of generating the T cell therapy will be known approximately 5 weeks after the collection of 200-400mL blood for therapy generation. The overall feasibility of generating LMP/EBNA-1-specific T cell therapy for the patient cohort will be calculated at the end of the study.
Primary outcome [2] 294484 0
To assess the safety of adoptive transfer of LMP/EBNA1-specific T cells into patients with progressive MS
Timepoint [2] 294484 0
At each treatment/cell transfer (weeks 1, 3, 5 and 7) and then 1 month and 2 months after the final cell transfer, and then twice at six-weekly intervals. If the patient receives four adoptive transfers, follow-up visits will occur at weeks 11, 15, 21 and 27.
Primary outcome [3] 294906 0
To assess the tolerability of adoptive transfer of LMP/EBNA1-specific T cells into patients with progressive MS. This outcome is assessed using the Kurtzke Expanded Disability Scale (EDSS)
Timepoint [3] 294906 0
At week 1 and 7 treatment/cell transfer and then at weeks 15 and 27.
Secondary outcome [1] 313433 0
nil
Timepoint [1] 313433 0
not applicable

Eligibility
Key inclusion criteria
1. Primary progressive or secondary progressive MS
2. Positive EBV serology
3. Age 18 years or above
4. Provision of informed consent
5. EDSS score of 5.0–8.0 (Kurtzke Expanded Disability Status Scale)
6. Life expectancy of at least 6 months, as determined by the Clinical Investigator
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Positive serology and/or nucleic acid testing (NAT) for human immunodeficiency virus (HIV)
2. Serology and/or NAT indicating active hepatitis B virus (HBV) infection or carrier status for HBV
3. Serology and/or NAT indicating active hepatitis C virus (HCV) infection
4. Positive serology for syphilis or human T cell lymphotrophic virus (HTLV I/II)
5. Significant non-malignant disease (e.g. severe cardiac or respiratory dysfunction)
6. Uncontrolled psychosis, uncontrolled depression, substance dependence, or any other psychiatric condition that may compromise the ability to participate in this trial
7. Inability to provide informed consent, including patients with severe cognitive impairment, intellectual disability, or mental illness
8. Clinically significant abnormalities of full blood count, renal function, or hepatic function
9. Any contraindication to Magnetic Resonance Imaging (MRI)
10. Prior cancers, except those diagnosed >5 years ago with no evidence of disease recurrence and clinical expectation of recurrence of <5%, or successfully treated non-melanoma skin cancer, or carcinoma in situ of the cervix
11. Immunomodulatory therapy (apart from short courses of corticosteroids) within the past year
12. Pregnant or unwilling to use adequate contraception

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)
Patients will be identified as candidates for the trial by the Clinical Investigator based on their diagnosis of progressive MS. Patients who are identified as candidates for the trial will be provided with the Participant Information and Consent Form.

The Clinical Investigator will conduct the informed consent discussion and answer any questions about the study and will check that the participant comprehends the information provided. Consent will be voluntary. The Investigator that conducts the consent discussion will also sign the PICF, attesting that they have provided the relevant explanation. A copy of the signed form will be given to the participant, and the participant’s consent to the study will be documented in the participant’s record.

Patients who provide written informed consent will have their details entered in the Subject Screening Log and will undergo screening. If a patient meets the eligibility criteria following this screening process, they will be enrolled in the trial and their details will be recorded in the Subject Enrolment Log.

Once eligibility is confirmed, the patient will donate a 200-400ml blood sample which will be used to generate LMP/EBNA1-specific T cells for 2–4 adoptive transfers. Once these cells have passed quality assurance assessment, treatments will be scheduled.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
not applicable, single group, non-randomised study
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
none
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical analysis of safety will be undertaken using the Kurtzke Expanded Disability Status Scale (EDSS). Based on the study by Confavreux and Vukusic (Brain, 126: 770–782, 2003) on the natural history of MS, two of the 10 patients are likely to experience an EDSS score increase of 1.0 point in a 6 month period. With a probability of that event occurring in a given patient being therefore 0.2, the probability of observing at least one subject experience an EDSS score increase of 1.0 point in a sample of 10 subjects is 0.90. There will be 80% power to detect a change in the proportion of the events from 0.2 to 0.58.

Recruitment
Recruitment status
Active, not 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)
QLD
Recruitment hospital [1] 3541 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 9344 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 290889 0
Charities/Societies/Foundations
Name [1] 290889 0
QIMR Berghofer Medical Research Institute
Address [1] 290889 0
300 Herston Rd
Herston QLD 4006
Country [1] 290889 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
QIMR Berghofer Medical Research Institute
Address
300 Herston Rd
Herston QLD 4006
Country
Australia
Secondary sponsor category [1] 289844 0
None
Name [1] 289844 0
Address [1] 289844 0
Country [1] 289844 0
Other collaborator category [1] 278387 0
Individual
Name [1] 278387 0
Professor Michael Pender
Address [1] 278387 0
Level 9, Health Sciences Building
Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029
Country [1] 278387 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292489 0
QIMR Berghofer Human Research Ethics Committee
Ethics committee address [1] 292489 0
300 Herston Rd
Herston QLD 4006
Ethics committee country [1] 292489 0
Australia
Date submitted for ethics approval [1] 292489 0
Approval date [1] 292489 0
17/07/2014
Ethics approval number [1] 292489 0
P1565
Ethics committee name [2] 292491 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [2] 292491 0
Royal Brisbane and Women's Hospital
Level 7 Block 7
Butterfield St
Herston QLD 4029
Ethics committee country [2] 292491 0
Australia
Date submitted for ethics approval [2] 292491 0
Approval date [2] 292491 0
15/09/2014
Ethics approval number [2] 292491 0
HREC/14/QRBW/366
Ethics committee name [3] 292492 0
The University of Queensland Medical Research Ethics Committee
Ethics committee address [3] 292492 0
UQ Research and Innovation
Cumbrae Stewart Building
Research Rd
Brisbane QLD 4072
Ethics committee country [3] 292492 0
Australia
Date submitted for ethics approval [3] 292492 0
Approval date [3] 292492 0
24/09/2014
Ethics approval number [3] 292492 0
2014001289

Summary
Brief summary
In this research project, we are trying to boost immune response against Epstein-Barr virus, with the aim of delaying the progression of multiple sclerosis (MS) and decreasing symptoms. Specifically, this trial aims to improve the killer T cell response against EBV, to enable the effective killing of virus-infected B cells. To do this, we are testing an experimental treatment for MS called adoptive immunotherapy.

Adoptive immunotherapy involves collecting a patient's own blood, and then stimulating their T cells in the laboratory. This stimulation causes the EBV-specific T cells to multiply. Once the patient's EBV-specific T cells have been grown in the laboratory, they will be transferred back into the patient's blood, with the aim that they will recognise EBV-infected B cells in the brain and kill them. However, because some laboratory studies have suggested that EBV-specific T cells might aggravate inflammation in the brain and actually worsen MS, this treatment needs to be used cautiously.
Trial website
none
Trial related presentations / publications
none to date
Public notes

Contacts
Principal investigator
Name 55554 0
Prof Rajiv Khanna
Address 55554 0
QIMR Berghofer Centre for Immunotherapy and Vaccine Devleopment, Tumour Immunology Laboratory
Level 10, CBCRC, QIMR Berghofer
300 Herston Rd
Herston QLD 4006
Country 55554 0
Australia
Phone 55554 0
+61 7 3362 0385
Fax 55554 0
Email 55554 0
Rajiv.Khanna@qimrberghofer.edu.au
Contact person for public queries
Name 55555 0
Dr Michelle Neller
Address 55555 0
QIMR Berghofer Medical Research Institute
300 Herston Rd
Herston QLD 4006
Country 55555 0
Australia
Phone 55555 0
+61 7 3362 0412
Fax 55555 0
+61 7 3845 3510
Email 55555 0
immunotherapy@qimrberghofer.edu.au
Contact person for scientific queries
Name 55556 0
Prof Rajiv Khanna
Address 55556 0
QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory
Level 10, CBCRC, QIMR Berghofer
300 Herston Rd
Herston QLD 4006
Country 55556 0
Australia
Phone 55556 0
+61 7 3362 0385
Fax 55556 0
Email 55556 0
Rajiv.Khanna@qimrberghofer.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary