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Trial registered on ANZCTR


Registration number
ACTRN12618001541291
Ethics application status
Approved
Date submitted
3/08/2018
Date registered
14/09/2018
Date last updated
26/02/2020
Date data sharing statement initially provided
16/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the use of Ibrutinib in combination with donated immune cells in patients with Epstein-Barr Virus positive lymphomas
Scientific title
An Open label, Multicentre, Phase I study of Ibrutinib and 3rd Party EBV specific T cells in Patients with immunosuppression related EBV-positive Brain and/or Systemic B cell lymphomas, that are relapsed/refractory or unsuitable for standard first-line treatments.
Secondary ID [1] 295735 0
None
Universal Trial Number (UTN)
Trial acronym
TREBL-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
EBV+ Lymphoma 309133 0
Condition category
Condition code
Cancer 308013 308013 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Ibrutinib (oral tablet) - daily 560mg orally weeks 1 to 78 weeks. Drug adherence monitored by direct observation.

Most closely HLA matched 3rd Party EBV-specific CTL intravenous infusions, x4 in total, once per week, at weeks 10, 11, 12, 13 (dose of 3x10^7/m2 per infusion, except for 2x10^7/m2 in alloSCT recipients).
Intervention code [1] 312056 0
Treatment: Drugs
Intervention code [2] 312335 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307002 0
Safety - analysed by reviewing documented adverse events occurring within the first 6 weeks of ibrutinib commencement and also within 21 days of last CTL infusion (week 16) and determining the nature, incidence, severity and likely causality of such events. Organ toxicity will be analysed according to standard criteria (NCI Common Toxicity Criteria ver 5.0).
Adverse events are directly reported into the electronic case report form (eCRF) database by site staff treating the event.
Timepoint [1] 307002 0
first 6 weeks of ibrutinib commencement and also within 21 days of last CTL infusion (week 16)
Primary outcome [2] 320734 0
Feasibility - Accrual rate over lifetime of the study; Number of patients remaining on ibrutinib at 8, 16, 34, 50, 78 weeks; Number of patients receiving 3rd Party EBV-specific T cells; Number of patients receiving 4 infusions of 3rd Party EBV-specific T cells; Number of patients receiving >1 infusion of 3rd Party EBV-specific T cells; Median number of 3rd Party EBV-specific T cell infusions; Proportion of patients remaining on study at 52 weeks.
Timepoint [2] 320734 0
at weeks 8, 16, 34, 50 and 78 evaluation time-points.
Primary outcome [3] 320735 0
Fold-change in EBV-specific T cell immunity from baseline - % of patients receiving 3rd Party EBV-specific CTL that have greater than or equal to 2 fold increase in EBV-specific T cell immunity from baseline, at a 1 hour post-infusion time-point; Median fold-change in in EBV-specific T cell immunity from baseline in patients receiving 3rd Party EBV-specific CTL.
Timepoint [3] 320735 0
At CTL infusion time-points - Weeks 10, 11, 12 and 13, both pre- and post-infusion.
Secondary outcome [1] 350318 0
Response rates (CR, PR, SD, PD) assessed by disease specific tests including biopsy and/or radiographic imaging
Timepoint [1] 350318 0
at weeks 8, 16, 34, 52, 78 evaluation time-points.

Eligibility
Key inclusion criteria

1. Histologically confirmed EBV+ve B cell NHLs or Hodgkin Lymphoma occurring in the immunosuppressed (acquired e.g. HIV, iatrogenic e.g. PTLD, methotrexate, primary e.g. inherited, congenital). If Hodgkin Lymphoma, then the rituximab is recommended but not mandated, in patients with PTLD (to assist with reduction in iatrogenic immunosuppression). Methodology for detection of EBV within the biopsy is not mandated, but it is expected will typically be EBER in situ hybridization. Other methodologies will need to be confirmed with the investigative team on a case-by-case basis.


2. Systemic and/or CNS lymphoma, including ocular lymphoma.


3. Patient has relapsed/refractory or (at physician’s discretion) unsuitable for standard first-line treatments.


4. At least 1 measurable site of disease according to the 2014 Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non Hodgkin Lymphoma – the Lugano Classification. The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement. Any clinical stage permitted.


5. Age greater than or equal to 18 years.


6. Provision by patient or legally acceptable representative of informed consent indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study.


7. ECOG performance status 0-3.


8. Minimum life expectancy of 3 months.


9. Haematology values must be within the following limits:

a. Absolute neutrophil count (ANC) greater than or equal to 0.75x109/L independent of growth factor support

b. Platelets greater than or equal to 75x109/L or greater than or equal to 50x109/L if bone marrow involvement independent of transfusion support in either situation.


10. Biochemical values within the following limits:

a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =less than or equal to 3 x upper limit of normal (ULN).

b. Total bilirubin less than or equal to 2.0 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin.

c. > 30 mL/min creatinine clearance permitted. Patients on dialysis are permitted irrespective of renal function and in these patients pharmacokinetics assays and guidance are mandated.


11. Patients requiring treatment with moderate CYP3A inhibitors (see Appendix 6) are permitted, but are recommended to commence with lower ibrutinib dosing, and then escalate as tolerated. Ibrutinib pharmacokinetic assays are available, if requested, to all patients, including those requiring treatment with moderate CYP3A inhibitors. Patients are ineligible from accrual if they are on a strong CYP3A4 inhibitor (see Appendix 6) unless an alternative medication can be found. The exception to this is posaconazole, as the investigative team have previously administered ibrutinib (420mg, then stepped to 560mg) without toxicity. In that scenario, pharmacokinetic monitoring and guidance is mandated. Patients requiring a strong CYP3A4 inhibitor at a later point during the course of the study, must cease ibrutinib. It can be restarted once the CYP3A4 inhibitor has ceased. If the CYP3A4 inhibitor is to be continued, ibrutinib can be restarted at a lower dose at physicians discretion. In this scenario, pharmacokinetic monitoring and guidance is mandated.


12. Patients that are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree not to donate sperm during and after the study.


13. HIV+ patients are permitted, providing patients have CD4 counts greater than or equal to 350m3, agree to adhere to ongoing combination antiretroviral therapy, and have an HIV RNA viral load <400 copies/ml. Strong CYP3A4 inhibitor anti-retrovirals are not permitted and patients will need to be switched to an alternative agent.


14. Patients with resolved (HBsAg negative, HBcAb positive) HBV are permitted providing they have prophylaxis with entecavir or equivalent and monitored with HBV markers (HBV serology/HBV viral load) 3 monthly.

a. Patients with occult HBV (HBsAg negative, detectable HBV viral load) are permitted but should have prophylaxis with entecavir or equivalent and monitored with HBV markers (HBV serology/HBV viral load) 3 monthly.
Duration of prophylaxis will be at least 18 months post completion of ibrutinib therapy.

b. Patients with chronic HBV (HBsAg positive, detectable HBV viral load) should have HBV treatment with entecavir and can only enter trial if viral load undetectable.

All patients meeting criteria 14.a-c should be referred to a hepatology specialist.

15.
a. Patients with past HCV (HCV antibody positive but HCV RNA viral load negative) are eligible.

b. Patients with chronic HCV (HCV antibody positive, HCV RNA viral load detectable) are eligible if they have completed HCV therapy and if they have a sustained undetectable viral load.

All patients meeting criteria 15.a-b should be referred to a hepatology specialist.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Primary Effusion, Burkitt’s, and ENKT lymphomas.

2. Contraindication to any drug in the proposed regimen.

3. Serious active co-morbid disease according to the investigator’s decision.

4. Poor hepatic function, defined as Alanine aminotransferase (ALT) and aspartate.
aminotransferase (AST) > 3 x upper limit of normal (ULN) and/or total bilirubin > 2.0 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin.

5. History of malignancy during the past 2 years, with the exception of non-melanoma skin cancers or stage 0 (in situ) carcinoma.

6. Treatment with any investigational drug within 30 days before the planned first cycle of chemotherapy.

7. Requires anticoagulation with warfarin or equivalent vitamin K antagonists.

8. Requires treatment with fish oil.

9. History of stroke or intracranial haemorrhage within 6 months of enrolment.

10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

11. Known severe bleeding disorders (e.g. severe von Willebrand’s disease).

12. Major surgery within 4 weeks of enrolment.

13. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.

14. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.

15. Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.

16. Vaccinated with live, attenuated vaccines within 4 weeks of enrolment.

17. HIV+ patients with a CD4 T cell count <350m3 and/or cannot commit to adhere to ongoing combination antiretroviral therapy, and/or have an HIV RNA viral load greater than or equal to 400 copies/ml. Strong CYP3A4 inhibitor anti-retrovirals are not permitted and patients will need to be switched to an alternative agent.

18. Women who are pregnant or lactating.

19. Previous severe adverse reaction to rituximab, ibrutinib, or 3rd Party EBV-specific CTL.

20. Participation in ongoing other therapeutic studies except for studies with a non-medical intervention.

21. Patients requiring anti-tuberculosis medication at time of study entry.

22. Patients are ineligible from accrual if they are on a strong CYP3A4 inhibitor (see eligibility criteria point 11) unless an alternative medication can be found. The exception to this is posaconazole, as the investigative team have previously administered ibrutinib (420mg, then stepped to 560mg) without toxicity. In that scenario, pharmacokinetic monitoring and guidance is mandated. Patients requiring a strong CYP3A4 inhibitor at a later point during the course of the study, must cease ibrutinib. It can be restarted once the CYP3A4 inhibitor has ceased. If the CYP3A4 inhibitor is to be continued, ibrutinib can be restarted at a lower dose at physicians discretion. In this scenario, pharmacokinetic monitoring and guidance is mandated.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

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,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 14234 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 14235 0
Westmead Hospital - Westmead
Recruitment hospital [3] 15996 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [4] 15997 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [5] 15998 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 15999 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 16000 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [8] 16001 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 29494 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 27228 0
2145 - Westmead
Recruitment postcode(s) [3] 29499 0
3004 - Melbourne
Recruitment postcode(s) [4] 29498 0
3084 - Heidelberg
Recruitment postcode(s) [5] 27227 0
4102 - Woolloongabba
Recruitment postcode(s) [6] 29497 0
5000 - Adelaide
Recruitment postcode(s) [7] 29495 0
6009 - Nedlands
Recruitment postcode(s) [8] 29496 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 300327 0
Government body
Name [1] 300327 0
Department of Health and Human Resources
Address [1] 300327 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 300327 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Ground Floor, 35 Elizabeth St Richmond, VIC 3121
Country
Australia
Secondary sponsor category [1] 299763 0
None
Name [1] 299763 0
Address [1] 299763 0
Country [1] 299763 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301138 0
Metro South Health HREC
Ethics committee address [1] 301138 0
Metro South Health
Level 3, R-Wing
199 Ipswich Road, Woolloongabba, QLD 4102
Ethics committee country [1] 301138 0
Australia
Date submitted for ethics approval [1] 301138 0
01/11/2018
Approval date [1] 301138 0
21/03/2019
Ethics approval number [1] 301138 0
HREC/2018/QMS/47212

Summary
Brief summary
This study is testing a combination of a medication called Ibrutinib and infusions of EBV-specific immune cells in the treatment of lymphoma.

Who is it for?
You may be eligible for this study if you are aged 18 or over and have confirmed EBV positive lymphoma, including Hodgkin-, non Hodgkin-, Systemic, central nervous system and ocular lymphomas.

Study details
All participants will take orally tablets of the medication Ibrutinib daily for 78 weeks (about one and a half years). In addition to this medication, participants will have 4 infusions, via needle, of virus-specific immune cells. Throughout the study various standard tests will be conducted including blood tests, radiographic imaging and questionnaires.

It is hoped this research will demonstrate that these infusions in combination with Ibrutinib will be a safe and effective therapy for lymphoma patients with compromised immune systems.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85982 0
Prof Maher Gandhi
Address 85982 0
The University of Queensland Diamantina Institute Translational Research Institute | Lvl 4 East, Kent St | Brisbane, QLD Australia 4102
Country 85982 0
Australia
Phone 85982 0
+61 (0)7 3443 8026
Fax 85982 0
Email 85982 0
maher.gandhi@maher.uq.edu.au
Contact person for public queries
Name 85983 0
Prof Maher Gandhi
Address 85983 0
The University of Queensland Diamantina Institute Translational Research Institute | Lvl 4 East, Kent St | Brisbane, QLD Australia 4102
Country 85983 0
Australia
Phone 85983 0
+61 (0)7 3443 8026
Fax 85983 0
Email 85983 0
maher.gandhi@maher.uq.edu.au
Contact person for scientific queries
Name 85984 0
Prof Maher Gandhi
Address 85984 0
The University of Queensland Diamantina Institute Translational Research Institute | Lvl 4 East, Kent St | Brisbane, QLD Australia 4102
Country 85984 0
Australia
Phone 85984 0
+61 (0)7 3443 8026
Fax 85984 0
Email 85984 0
maher.gandhi@maher.uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
No other documents available
Summary results
No Results