Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001189718
Ethics application status
Approved
Date submitted
23/08/2022
Date registered
6/09/2022
Date last updated
22/04/2024
Date data sharing statement initially provided
6/09/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
An multi site clinical trial for patients with EBV associated Lymphomas - ALLG NHL36
Scientific title
An early phase, open label, multicentre, trial study to assess safety and efficacy of front-line therapy for EBV-associated Lymphomas 2 (TREBL-2) - ALLG NHL36
Secondary ID [1] 307821 0
TREBL-2
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphoma 327421 0
Condition category
Condition code
Cancer 324547 324547 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Summary of treatment regimen:
There are 4 phases in the treatment regiment for this trial:
1. induction
2. combination
3. cell therapy
4. maintenance
Patients will only move on to the next consecutive phase once the previous phase is completed. All treatment will be administered by the study team.

Induction
200mg Tislelizumab given (intravenously) IV and 375mg/m2 Rituximab delivered IV given on day 1 of every week in the 21 day cycle. There are 3 cycles in this induction period. Patients are monitored for at least 60 minutes (Cycles 1 and 2) or 30 minutes (cycle 3) afterward in an area with resuscitation equipment and emergency agents.

Combination
Six cycles of combination therapy, each cycle is 3 weeks (21 days). The drugs received are:
*200mg Tislelizumab IV D1
*Rituximab 375mg/m2 IV D1
*Cyclophosphamide 750mg/m2 IV D1
*Doxorubicin 50mg/m2 IV D1
*Vincristine 1.4mg/m2 (max 2mg) IV D1
*Prednisolone 100mg orally (tablet) on D1-5 inclusive

Cell Therapy
Two infusions of autologous EBV virus specific T cells (VST) will be given a week a part. The infusions will be given IV by a member of the medical or nursing staff trained in the administration of cellular products. Each infusion of VST will be administered at a dosage of 3x10^7/m2.

Maintenance
Eight cycles of maintenance will be delivered, each cycle is 6 weeks duration.
400mg Tislelizumab IV will be delivered on day 1 of each cycle.
Intervention code [1] 324288 0
Treatment: Drugs
Comparator / control treatment
NA
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332371 0
The safety profile of Tislelizumab.
Timepoint [1] 332371 0
Patients ceasing trial therapy due to Tislelizumab-related adverse events (occurring during either Induction, Combination or Maintenance). Adverse events will be reviewed during the patients clinic revisits, blood tests and physical assessments at the start of each Phase and end of Combination and Cellular Therapy phases. Clinic visits will occur every 3 weeks during induction and combination phases, weekly for cellular therapy and every 6 weeks for Maintenance phase. This primary endpoint will not be completed until after all eligible patients have reached the 3rd Maintenance therapy cycle.
Examples of Tislelizumab-related adverse events include pyrexia, hypothyroidism, pruritus and decreased white blood cell count.
Primary outcome [2] 332372 0
The rate of EBV - specific T cell immunity
Timepoint [2] 332372 0
The rate of EBV specific T cell immunity will be determined when a responsive patient is defined as having a 10% increase in EBV-specific effector T cell function vs. baseline. This will not be completed until all eligible patients have completed the 4th blood draw (at 12months after cellular therapy). EBV-specific T-cell immunity will be compared at sequential time-points relative to baseline.
Secondary outcome [1] 413225 0
Complete Response (CR) at PET/CT4 and PET/CT5
Timepoint [1] 413225 0
The CR rate will be determined once all patients have completed PET/CT5. Response rates are determined using the PET scan. PET/CT scans will occur at the end of Induction, Combination and Cellular Therapy phases.
Secondary outcome [2] 413226 0
Progression free survival (PFS) at 3 years
Timepoint [2] 413226 0
PFS will be analysed at 3 years from the start of the trial. Progression is determined by assessing the patients PET/CT scans, blood results and bone marrow results.
Secondary outcome [3] 413246 0
Overall Survival (OS) at 3 years
Timepoint [3] 413246 0
OS will be analysed at 3 years from the start of the trial. OS is determined by assessing the patients PET/CT scans, blood results and bone marrow results.
Secondary outcome [4] 413247 0
Duration of response from Complete Remission (CR) obtained via SoC follow-up visits.
Timepoint [4] 413247 0
Duration of response is determined by the time from the date of first CR post Combination, to first documented progression/any cause of death. Starting at end of treatment, patients will initially be followed up for 1.5 years (3 monthly x6) from end of maintenance (to allow 3 year PFS/OS).
Then, study participants will be followed up 4 monthly for 1 year, then 6 monthly for 2 years, for clinical evaluation (Disease Status, Survival and Second Malignancies).
Secondary outcome [5] 413248 0
Patient Reported Outcomes (PROs) for quality of life assessment - QLQ-C30
Timepoint [5] 413248 0
PROs will be assessed by scoring questionnaires completed by patients during clinic visits at baseline and each following timepoint until end of treatment. From then on, follow up questionnaires will be completed 3 monthly for the first 1.5 years, 4 monthly for the next 1 year and 6 monthly for the next 1 year.
Secondary outcome [6] 413633 0
Patient Reported Outcomes (PROs) for quality of life assessment - EuroQOL EQ-5D
Timepoint [6] 413633 0
PROs will be assessed by scoring questionnaires completed by patients during clinic visits at baseline and each following timepoint until end of treatment. From then on, follow up questionnaires will be completed 3 monthly for the first 1.5 years, 4 monthly for the next 1 year and 6 monthly for the next 1 year.

Eligibility
Key inclusion criteria
1. Local histological diagnosis (on core or excision biopsy) of de-novo systemic CD20+ EBV-associated DLBCL by EBER-ISH (positive is equals to or greater than 50% of lymphoma cells) without immunosuppression. (Immunosuppression includes lymphomas occurring after methotrexate, in patients with HIV, or following solid organ or haematopoietic stem cell transplant, and patients with inherited immunodeficiencies).
2. Stages II-IV (or I with bulk equal to or greater than 7.5cm or systemic ‘B’ symptoms).
3. Aged greater than 45 years
4. Adequate major organ function defined as
a. ANC (segs + bands) equal to or greater than 1.0 x 10^9/L (can be supported by G-CSF).
b. Platelet count equal to or greater than 75 x 10^9/L (or 50 if bone marrow is involved)
c. Total bilirubin equal to or less than 1.5 x ULN (unless rise in bilirubin is due to Gilbert’s syndrome or of non-hepatic origin
d. ALT and AST equal to or less than 3 x ULN
e. Creatinine clearance equal to or greater than 30ml / min / 1.73m2 (Cockcroft-Gault formula)
f. LVEF within institutional normal limits (determined either by echocardiography or gated heart pool scan).
5. ECOG status 0-2 (2 if related to lymphoma)
6. Written informed consent.
7. Life expectancy at least 3 months
8. Men who are sexually active with women of child-bearing potential, and women of child-bearing potential, must use any highly effective contraceptive method during the study (failure rate greater then 1% per year) and for a period of 120 days after the last dose of therapy. Should pregnancy occur during therapy or before 120 days, the treating physician should be informed immediately.
9. PET/CT avid disease at baseline.
10. Positive EBV IgG serology.
11. Subjects must agree not to donate blood, semen or sperm while on study treatment and for least 120 days after treatment discontinuation
12. Subjects must agree not to share their medication and to return unused supplies
13. To take part in the PRO component of the study the subject must be able to read/write in English. Patients who do not meet this criteria can participate in the rest of the trial.
Minimum age
45 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. T cell lymphoma, transformed or 3B Follicular Lymphoma
2. CNS / meningeal / spinal cord involvement with lymphoma
3. Prior anti-PD-1 mAb
4. Active autoimmunity that might deteriorate when receiving an immunostimulatory agent. Note: Patients with the following diseases are not excluded and may proceed to further screening:
a. Controlled Type I diabetes
b. Hypothyroidism (provided it is managed with hormone replacement therapy only)
c. Controlled celiac disease
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia)
e. Any other disease that is not expected to recur in the absence of external triggering factors
5. Chronic prednisolone is greater than 10mg (or equivalent). Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses is equal to 10 mg or 10 mg equivalent prednisone per day. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.
6. Uncontrolled systemic infection, including active Hepatitis B/C. Patients with Hep B core Ab positive and Hep B surface antigen negative are permitted in the trial only if they have negative HBV DNA and must be on HBV prophylaxis (choice of prophylaxis is at physician’s discretion, with local guidance). Patients who are Hep B surface antigen positive are NOT allowed. Prior treated Hep C is allowed, provided HCV RNA is not detected.
7. As there is ‘chemo-free’ induction, patients requiring urgent cyto-reductive therapy for life-threatening disease are excluded. Requirement for urgent treatment due to life-threatening complications include for example: Compressive symptoms due to disease (which may or may not be bulky), such as superior vena caval obstruction; significant organ involvement causing compromise of organ function (including but not limited to liver, renal obstruction), malignant, symptomatic hypercalcaemia
8. Anticipated to be unable to receive full-dose R-CHOP
9. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal, squamous cell skin cancer, low risk melanoma, superficial bladder cancer, localised cancer of the prostate cancer, cervix, or breast
10. Immunosuppression related lymphoma (e.g. PTLD, HIV, methotrexate).(Immunosuppression related lymphomas include those occurring after methotrexate, in patients with HIV, or following solid organ or haematopoietic stem cell transplant, and patients with inherited immunodeficiencies).
11. Previous treatment for current lymphoma (including chemotherapy, radiotherapy or investigational drug). Prior treatment for a histologically distinct lymphoma is permitted.
12. No concurrent uncontrolled medical condition as determined by investigator
13. Prior immune checkpoint blockade therapy
14. Use of pre-phase corticosteroids is discouraged (but permitted) due to the potential for reduction in Tislelizumab activity. However, if patients have received pre-phase steroids for symptom relief prior to screening they are not excluded.
15. Prior organ transplantation including allogeneic stem cell transplantation
16. Past history of interstitial lung disease (a rare side-effect of PD-1 blockade), non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc.)
17. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3 NCI-CTCAE v6), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
18. Major surgery for any reason, except diagnostic biopsy, within 4 weeks of enrolment and/or if the subject has not fully recovered from the surgery within 4 weeks of enrolment
19. Pregnancy or lactation.
20. Serious active co-morbid disease according to investigator’s discretion.
21. Previous adverse reaction to the trial drugs.
22. Any of the following cardiovascular risk factors:
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, within 28 days (inclusive) before first dose of study drug
b. Pulmonary embolism within 28 days (inclusive) before first dose of study drug
c. Any history of acute myocardial infarction within 6 months (inclusive) before or first dose of study drug
d. Any history of heart failure meeting New York Heart Association (NYHA Classification III or IV within 6 months (inclusive) before or first dose of study drug
e. Any event of ventricular arrhythmia greater than or equal to Grade 2 in severity within 6 months (inclusive) before first dose of study drug
f. Any history of cerebrovascular accident within 6 months (inclusive) before first dose of study drug
g. Uncontrolled hypertension: systolic pressure greater than or equal to 160 mmHg or diastolic pressure greater than or equal to 100 mmHg despite anti-hypertension medications within 28 days (inclusive) before first dose of drug
h. Any episode of syncope or seizure within 28 days (inclusive) before first dose of study drug
23. Was administered a live vaccine within 4 weeks (inclusive) before first dose of study drug. COVID vaccines and seasonal vaccines for influenza are allowed.

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 / Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/04/2024
Actual
Date of last participant enrolment
Anticipated
27/03/2026
Actual
Date of last data collection
Anticipated
25/04/2031
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 26464 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 26465 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 42445 0
2145 - Westmead
Recruitment postcode(s) [2] 42444 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 312092 0
Other Collaborative groups
Name [1] 312092 0
Australasian Leukaemia and Lymphoma Group
Country [1] 312092 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
ALLG
Ground floor, 35 Elizabeth St
Richmond
VIC
3121
Country
Australia
Secondary sponsor category [1] 313612 0
None
Name [1] 313612 0
Address [1] 313612 0
Country [1] 313612 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311498 0
Bellberry Human Research Ethics Committee G
Ethics committee address [1] 311498 0
https://bellberry.com.au/
Ethics committee country [1] 311498 0
Australia
Date submitted for ethics approval [1] 311498 0
20/03/2023
Approval date [1] 311498 0
21/06/2023
Ethics approval number [1] 311498 0
Ethics committee name [2] 315175 0
Metro South Human Research Ethics Committee
Ethics committee address [2] 315175 0
https://metrosouth.health.qld.gov.au/research/about-us/hrec
Ethics committee country [2] 315175 0
Australia
Date submitted for ethics approval [2] 315175 0
16/08/2022
Approval date [2] 315175 0
15/11/2022
Ethics approval number [2] 315175 0

Summary
Brief summary
The purpose of this study is to assess the safety and immune system response to treatment with Tislelizumab in patients with Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL).

Who is it for?
You may be eligible to join this study if you are aged 45 years or older and have been diagnosed with EBV-associated DLBCL, without immunosuppression.

Study details
All patients enrolled in this study will receive treatment based on 21-day cycles, with 4 stages:
1. "Induction" stage, involving intravenous Tislelizumab (200mg) and Rituximab (375mg/m2) on day 1 of each cycle over 3 cycles (9 weeks total).
2. "Combination" stage, involving Tislelizumab (200mg), Rituximab (375mg/m2), Cyclophosphamide (750mg/m2), Doxorubicin (50mg/m2), Vincristine (1.4mg/m2, up to a maximum of 2mg) on day 1 of each cycle; and oral tablet Prednisolone (100mg) daily on days 1 to 5 of each cycle. There are 6 cycles for this stage (18 weeks total).
3. "Cell Therapy" stage, involving intravenous Epstein-Barr Virus (EBV) virus specific T-cells (Auto-EBV-VST). Two infusions of 3x10^7/m2 each will be given a week apart. Six weeks after the 2nd infusion, patients will have a PET/CT scan to assess if the cancer has disappeared. If so, the patient will move to the next stage, "Maintenance". (However, if the cancer has not disappeared, the patient will be withdrawn from the treatment phase of this trial.)
4. "Maintenance" stage, involving intravenous Tislelizumab (400mg) on day 1 of every second cycle over 16 cycles (48 weeks total).
Overall, the study will take 83 weeks.

Other testing that will be performed includes serology, blood tests, bone marrow assessment and ECHO scans (at baseline and end of treatment).

It is hoped that the research will provide evidence for the safety of this immune-based approach, and lead to better outcomes for EBV-associated DLBCL lymphoma patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121310 0
Prof Maher Gandhi
Address 121310 0
Level 7 University of Queensland Mater Research Institute, Translational Research Institute, Kent Street, Woollongabba, Brisbane, QLD, 4102
Country 121310 0
Australia
Phone 121310 0
+617 3176 2111
Fax 121310 0
Email 121310 0
Maher.Gandhi@mater.uq.edu.au
Contact person for public queries
Name 121311 0
Miss Delaine Smith
Address 121311 0
Australasian Leukaemia and Lymphoma Group
Ground Floor
35 Elizabeth St
Richmond 3121 VIC
Country 121311 0
Australia
Phone 121311 0
+61383739701
Fax 121311 0
Email 121311 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 121312 0
Miss Delaine Smith
Address 121312 0
Australasian Leukaemia and Lymphoma Group
Ground Floor
35 Elizabeth St
Richmond 3121 VIC
Country 121312 0
Australia
Phone 121312 0
+61 0383739701
Fax 121312 0
Email 121312 0
delaine.smith@allg.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be shared publicly. Aggregate patient data and final results will be presented in the final report


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.