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Trial registered on ANZCTR


Registration number
ACTRN12625000001493p
Ethics application status
Not yet submitted
Date submitted
9/12/2024
Date registered
7/01/2025
Date last updated
7/01/2025
Date data sharing statement initially provided
7/01/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
ALLG NHL41: A phase I clinical trial investigating the combination of chimeric antigen receptor-T cell (CAR-T) cell therapy with Zanubrutinib bridging and subsequent Zanubrutinib and Tislelizumab consolidation in patients with relapsed/refractory Primary Central Nervous System Lymphoma (PCNSL).
Scientific title
ALLG NHL41: A phase I clinical trial investigating the feasibility and safety of the combination of CAR-T cell therapy with Zanubrutinib bridging and subsequent Zanubrutinib and Tislelizumab consolidation in patients with relapsed/refractory PCNSL
Secondary ID [1] 312997 0
None
Universal Trial Number (UTN)
Trial acronym
BrainCAR19
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary Central Nervous System Lymphoma (PCNSL) 335185 0
Condition category
Condition code
Cancer 331674 331674 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The treatment strategy is in 3 parts:

Part I: Zanubrutinib induction therapy
Patients will receive Zanubrutinib 320mg once-daily orally as induction bridging therapy until lymphodepletion prior to CAR-T cell therapy. Day 1 of zanubrutinib will be the first day of oral drug. This duration of this part of the trial will likely be variable and will be dependent on when CAR-T cells can be collected. Patients can continue Zanubrutinib throughout the apheresis procedure and up until planned lymphodepletion. The 1st dose of Zanubrutinib must start within 14 days of registration to the trial and can continue for up to 90 days of therapy on Part 1. Zanubrutinib is ceased the day before commencing lymphodepletion.

CAR-T Manufacturing steps:
Cell collection- Patients will require a standard non-mobilised leukapheresis, also known as mononuclear cell apheresis, abbreviated MNC(A). Patients must be assessed and pass specific criteria to proceed with cell collection, such as minimum CD3 T cell count and ECOG status If a patient does not pass the criteria for collection, they will come off trial and move into follow up and commence standard of care treatment per the treating clinician’s discretion
Shipment - This MNC(A) product will be used to manufacture a CD19 directed CAR T cell product. It will take ~12-14 days from apheresis to manufacture.
The MNC(A) product will be shipped at 2 – 8C fresh to the manufacturing sites RBWH or Westmead for manufacturing within 24 hours of apheresis.
T-cell expansion and collection - The cells are then enriched for T cells by CD4 and CD8 immunomagnetic selection. The enriched T cell fraction is activated with CD3/CD28 antibodies and transduced with a CAR19 lentiviral vector 24 hours later. The transduced cells are cultured and expanded in the identical closed-system manufacturing device (CliniMACS Prodigy), at the end of which they are harvested, characterised and undergo quality assurance testing.
The cells are cryopreserved in aliquots, adjusted for the percentage of CAR T cells (generally between 20 – 35% of total T cells) and patient weight. The CAR-T cells are transported to the certified centre performing the re-infusion.

Part II: Lymphodepletion chemotherapy and single CAR-T cell infusion
Part II commences on the first day of lymphodepletion chemotherapy and coincides with cessation of Zanubrutinib.
Standard Lymphodepleting chemotherapy will be administered consisting of Fludarabine 25mg per m2 for 3 days (Days –5, -4, -3) and Cyclophosphamide 250mg per m2 for 3 days (Days –5, -4, -3).
On the day of CAR T cell infusion (day 0), the patient must be reviewed by the treating physician or delegated team member qualified to perform cell infusion. The CAR-T cells will be delivered fresh and infused intravenously. Patients are planned to receive a single dose of 2 x 10^6 per kg CD19 directed CAR T cells following induction therapy with Zanubrutinib. The ALLG will undertake site assessment and administration will only be allowed at qualified sites by a qualified member of the trial team who has been delegated this duty and as per local institutional guidelines for CAR-T cell infusions.

Part III: Tislelizumab followed by combination Tislelizumab and Zanubrutinib consolidation
Part III of the NHL41 trial will commence once at least 35 days (and up to day 77) have elapsed since CAR-T cell reinfusion and no acute CAR-T cell toxicities of concern are present with toxicities such as ICANs and CRS resolved for at least 7 days. Cycles are 21 days and consolidation treatment is for 16 cycles in total (16 Tislelizumab and 15 Zanubrutinib cycles in total). Consolidation will commence in a stepped phase with the first cycle of Tislelizumab to commence as a single agent. 200mg if Tiselizumab will be administered by intravenous (IV) infusion on day 1 of every 3 weeks (1 cycle). Zanubrutinib will be added in on day 1 post the 2nd infusion (cycle 2) of Tislelizumab. Zanubrutinib will be orally administered at 320mg once a day, every 3 weeks
Intervention code [1] 330128 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 340102 0
To determine the feasibility of CAR-T cell therapy in patients with rPCNSL with initial Zanubrutinib bridging and post CAR-T consolidation with Tislelizumab and Zanubrutinib.
Timepoint [1] 340102 0
Assessed at the end of the trial
Primary outcome [2] 340103 0
To determine the safety of CAR-T cell therapy in patients with rPCNSL with initial Zanubrutinib bridging and post CAR-T consolidation with Tislelizumab and Zanubrutinib.
Timepoint [2] 340103 0
Assessed at each visit timepoint and the end of the trial.
Secondary outcome [1] 442720 0
Evaluate preliminary efficacy
Timepoint [1] 442720 0
At day 30 post initial infusion of CAR-T cells.
Secondary outcome [2] 442721 0
Progression free survival (PFS) in the setting of initial bridging therapy with Zanubrutinib, and post CAR-T consolidation with anti-PD1 therapy (Tislelizumab and Zanubrutinib)
Timepoint [2] 442721 0
Assessed on day 30 and 1 year post CAR-T infusion
Secondary outcome [3] 442722 0
Overall Survival (OS) of CAR-T cells in rPCNSL in the setting of initial bridging therapy with Zanubrutinib, and post CAR-T consolidation with anti-PD1 therapy (Tislelizumab) and Zanubrutinib.
Timepoint [3] 442722 0
Assessed on day 30 and 2 years post CAR-T infusion

Eligibility
Key inclusion criteria
1. Histologically confirmed diagnosis of CD19 positive PCNSL as per WHO 2017 classification and have relapsed after at least one line of therapy that includes high dose methotrexate or similar regimens or are refractory to the prior line of treatment as demonstrated by MRI evidence of progression or refractory disease. If eligible and the patient has not received ASCT in front line setting, then this should be considered prior to enrolment on this study accepting that expected outcomes at relapse to salvage and ASCT is expected to be low particularly if relapse occurs within 3 years of original diagnosis. Patients with Relapsed or Refractory Primary Intraocular Lymphoma are eligible. CD19 expression within 3 months of signing informed consent is recommended but not mandatory.
2. Measurable disease on MRI on trial entry and/or demonstration of CD19-positive lymphoma cells in the CSF or tissue brain biopsy at the time of most recent relapse/refractory disease period.
3. Adequate haematological parameters defined as:
a. ANC (segs + bands) more than 1.0 x 10^9 per L
b. Platelet count of more than 50 x 10^9 per L
c. Absolute lymphocyte count (ALC) of at least 300 per microliter or absolute CD3-positive T cell count of at least 150 per microliter (within 30 days of signing informed consent).
4. Adequate renal and hepatic function defined as:
a. Total bilirubin less than 2.0 x ULN unless known Gilberts syndrome
b. AST or ALT less than 5 x ULN
c. Calculated creatinine clearance more than 40ml per min at Screening
5. Adequate pulmonary function defined by:
a. SaO2 on Room air greater than 91%
6. An ECOG performance status score of between 0-2.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient is less than 18 years or more than 80 years of age at screening.
2. Secondary spread of disease to the CNS from systemic DLBCL.
3. PCNSL in the setting of solid organ transplantation (PCNSL-PTLD) or in the setting of HIV infection.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 317437 0
Other Collaborative groups
Name [1] 317437 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Country [1] 317437 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Country
Australia
Secondary sponsor category [1] 320341 0
None
Name [1] 320341 0
Nil
Address [1] 320341 0
Country [1] 320341 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 316155 0
Metro North Health Human Research Ethics Committee A
Ethics committee address [1] 316155 0
https://metronorth.health.qld.gov.au/research/ethics-and-governance/human-research-ethics-committee
Ethics committee country [1] 316155 0
Australia
Date submitted for ethics approval [1] 316155 0
01/07/2025
Approval date [1] 316155 0
Ethics approval number [1] 316155 0

Summary
Brief summary
PCNSL is a subtype of diffuse large B-cell lymphoma (DLBCL) that affects the brain. While regular DLBCL (found outside the brain) responds well to treatments such as chemotherapy and immunotherapy, these approaches don’t work as well for PCNSL as the brain is protected by the blood-brain barrier. Past treatments such as stem cell transplants or whole brain radiation cause serious side effects and don't lead to good outcomes. There are many clinical trials testing new treatments for relapsed systemic DLBCL but these trials do not include patients with PCNSL. Patients with relapsed PCNSL have very few treatment options available.

The NHL41 clinical trial is testing a new approach that combines three treatments across three phases; Zanubrutinib, CAR-T cell therapy and Tislelizumab. The main goal of this study is to assess if this combination is a safe and feasible treatment option.

Who is it for?
You may be eligible for this study if you are aged between 18 and 80, and have been diagnosed with PCNSL.

Study details
Participants who choose to participate in this trial will undergo treatment in three phases:
Part I: Zanubrutinib induction therapy
Patients will receive Zanubrutinib as induction bridging therapy until lymphodepletion prior to CAR-T cell therapy.
Part II: Lymphodepletion chemotherapy and single CAR-T cell infusion
Standard Lymphodepleting chemotherapy will be administered. On the day of CAR T cell infusion, CAR-T cells will be delivered fresh and infused intravenously.
Part III: Tislelizumab followed by combination Tislelizumab and Zanubrutinib consolidation
The first cycle of Tislelizumab will commence as a single agent. Zanubrutinib will be added in on day 1 post the 2nd infusion of Tislelizumab.

This study aims to address this major unmet need by determining a safe and feasible treatment option for rPCNSL patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136962 0
A/Prof Colm Keane
Address 136962 0
Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, Brisbane QLD 4102
Country 136962 0
Australia
Phone 136962 0
+61 7 3443 7912
Fax 136962 0
Email 136962 0
[email protected]
Contact person for public queries
Name 136963 0
Delaine Smith
Address 136963 0
Australasian Leukaemia & Lymphoma Group, 35 Elizabeth St, Richmond, VIC 3121
Country 136963 0
Australia
Phone 136963 0
+61 3 8373 9701
Fax 136963 0
Email 136963 0
[email protected]
Contact person for scientific queries
Name 136964 0
Delaine Smith
Address 136964 0
Australasian Leukaemia & Lymphoma Group, 35 Elizabeth St, Richmond, VIC 3121
Country 136964 0
Australia
Phone 136964 0
+61 3 8373 9701
Fax 136964 0
Email 136964 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified IPD data for all data collected during the trial
When will data be available (start and end dates)?
Data available 3 months following publication, for an indefinite period
Available to whom?
Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply that the requester must agree to before access is granted
Available for what types of analyses?
Any type of analysis
Assessed on a case-by-case basis
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
24390Study protocol  [email protected] Access can be requested via the Health Data Austra... [More Details]



Results publications and other study-related documents

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