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).

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