Identifying Ultra-High Risk Large B-Cell Lymphoma Patients for Early Treatment with Axicabtagene Ciloleucel: A therapeutic arm of the ALLG NHL34 CLARIFY Study

This is an investigational combination treatment arm within the ALLG NHL34 CLARIFY trial platform, which is registered on ANZCTR with ID ACTR12619001656123. This study is for patients with Primary refractory and early relapsed diffuse large B cell lymphoma (DLCBL) who enter the NHL34 Prognostic arm. These patients may then be identified as Ultra High Risk (UHR) Large B-Cell Lymphoma (LBCL). Specifically, it aims to targets patients early on who indicate a suboptimal response to initial treatments and who may benefit from CAR-T cell therapy. The investigation product is a single Chimeric Antigen Receptor T cells (CAR-T) infusion with Axicabtagene Ciloleucel (Axi-cel) administered intravenously at a target dose of 2x10^6 cells/kg of treatment following lymphodepletion. A patient is identified and confirmed as Ultra High Risk (UHR) Large B Cell Lymphoma (LBCL) from the NHL34 Prognostic arm by the CLARIFY-Prognostic Reference Committee (CPRC). The patient can be treated with CAR-T infusion with Axi-cel satisfying either a 1) Positron Emission Tomography (PET) or 2) Minimal Residual Disease (MRD) criteria. Satisfying a PET criteria means there is a suboptimal response at interim cycle 4 of treatment at day 15, defined as: 1) Stable disease, or 2) Partial Metabolic Response of less than 70 percent change in Standardised Uptake Value (SUV) at any lesion, or 3) Partial Metabolic Response demonstrating Deauville V avidity. A patient may also be identified as UHR by satisfying a MRD criteria: Patients either in complete or partial metabolic response with detectable MRD by PVSeq at end-of-induction on cycle 6 of treatment on day 15 (C6D15). "Leukapheresis": Patients will undertake leukapheresis within 21 days of registration. Once a leukapheresis date is planned, patients must enroll in the appropriate Kite portal. The Kite portal is the web-based platform used to manage trials involved in CAR-T cell therapies. The collection of peripheral blood mononuclear cells (PBMCs) will be collected from the patient to obtain T cells for the manufacture of Axicabtagene Ciloleucel (Axi-cel). Leukapheresed cells obtained at participating collection centres will be shipped to the manufacturer’s facility. -Glucocorticoids must be avoided for 7 days prior to leukapheresis if administered at a pharmacological dose (greater or equal to 5mg/day of prednisone or equivalent doses of other corticosteroids). -Administration of systemic immunochemotherapy must not be administered a minimum of 14 day prior to leukapheresis. "Bridging therapy-Optional". At discretion of the investigator. Bridging therapy is used to prevent disease progression, maintain patient stability, and/or optimize CAR-T effectiveness by reducing cancer burden before CAR-T cell infusion. Administration will be at the discretion of the investigator. There are two options for bridging therapy: non-chemotherapy and chemotherapy. The non-chemotherapy option includes: 1) Corticosteroid (max 100mg prednisone or equivalent daily for a maximum 14 days), 2) Rituximab monotherapy (375mg/m2 administered weekly for a maximum of 4 doses), 3) Localized radiation therapy for symptom control may also be allowed alone or in combination with other bridging therapies. The chemotherapy-based options includes 1) Rituximab at 375 mg/m2, 2) Oxaliplatin at 100mg/m2, and 3) Gemcitabine at 1000mg/m2. All administered via intravenous (IV) infusion on Day 1. A cycle of this bridging chemotherapy typically lasts 14 days but can be adjusted based on an individual circumstances. Patients will receive at least one cycle with up to four cycles permitted if additional time is needed to generate CAR-T cells. Other systemic chemotherapy-containing bridging therapies are not allowed. At the physician's discretion, Rituximab, gemcitabine, and oxaliplatin drug combination can be supplemented with radiotherapy for bulky or symptomatic lesions. "Lymphodepleting Chemotherapy" Once availability of Axi-cel is confirmed and there is no indications of the following: 1) Systemic antimicrobials received within 48hr of commencing on day 5 2) Recorded temperatures (over 38 degree Celsius) within 72 hours of commencing on day 5 3) C-reactive protein (CRP) of greater than 100mg/L within 5 days of commencing on day 5 4) Signs or symptoms of new active infection. Fludarabine at 30 mg/m2 and cyclophosphamide 500 mg/m2 is administered each day for 3 days, followed by 2 rest days through IV infusion. This is to deplete the patient's lymphocytes and create a favorable environment for the infused CAR-T cells. "CAR-T infusion with Axicabtagene Ciloleucel (Axi-cel)" CAR-T infusion with Axi-cell will be administered intravenously at a target dose of 2x10^6 cells/kg. Upon administration, the date will be noted as Day 0 and referred to for post-treatment and 24 month follow up purposes. All patients will be monitored daily for 7 days post infusion for signs and symptoms of Cytokine Release Syndrome (CRS) and neurologic events. All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance. Only Kite accredited sites will be permitted to administer Axi-cel. The product is labelled per local regulations with the patient's unique subject identification number assigned at the time of registration.