A Phase 2 Trial to Evaluate the Efficacy and Safety of WZTL-002 in Patients With Relapsed or Refractory Large B-cell Lymphoma (ENABLE-2)
The goal of this clinical trial is to learn if a new type of chimeric antigen receptor (CAR) T-cell therapy called WZTL-002 is effective and safe for the treatment large B-cell lymphomas (LBCL) that have not responded to or have come back after standard chemotherapy. The main questions this trial aims to answer are: * What is the likelihood of complete response of the lymphoma after WZTL-002 treatment? * What is the risk of altered brain function (neurotoxicity) after WZTL-002? All eligible participants will receive WZTL-002; the researchers will compare the complete response rate and neurotoxicity rate with historical groups of patients who were treated with similar therapies. Participants will: * Have a procedure to gather white blood cells * Receive chemotherapy to prepare for the CAR T-cells * Receive WZTL-002 CAR T-cells through a vein * Be monitored closely for the first 14 days for certain side effects * Have scans 28 days and 3, 6, 12 and 24 months after WZTL-002 CAR T-cells to check if the treatment has worked
• Age 18 to 75 years (inclusive) at the time of informed consent
• Signed written informed consent for this trial
• Biopsy-proven relapsed or treatment-refractory B-cell non-Hodgkin lymphoma of the following subtypes, as per the 2022 WHO classification of haematolymphoid tumours
‣ Large B-cell lymphomas of the following histological subtypes:
• Diffuse LBCL, not otherwise specified
∙ Diffuse large B-cell lymphoma/high grade B-cell lymphoma with MYC and BCL2 rearrangements
∙ Large B-cell lymphoma with IRF4 rearrangement
∙ High grade B-cell lymphoma with 11q aberrations
∙ High grade B-cell lymphoma, not otherwise specified
∙ Primary mediastinal large B-cell lymphoma
∙ Follicular large B-cell lymphoma
∙ EBV-positive diffuse large B-cell lymphoma, not otherwise specified
∙ Diffuse large B-cell lymphoma associated with chronic inflammation
∙ Primary cutaneous DLBCL, leg type
⁃ Large B-cell lymphoma of one of the above subtypes that has transformed from follicular or marginal zone lymphoma
• Received adequate first-line lymphoma therapy for the qualifying histology (as defined in inclusion criterion 3 above), comprising at least 2 cycles of a standard combination regimen incorporating an anthracycline and an anti-CD20 monoclonal antibody
• Relapsed or refractory disease meeting one of the following criteria:
‣ Relapsed or refractory within 12 months of first-line chemoimmunotherapy, defined as:
• Progressive disease following ≥ 2 cycles of chemoimmunotherapy, or
∙ Stable disease following ≥ 4 cycles of chemoimmunotherapy, or
∙ Partial response following ≥ 6 cycles of chemoimmunotherapy, or
∙ Complete response followed by biopsy-proven relapse within 12 months of completing first-line chemoimmunotherapy.
⁃ Relapsed or refractory following second-line chemoimmunotherapy, defined as:
• Lack of complete response to, or relapse following, autologous stem cell transplantation as part of second-line therapy for the qualifying histology, or
∙ Inability to proceed to autologous stem cell transplantation due to lack of response to 2 cycles of second-line chemoimmunotherapy incorporating both a platinum agent and an anti-CD20 monoclonal antibody
• Positron emission tomography (PET) positive disease according to the Lugano 2014 criteria
• Available tumour tissue (comprising a tissue block or at least 6 unstained slides) for central histological review
• Lymphoma-related life expectancy at least 12 weeks, and life expectancy related to conditions other than lymphoma at least 12 months
• ECOG performance status of 0 or 1
⁃ Adequate haematologic function, defined by:
∙ Neutrophils ≥ 1.0 × 10\^9/L, and Platelets ≥ 75 × 10\^9/L, and
‣ Lymphocytes ≥ 0.3 × 10\^9/L
⁃ Adequate renal function, defined by estimated creatinine clearance (eCrCl) or glomerular filtration rate (eGFR) \>/= 45mL/min using the Cockroft Gault estimation, CKD-EPI equation or as assessed by direct measurement.
⁃ Adequate hepatic function, defined by serum bilirubin \< 2.5 × upper limit of normal (ULN) (unless attributable to Gilbert's syndrome) and alanine transaminase and aspartate aminotransferase \< 3 × ULN.
⁃ Adequate lung function, defined as ≤ Grade 1 dyspnoea according to NCI CTCAE v5.0, and oxygen saturation (sO2) ≥ 92% on room air.
⁃ Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram or multigated acquisition (MUGA), performed within 28 days of commencing screening.
⁃ For female participants:
∙ Agree to use a condom if undertaking sexual activity with any partner during lymphodepleting chemotherapy, and
‣ If of reproductive potential agree to use a highly effective method of contraception from the time of enrolment until at least 12 months after administration of WZTL-002, or
‣ Are not of reproductive potential defined as either,
⁃ being amenorrhoeic for at least 12 consecutive months with FSH 30 ≥ IU/L, or
• previously undergone a sterilisation procedure
⁃ For male participants:
∙ Agree to use a condom if undertaking sexual activity with any partner during lymphodepleting chemotherapy, and
‣ If undertaking sexual activity with a female partner of reproductive potential agree to use a highly effective method of contraception from the time of enrolment until at least 12 months after administration of WZTL-002, and
‣ Agree not to donate sperm for conception, or to provide gametes for in vitro fertilisation for at least 12 months after administration of WZTL-002
⁃ Participant agrees not to donate blood components at any time after receiving WZTL-002