Status and phase
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About
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:
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:
Full description
WZTL-002 is a third-generation CAR T-cell product comprising autologous T-cells transduced to express a CAR directed against CD19 and incorporating a Toll-like receptor 2 (TLR2) co-stimulatory domain interposed between CD28 and CD3ζ signalling domains. The trial will screen up to 80 patients in order to enrol and treat approximately 60 participants with WZTL-002. This is a single arm open-label phase 2 trial designed to evaluate the efficacy, safety, cellular kinetics and pharmacodynamic properties of WZTL-002 for the second- or third-line treatment of r/r LBCL.
Eligible participants will undergo leukapheresis to harvest peripheral blood mononuclear cells, the starting material for the manufacture of the autologous third generation anti-CD19 CAR T-cell product, WZTL-002. After WZTL-002 manufacture and confirmation that product release criteria are met, participants will receive lymphodepleting chemotherapy comprising fludarabine and cyclophosphamide on days -5 to day -3, inclusive. WZTL-002 will be administered intravenously on day 0 as a single dose.
After WZTL-002 administration, participants will be monitored closely for 14 days including targeted assessments for the specific CAR T-cell related toxicities Cytokine Release Syndrome (CRS) and Immune Effector Cell Neurotoxicity Syndrome (ICANS). CRS, ICANS and grade 3 or higher neutropenia, thrombocytopenia or anemia persisting beyond day 30 will be recorded as adverse events of special interest. PET/CT scans to assess treatment response will take place at screening, pre-lymphodepletion and at 28 days, 3 months and 6 months after WZTL-002 infusion, and CT scans to assess duration of response at 12 and 24 months after WZTL-002 infusion. Samples will be taken to determine WZTL-002 cellular kinetics and the depth and duration of B-cell aplasia (pharmacodynamic analysis).
Follow-up beyond month 24 will take place within the Center for International Blood and Marrow Transplant Research (CIBMT) Cellular Therapies Registry or the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR), and in a subsequent long-term follow-up study.
Enrollment
Sex
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Volunteers
Inclusion criteria
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:
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:
Relapsed or refractory following second-line chemoimmunotherapy, defined as:
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:
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,
For male participants:
Participant agrees not to donate blood components at any time after receiving WZTL-002
Exclusion criteria
Active central nervous system (CNS) involvement by lymphoma. In patients with a history of CNS disease or a clinical suspicion of current CNS disease, lumbar puncture and MRI brain must be performed within 30 days of enrolment to exclude current CNS involvement.
Active CNS pathology including: epilepsy, seizure within the preceding year, aphasia, paresis, stroke, dementia, psychosis within the preceding year, severe brain injury, Parkinson disease, or cerebellar disease
B-cell non-Hodgkin lymphoma of the following subtypes, as per the 2022 WHO classification of haematolymphoid tumours:
Patient has received 3 or more prior lines of therapy for LBCL, where 1 line of therapy is defined as 1 or more cycles of a combination chemoimmunotherapy with or without pre-planned consolidation therapy (radiotherapy, autologous stem cell transplant or immunotherapy)
Requirement for urgent lymphoma therapy due to tumour-related symptoms, or due to imminent risk of blood vessel, airway, urinary tract, gastrointestinal tract, nerve or spinal cord compression
Active autoimmune disease requiring current systemic immunosuppression
Active sarcoidosis
Prior solid organ transplantation or prior allogeneic stem cell transplantation (allo-SCT)
Peripheral blood CD3+ T cells < 150/μL (0.15 x10^9/L) as assessed by lymphocyte subset analysis
History of active malignancy other than B-cell malignancy within 2 years prior to enrolment, with the exception of: adequately treated in situ carcinoma of the cervix; adequately treated basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) of the skin; other localised malignancy surgically resected (or radically treated with another treatment modality) with curative intent
Prior treatment with:
Pregnant or lactating female
Known sensitivity to immunoglobulin or to components of the IP
Current or prior HIV infection
Vaccination with a live virus within the 4 weeks of enrolment
Inadequately-controlled systemic infection
Serologic status reflecting active viral hepatitis B or active hepatitis C infection as follows:
Current New York Heart Association (NYHA) class 2 or higher cardiac symptoms, or myocardial infarction, unstable angina or other clinically significant cardiac disease within the past 6 months
Significant concomitant illnesses which would in the Investigators opinion make the patient an unsuitable candidate for the trial
Patients who have diminished capacity or any circumstance that would prohibit them from understanding and providing informed consent in accordance with ICH-GCP
Patient does not provide consent to enrol to an International Cellular Therapy Registry
Primary purpose
Allocation
Interventional model
Masking
60 participants in 1 patient group
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Central trial contact
Brittany Lavender
Data sourced from clinicaltrials.gov
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