A Study of WZTL-002 CAR T-cells for Adults With Relapsed Large B-cell Lymphoma

Launched by MALAGHAN INSTITUTE OF MEDICAL RESEARCH · Jun 26, 2024

Keywords

ClinConnect Summary

This clinical trial is studying a new treatment called WZTL-002 CAR T-cell therapy for adults with certain types of large B-cell lymphoma, which is a type of cancer that affects the immune system. The main goals of the study are to find out how well this treatment works in getting rid of the lymphoma and to assess any potential side effects, particularly those that may affect brain function. Participants will receive WZTL-002 after undergoing a procedure to collect their white blood cells and a round of chemotherapy to prepare their bodies for the treatment.

To be eligible for this trial, participants must be between 18 and 75 years old and have been diagnosed with specific types of large B-cell lymphoma that have not responded to previous treatments. They should also be in good overall health, with certain blood and organ function requirements. If enrolled, participants will receive the treatment through an IV and will be carefully monitored for the first two weeks for side effects. They will have follow-up scans at various points after treatment to see how well the therapy is working. This trial is currently recruiting participants, and it offers a potential new option for those facing challenging lymphoma cases.

Gender

ALL

Eligibility criteria

• Inclusion Criteria:
• • 1. Age 18 to 75 years (inclusive) at the time of informed consent
• • 2. Signed written informed consent for this trial
• • 3. 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
• • 4. 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
• 5. 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
• • 6. Positron emission tomography (PET) positive disease according to the Lugano 2014 criteria
• • 7. Available tumour tissue (comprising a tissue block or at least 6 unstained slides) for central histological review
• • 8. Lymphoma-related life expectancy at least 12 weeks, and life expectancy related to conditions other than lymphoma at least 12 months
• • 9. ECOG performance status of 0 or 1
• 10. Adequate haematologic function, defined by:
• • Neutrophils ≥ 1.0 × 10\^9/L, and Platelets ≥ 75 × 10\^9/L, and
• • Lymphocytes ≥ 0.3 × 10\^9/L
• • 11. 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.
• • 12. 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.
• • 13. Adequate lung function, defined as ≤ Grade 1 dyspnoea according to NCI CTCAE v5.0, and oxygen saturation (sO2) ≥ 92% on room air.
• • 14. 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.
• 15. 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
• 16. 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
• • 17. Participant agrees not to donate blood components at any time after receiving WZTL-002
• Exclusion Criteria:
• • 1. 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.
• • 2. 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
• 3. B-cell non-Hodgkin lymphoma of the following subtypes, as per the 2022 WHO classification of haematolymphoid tumours:
• • Richter transformation of chronic lymphocytic leukaemia
• • T-cell/histiocyte rich LBCL
• • Primary LBCL of immune-privileged sites
• • Fluid overload associated LBCL
• • Fibrin-associated LBCL
• • Plasmablastic lymphoma
• • Mediastinal grey zone lymphoma
• • Intravascular LBCL
• • ALK-positive large B-cell lymphoma
• • Lymphomatoid granulomatosis
• • Burkitt lymphoma
• • Primary effusion lymphoma
• • KSHV/HHV8-positive diffuse large B-cell lymphoma
• • 4. 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)
• • 5. 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
• • 6. Active autoimmune disease requiring current systemic immunosuppression
• • 7. Active sarcoidosis
• • 8. Prior solid organ transplantation or prior allogeneic stem cell transplantation (allo-SCT)
• • 9. Peripheral blood CD3+ T cells \< 150/μL (0.15 x10\^9/L) as assessed by lymphocyte subset analysis
• • 10. 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
• 11. Prior treatment with:
• • gene therapy (including CAR T-cell therapy) or CD19-targeted immunotherapy, or
• • purine analogue (including bendamustine) or alemtuzumab within 6 months of enrolment, or
• • bispecific T-cell engager, radiotherapy or an investigational medicine within 4 weeks of enrolment, or
• • cytotoxic chemotherapy, systemic corticosteroids (at doses of ≥ 10 mg prednisone daily or equivalent), monoclonal antibody or antibody-drug conjugate (other than alemtuzumab) within 2 weeks of enrolment.
• • 12. Pregnant or lactating female
• • 13. Known sensitivity to immunoglobulin or to components of the IP
• • 14. Current or prior HIV infection
• • 15. Vaccination with a live virus within the 4 weeks of enrolment
• • 16. Inadequately-controlled systemic infection
• 17. Serologic status reflecting active viral hepatitis B or active hepatitis C infection as follows:
• • Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (or is \< 20 IU/mL), and if they are willing to receive appropriate antiviral prophylaxis.
• • Presence of active Hepatitis C infection as determined by Hepatitis C virus (HCV) RNA detected by PCR or nucleic acid testing (NAT). Patients with presence of HCV antibody, are eligible if HCV RNA is undetectable.
• • 18. 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
• • 19. Significant concomitant illnesses which would in the Investigators opinion make the patient an unsuitable candidate for the trial
• • 20. Patients who have diminished capacity or any circumstance that would prohibit them from understanding and providing informed consent in accordance with ICH-GCP
• • 21. Patient does not provide consent to enrol to an International Cellular Therapy Registry