A Study of Atlacabtagene Autoleucel CAR T-cells for Adults With Relapsed Large B-cell Lymphoma

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 atlacabtagene autoleucel 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 atlacabtagene autoleucel treatment?
• What is the risk of altered brain function (neurotoxicity) after atlacabtagene autoleucel?

All eligible participants will receive atlacabtagene autoleucel; 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 atlacabtagene autoleucel 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 atlacabtagene autoleucel CAR T-cells to check if the treatment has worked

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.

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 atlacabtagene autoleucel, 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 atlacabtagene autoleucel, and
    • Agree not to donate sperm for conception, or to provide gametes for in vitro fertilisation for at least 12 months after administration of atlacabtagene autoleucel

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) with hepatitis B virus (HBV) DNA > 20 IU/mL. Patients with presence of HBcAb and/or HBsAg remain eligible if HBV DNA is undetectable (or is < 20 IU/mL), and provided they are receiving 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