A Phase I Dose Escalation Trial of Autologous Third-generation Anti-CD19 Chimeric Antigen Receptor T-cells (WZTL-002) for Relapsed and Refractory B-cell Lymphomas

WZTL002-1

This Phase 1, single centre, open label dose escalation study aims to identify a safe dose of third-generation anti-CD19 CAR T-cells (WZTL-002) in the treatment of patients with relapsed or refractory (r/r) B-cell Non Hodgkin Lymphoma, for use in further efficacy trials. An expansion cohort will assess automated closed-system manufacture of WZTL-002 and outpatient management of participants.

2019-10-11

2024-05-01

2029-02-01

Recruiting

Early phase I

30

Inclusion Criteria: * Age 16 to 75 years (inclusive) * Biopsy-proven relapsed or treatment refractory aggressive B-cell non-Hodgkin lymphoma of the following subtypes per World Health Organisation (WHO) classification: DLBCL and its variants, PMBCL, tFL, FL, MCL * Requirement for treatment in the opinion of the investigator * Presence of measurable disease as per Lugano 2014 Criteria * No other curative treatments available, or not suitable due to patient or disease characteristics or lack of stem cell donor * Malignancy documented to express CD19 based on flow cytometric or immunohistochemical staining * Provision of written informed consent for this study * Lymphoma-related life expectancy at least 12 weeks, and life-expectancy from non-lymphoma related causes of \> 12 months * European Cooperative Oncology Group (ECOG) performance status of 0 to 2 inclusive * Adequate haematologic function, defined by neutrophils ≥ 1.0 × 10\^9/L and platelets ≥ 50 × 10\^9/L * No serious cardiac, pulmonary, hepatic or renal disease. * Serum bilirubin \< 2.5 times Upper limit of normal (ULN) * Estimated creatinine clearance (CrCl) ≥ 50 mL/min using the modified Cockroft Gault estimation or as assessed by direct measurement * Cardiac Ejection Fraction ≥ 50% as determined by Echocardiogram or MUGA Scan * Oxygen saturations \> 92% on room air * Diffuse Capacity of the lungs for carbon monoxide (DLCO) or Carbon monoxide transfer coefficient (KCO), Forced expiratory volume in one second (FEV1) and Forced Vital Capacity (FVC) are all ≥ 50% of predicted by spirometry after correcting for haemoglobin and/or volume on lung function testing. Exclusion Criteria: * Confirmed active or prior central nervous system (CNS) involvement by lymphoma. In patients with a clinical suspicion of CNS disease, lumbar puncture and MRI brain must be performed * 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 * Richter Syndrome * Active autoimmune disease requiring systemic immunosuppression * Prior solid organ transplantation * Allogeneic stem cell transplantation within the preceding three months or still requiring systemic immunosuppression * Current grade II - IV acute graft versus host disease (GVHD), any prior grade IV acute GVHD, or current moderate or severe chronic GVHD * Systemic corticosteroids at doses of ≥ 20mg prednisone daily or equivalent within 7 days of enrolment * Peripheral blood lymphocytes \< 0.3 x 10\^9/L as assessed by complete blood count * Peripheral blood CD3+ T cells \< 150/μL as assessed by lymphocyte subset analysis * Pregnant or lactating female * Women of child-bearing potential who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration * Men who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration * Men who have a pregnant partner and are not willing to use a condom while performing sexual activity during study participation and for at least 3 months after WZTL-002 administration * Participants with known sensitivity to immunoglobulin or to components of the investigational product (IP) * History of active malignancy other than B-cell malignancy within two years prior to enrolment, with the exception of: adequately treated in situ carcinoma of the cervix; adequately treated basal cell carcinoma (BCC) or localized squamous cell carcinoma (SCC) of the skin; other localised malignancy surgically resected (or radically treated with another treatment modality) with curative intent * Current or prior human immunodeficiency virus (HIV) infection * Vaccination with a live virus within the preceding four weeks * Treatment with a purine analogue within the preceding four weeks * Treatment with alemtuzumab within the preceding 12 weeks * Cytotoxic chemotherapy, radiotherapy or monoclonal antibody therapy (other than alemtuzumab) within 2 weeks of enrolment * Prior gene therapy, including prior anti-CD19 chimeric antigen receptor T-cell therapy * Receipt of an investigational medicine within another clinical trial within the preceding four weeks * Inadequately controlled systemic infection * Serologic status reflecting active viral hepatitis B or any history of 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 (\< 20 IU), and if they are willing to receive appropriate anti-viral prophylaxis. * Presence of hepatitis C virus (HCV) antibody * Presence of New York Heart Association (NYHA) class 2 or higher cardiac symptoms not related to lymphoma * Significant concomitant illnesses which would in the investigator's opinion make the patient an unsuitable candidate for the trial * Participants who have diminished capacity or any circumstance that would prohibit them from understanding and providing informed consent in accordance with ICH-GCP (International Conference on Harmonisation, Good Clinical Practice) * Participant does not provide consent to enrol onto International Cellular Therapy Registry

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2023-07-03