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A starting WZTL-002 dose of 5 × 10\^4 CAR T-cells/kg has been selected with four possible dose level cohorts proposed.

Escalation to a higher dose cohort will be based on assessment of dose limiting toxicities to determine safety at a given dose level.

WZTL-002 comprises autologous third-generation anti-CD19 chimeric antigen receptor T-cells (termed 1928T2z). The chimeric antigen receptor in WZTL-002 incorporates the FMC63 anti-CD19 soluble chain variable fragment extracellularly, and portions of both CD28 and the Toll/interleukin-1 receptor (TIR) domain of Toll Like Receptor 2 (TLR2) as intracellular co-stimulatory domains, alongside CD3ζ. WZTL-002 (autologous 1928T2z CAR T-cells) will be administered on D0 as a single IV infusion, following lymphodepleting chemotherapy.

WZTL002-1 (1928T2z CAR-T cells)

Cyclophosphamide 500 mg/m\^2 IV on days -5 to -3, inclusive. Fludarabine 30 mg/m\^2 IV on days -5 to -3, inclusive

Cyclophosphamide and Fludarabine lymphodepleting chemotherapy

Robert Weinkove, MBBS, PhD

Tess Ostapowicz, BA

Robert Weinkove, Dr.

Philip George

Philip E George, MBChB

Alwyn AB D'Souza, MBChB

Travis N Perera, MBChB

Robert C Fyfe, MBChB

Stefan Mullins, MBBCh

Hayden Jina, MBChB

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.

This is a Phase 1 study, designed to evaluate the safety, feasibility, efficacy and kinetics of third-generation autologous anti-CD19 CAR T-cells, WZTL-002, in patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma without other curative options. The initial dose escalation cohort will use a 3+3 dose escalation design to identify a Maximum Tolerated Dose (MTD) of WZTL-002 using pre-defined Dose Limiting Toxicity (DLT) criteria. Within a subsequent dose expansion cohort at the recommended phase 2 dose, an automated closed-system manufacturing process for WZTL-002 and outpatient clinical management will be implemented.

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.

Following WZTL-002 administration, participants will be monitored closely for 14 days, including targeted assessments for the specific CAR T-cell related toxicities of Cytokine Release Syndrome (CRS) and Immune Effector Cell Neurotoxicity Syndrome (ICANS). Initial DLT assessment will occur at day 21 after WZTL-002 infusion. A PET/CT Scan to assess treatment response will take place 3 months after WZTL-002 infusion, marking the end of the primary follow up period. The secondary follow up period will occur between 3 months up until 2 years after WZTL-002 treatment. Long term follow up within the trial will occur annually from 2 to 5 years after WZTL-002 treatment, with further follow-up within the Center for International Blood and Marrow Transplant Research (CIBMT) Cellular Therapies Registry and the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR). In addition to clinical data, this study incorporates sample collection for exploratory endpoints including serum cytokine profile following WZTL-002 infusion, and WZTL-002 expansion, persistence and phenotype.

ENABLE (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy)

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

All IPD that underlie results in a publication

Determine the safety profile of WZTL-002, anti-CD19 CAR T-cells by measuring frequency and severity of adverse events

To investigate the feasibility of manufacture and treatment with WZTL-002, as determined by the proportion of enrolled participants undergoing at least one study leukapheresis procedure that receive WZTL-002

To estimate the overall response rate (ORR) as determined by complete response (CR) plus partial response (PR) 3 months after WZTL-002 administration

To determine the cumulative CR rate 6 months after WZTL-002 administration

To estimate the relapse-free survival (RFS) for subjects treated with WZTL-002 over a period of 24 months after WZTL-002 administration

To estimate the overall survival (OS) distribution for subjects treated with WZTL-002 over a period of 24 months after WZTL-002 administration

To determine the recommended phase 2 dose of WZTL-002 for treatment of R/R B-NHL

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
ENABLE (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy)	NCT04049513	Lymphomas Non-H... Diffuse Large B... Primary Mediast... Transformed Fol... Follicular Lymp... Mantle Cell Lym...	WZTL002-1 (1928... Cyclophosphamid...	16 Years - 75 Years	Malaghan Institute of Medical Research
ENABLE (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy)	NCT04049513	Lymphomas Non-H... Diffuse Large B... Primary Mediast... Transformed Fol... Follicular Lymp... Mantle Cell Lym...	WZTL002-1 (1928... Cyclophosphamid...	16 Years - 75 Years	Malaghan Institute of Medical Research

Spots Global Cancer Trial Database for cyclophosphamide and fludarabine lymphodepleting chemotherapy