ENABLE (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy) (ENABLE)
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|ClinicalTrials.gov Identifier: NCT04049513|
Recruitment Status : Recruiting
First Posted : August 8, 2019
Last Update Posted : September 30, 2019
|Condition or disease||Intervention/treatment||Phase|
|Lymphomas Non-Hodgkin's B-Cell Diffuse Large B-cell Lymphoma (DLBCL) Primary Mediastinal B-cell Lymphoma (PMBCL) Transformed Follicular Lymphoma (TFL) Follicular Lymphoma (FL) Mantle Cell Lymphoma (MCL)||Biological: WZTL002-1 (1928T2z CAR-T cells) Drug: Cyclophosphamide and Fludarabine lymphodepleting chemotherapy||Phase 1|
This is a Phase 1 dose escalation 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. A 3+3 dose escalation design will be used to identify a Maximum Tolerated Dose (MTD) of WZTL-002 using pre-defined Dose Limiting Toxicity (DLT) criteria.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||12 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||Modified 3+3 dose escalation scheme.|
|Masking:||None (Open Label)|
|Official Title:||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|
|Estimated Study Start Date :||September 2019|
|Estimated Primary Completion Date :||September 2021|
|Estimated Study Completion Date :||August 2026|
Experimental: WZTL002-1 (1928T2z CAR T-cells)
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.
Biological: WZTL002-1 (1928T2z CAR-T cells)
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.
Drug: Cyclophosphamide and Fludarabine lymphodepleting chemotherapy
Cyclophosphamide 500 mg/m^2 IV on days -5 to -3, inclusive. Fludarabine 30 mg/m^2 IV on days -5 to -3, inclusive
- Number and severity of adverse events assessed by CTCAE v5.0, except for Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome, which will be assessed by ASTCT consensus grading criteria [ Time Frame: 3 months after administration ]Determine the safety profile of WZTL-002, anti-CD19 CAR T-cells by measuring frequency and severity of adverse events
- Feasibility of Manufacture [ Time Frame: 3 months after administration ]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
- Overall Response Rate [ Time Frame: 3 months after administration ]To estimate the overall response rate (ORR) as determined by complete response (CR) plus partial response (PR) 3 months after WZTL-002 administration
- Cumulative CR rate [ Time Frame: 6 months after administration ]To determine the cumulative CR rate 6 months after WZTL-002 administration
- Relapse-free survival [ Time Frame: 24 months after administration ]To estimate the relapse-free survival (RFS) for subjects treated with WZTL-002 over a period of 24 months after WZTL-002 administration
- Overall survival [ Time Frame: 24 months after administration ]To estimate the overall survival (OS) distribution for subjects treated with WZTL-002 over a period of 24 months after WZTL-002 administration
- Recommended dose [ Time Frame: 3 months after administration ]To determine the recommended phase 2 dose of WZTL-002 for treatment of R/R B-NHL
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04049513
|Contact: Robert Weinkove, MBBS, PhD||+64 4 918 5117||Robert.Weinkove@ccdhb.org.nz|
|Contact: Tess Ostapowicz, BA||+64 4 918 5117||Tess.Ostapowicz@ccdhb.org.nz|
|Wellington Hospital, Capital & Coast District Health Board||Recruiting|
|Wellington, New Zealand, 6021|
|Contact: Robert Weinkove, Dr.|
|Contact: Philip George|
|Principal Investigator: Robert Weinkove, MBBS, PhD|
|Sub-Investigator: Philip E George, MBChB|
|Sub-Investigator: Alwyn AB D'Souza, MBChB|
|Sub-Investigator: Travis N Perera, MBChB|
|Principal Investigator:||Robert Weinkove, MBBS, PhD||Capital and Coast District Health Board|