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Clinical Trial NCT04049513 (ENABLE-1) for 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) is active, not recruiting. See the Trial Radar Card View and AI discovery tools for all the details. Or ask anything here. | ||
ENABLE-1 (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy) Phase 1 30 Dose Escalation Open-Label
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
- ENABLE-1
- WZTL002-1
- U1111-1216-2053 (Other Identifier) (World Health Organisation)
Chimeric antigen receptor T-cell
| Participant Group/Arm | Intervention/Treatment |
|---|---|
ExperimentalWZTL002-1 (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. | 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 192...Show More 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 |
| Outcome Measure | Measure Description | Time Frame |
|---|---|---|
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 | Determine the safety profile of WZTL-002, anti-CD19 CAR T-cells by measuring frequency and severity of adverse events | 3 months after administration |
| Outcome Measure | Measure Description | Time Frame |
|---|---|---|
Feasibility of Manufacture | 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 | 3 months after administration |
Overall Response Rate | To estimate the overall response rate (ORR) as determined by complete response (CR) plus partial response (PR) 3 months after WZTL-002 administration | 3 months after administration |
Cumulative CR rate | To determine the cumulative CR rate 6 months after WZTL-002 administration | 6 months after administration |
Relapse-free survival | To estimate the relapse-free survival (RFS) for subjects treated with WZTL-002 over a period of 24 months after WZTL-002 administration | 24 months after administration |
Overall survival | To estimate the overall survival (OS) distribution for subjects treated with WZTL-002 over a period of 24 months after WZTL-002 administration | 24 months after administration |
Recommended dose | To determine the recommended phase 2 dose of WZTL-002 for treatment of R/R B-NHL | 3 months after administration |
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.
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
Malaghan Institute of Medical ResearchWellington Zhaotai Therapies Limited