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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06486051




Registration number
NCT06486051
Ethics application status
Date submitted
20/06/2024
Date registered
3/07/2024
Date last updated
22/07/2024

Titles & IDs
Public title
A Study of WZTL-002 CAR T-cells for Adults With Relapsed Large B-cell Lymphoma
Scientific title
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)
Secondary ID [1] 0 0
U1111-1305-7917
Secondary ID [2] 0 0
WZTL002-2
Universal Trial Number (UTN)
Trial acronym
ENABLE-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Large B-cell Lymphoma 0 0
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified 0 0
Primary Mediastinal Large B-cell Lymphoma (PMBCL) 0 0
Transformed Non-Hodgkin Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cyclophosphamide
Treatment: Other - WZTL-002 CAR T-cells

Experimental: WZTL002 CAR T-cells - Target dose of 0.85×10\^6 CAR+ cells per kg body weight (target range 0.5 to 1.0×10\^6 CAR+ cells/kg; dose cap 1×10\^8 cells)


Treatment: Drugs: Fludarabine
30 mg/m\^2/day IV for three consecutive days

Treatment: Drugs: Cyclophosphamide
500 mg/m\^2/day IV for three consecutive days

Treatment: Other: WZTL-002 CAR T-cells
WZTL-002 comprises autologous T-cells transduced to express the third-generation 1928T2z chimeric antigen receptor, which recognises the CD19 antigen present on malignant and normal B-cells. The chimeric antigen receptor (CAR) incorporates an extracellular scFv specific for CD19, the intracellular signalling domains of CD28 and CD3?, and an intracellular co-stimulatory domain derived from TLR2 interposed between CD28 and CD3?.

On Day 0, the WZTL-002 CAR T-cell product is administered intravenously two days after completing lymphodepleting chemotherapy.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Complete response (CR) rate per Investigator assessment
Timepoint [1] 0 0
3 months after WZTL-002 administration
Primary outcome [2] 0 0
Immune effector cell-associated neurotoxicity syndrome (ICANS) rate
Timepoint [2] 0 0
3 months after WZTL-002 administration
Secondary outcome [1] 0 0
Complete response (CR) rate per central assessment
Timepoint [1] 0 0
3 months after WZTL-002 administration
Secondary outcome [2] 0 0
Objective response rate (ORR) per investigator and per central assessment
Timepoint [2] 0 0
At 3 and at 6 months after WZTL-002 administration
Secondary outcome [3] 0 0
Progression free survival (PFS), Event-free survival (EFS), Overall survival (OS) and Duration of Response (DOR)
Timepoint [3] 0 0
At Months 3, 6, 9, 12, 18, and 24 after WZTL-002 administration
Secondary outcome [4] 0 0
Cytokine release syndrome (CRS) rate and grade
Timepoint [4] 0 0
3 months after WZTL-002 administration
Secondary outcome [5] 0 0
Number and severity of adverse effects
Timepoint [5] 0 0
From screening until 24 months after WZTL-002 administration
Secondary outcome [6] 0 0
Hospitalisation (inpatient) days
Timepoint [6] 0 0
3 months after WZTL-002 administration
Secondary outcome [7] 0 0
Health-related quality of life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)
Timepoint [7] 0 0
Upto 24 months after WZTL-002 administration
Secondary outcome [8] 0 0
European Quality of Life 5-Dimensions 5-Levels Health Questionnaire (EQ-5D-5L)
Timepoint [8] 0 0
Upto 24 months after WZTL-002 administration

Eligibility
Key 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
* 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 creatinine clearance (CrCl) = 45 mL/min using the modified Cockroft Gault estimation 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 WZTL-002, 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 WZTL-002, and
* Agree not to donate sperm for conception, or to provide gametes for in vitro fertilisation for at least 12 months after administration of WZTL-002
17. Participant agrees not to donate blood components at any time after receiving WZTL-002
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (or is < 20 IU/mL), and if they are willing to receive 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
12/07/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2028
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
New Zealand
State/province [1] 0 0
Wellington

Funding & Sponsors
Primary sponsor type
Other
Name
Malaghan Institute of Medical Research
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
BioOra Limited
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Wellington Zhaotai Therapies Limited
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Philip George, MBChB
Address 0 0
Te Whatu Ora Health New Zealand, Capital Coast & Hutt Valley
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Brittany Lavender
Address 0 0
Country 0 0
Phone 0 0
+64 4 499 6914
Fax 0 0
Email 0 0
clinicaltrialmanagement@malaghan.org.nz
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT06486051