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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04049513




Registration number
NCT04049513
Ethics application status
Date submitted
29/07/2019
Date registered
8/08/2019
Date last updated
3/07/2023

Titles & IDs
Public title
ENABLE (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy)
Scientific 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
Secondary ID [1] 0 0
U1111-1216-2053
Secondary ID [2] 0 0
WZTL002-1
Universal Trial Number (UTN)
Trial acronym
ENABLE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphomas Non-Hodgkin's B-Cell 0 0
Diffuse Large B-cell Lymphoma (DLBCL) 0 0
Primary Mediastinal B-cell Lymphoma (PMBCL) 0 0
Transformed Follicular Lymphoma (TFL) 0 0
Follicular Lymphoma (FL) 0 0
Mantle Cell Lymphoma (MCL) 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
Other interventions - WZTL002-1 (1928T2z CAR-T cells)
Treatment: Drugs - Cyclophosphamide and Fludarabine lymphodepleting chemotherapy

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.


Other interventions: 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 CD3?. WZTL-002 (autologous 1928T2z CAR T-cells) will be administered on D0 as a single IV infusion, following lymphodepleting chemotherapy.

Treatment: Drugs: 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
Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
3 months after administration
Secondary outcome [1] 0 0
Feasibility of Manufacture
Timepoint [1] 0 0
3 months after administration
Secondary outcome [2] 0 0
Overall Response Rate
Timepoint [2] 0 0
3 months after administration
Secondary outcome [3] 0 0
Cumulative CR rate
Timepoint [3] 0 0
6 months after administration
Secondary outcome [4] 0 0
Relapse-free survival
Timepoint [4] 0 0
24 months after administration
Secondary outcome [5] 0 0
Overall survival
Timepoint [5] 0 0
24 months after administration
Secondary outcome [6] 0 0
Recommended dose
Timepoint [6] 0 0
3 months after administration

Eligibility
Key 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.
Minimum age
16 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
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
Other
Other design features
Phase
Phase 1
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
11/10/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/02/2029
Actual
Sample size
Target
30
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
Wellington Zhaotai Therapies Limited (WZTL)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04049513
Trial related presentations / publications
George P, Dasyam N, Giunti G, Mester B, Bauer E, Andrews B, Perera T, Ostapowicz T, Frampton C, Li P, Ritchie D, Bollard CM, Hermans IF, Weinkove R. Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE). BMJ Open. 2020 Feb 9;10(2):e034629. doi: 10.1136/bmjopen-2019-034629.
Public notes

Contacts
Principal investigator
Name 0 0
Robert Weinkove, MBBS, PhD
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
Robert Weinkove, MBBS, PhD
Address 0 0
Country 0 0
Phone 0 0
+64 4 918 5117
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04049513