ENABLE-1 (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy)

NCT04049513 | Active Not Recruiting Phase 1 DMC

• 2 other identifiers: WZTL002-1U1111-1216-2053
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

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)

Keywords

Lymphomas Non-Hodgkin's B-Cell; Chimeric antigen receptor T-cell

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (6)

• Feasibility of Manufacture

  3 months after administration

• Overall Response Rate

  3 months after administration

• Cumulative CR rate

  6 months after administration

• Relapse-free survival

  24 months after administration

• Overall survival

  24 months after administration

Study Arms (1)

WZTL002-1 (1928T2z CAR T-cells)

EXPERIMENTAL

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); Drug: Cyclophosphamide and Fludarabine lymphodepleting chemotherapy

Interventions

WZTL002-1 (1928T2z CAR-T cells) BIOLOGICAL

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 and Fludarabine lymphodepleting chemotherapy DRUG

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

WZTL002-1 (1928T2z CAR T-cells)

Eligibility Criteria

• Age: 16 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Malaghan Institute of Medical Research: lead
• Wellington Zhaotai Therapies Limited: collaborator

Study Sites (1)

Wellington Hospital, Te Whatu Ora Health New Zealand Capital Coast & Hutt Valley

Wellington, 6021, New Zealand

Location

Related Publications (4)

• 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.

  PMID: 32041862 BACKGROUND

• Weinkove R, George P, Ruka M, Haira TH, Giunti G. Chimeric antigen receptor T-cells in New Zealand: challenges and opportunities. N Z Med J. 2021 Sep 17;134(1542):96-108.

  PMID: 34531588 DERIVED

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

  PMID: 34515338 DERIVED

• Dasyam N, George P, Weinkove R. Chimeric antigen receptor T-cell therapies: Optimising the dose. Br J Clin Pharmacol. 2020 Sep;86(9):1678-1689. doi: 10.1111/bcp.14281. Epub 2020 Mar 24.

  PMID: 32175617 DERIVED

MeSH Terms

Conditions

Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, Mantle-Cell

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Robert Weinkove, MBBS, PhD

  Te Whatu Ora Health New Zealand Capital Coast & Hutt Valley

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Modified 3+3 dose escalation scheme.

Study Record Dates

• First Submitted: July 29, 2019
• First Posted: August 8, 2019
• Study Start: October 11, 2019
• Primary Completion: June 12, 2024
• Study Completion (Estimated): March 1, 2029
• Last Updated: August 21, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share

Locations

NZ (1)