A Study of Anti-Lewis Y Chimeric Antigen Receptor-T Cells (LeY-CAR-T) in Patients With Solid Tumours

NCT03851146 | Completed Phase 1 DMC

• 2 other identifiers: LeYPh1-02ACTRN12616001580460
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical trial is an open-label, single-centre, phase I study designed to investigate the safety and tolerability of a single infusion of autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-ζ vector (LeY CAR T-cells) The primary aim of the trial is to evaluate the safety and tolerability of LeY CAR T cells in patients with Lewis Y antigen-expressing, advanced solid tumours. The secondary aim of the trial is to assess the anti-tumour activity of LeY CAR T cells in patients with LeY antigen-expressing, advanced solid tumours. Patients aged 18 years or older with advanced solid tumours have consented to pre-screening that allows their tumours to be assessed for LeY expression by immunohistochemistry. Patients whose tumours test positive for LeY were then able to proceed to eligibility screening and, if found to fulfil the eligibility criteria, were registered in the study. The study involves an initial dose escalation phase followed by an expansion phase.

Conditions

Advanced Cancer

Outcome Measures

Primary Outcomes (2)

• The Maximum Tolerated Dose (MTD) of LeY CAR T-cell infusion

  To determine the maximum tolerated dose of a single intravenous infusion of Le Y CAR T-cells in patients with LeY expressing advanced solid tumours.This outcome will be assessed by evaluating occurrence, type, severity and relationship to treatment of adverse events (AEs) according to NCI CTCAE v4.03 and laboratory abnormalities. To be reported as Total Number of Le Y CAR T-cells infused eg. Y x 10e(9)

  4 weeks

• The Dose-Limiting Toxicities (DLTs) associated with LeY CAR T-cell infusion

  To determine the rate of dose limiting toxicities of a single intravenous infusion of Le Y CAR T-cells in patients with LeY expressing advanced solid tumours. DLT Definition: 1. Any treatment-emergent Grade 4 or 5 (death) AEs related to LeY CAR T cells, excluding laboratory values deemed not clinically significant. 2. Any treatment-emergent Grade 3 AEs related to LeY CAR T cells that do not resolve to ≤ Grade 2 within 7 days, excluding laboratory values deemed not clinically significant 3. Any treatment-emergent Grade 3 or 4 seizure 4. Any treatment-emergent autoimmune event ≥ Grade 3. All Adverse Events(AEs) will recorded in the eCRF using the severity grade according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  4 weeks

Secondary Outcomes (5)

• To assess the Overall Response (OR) to anti-tumour activity of LeY CAR T-cells

  5 years

• To assess the Duration of Response (PR) to anti-tumour activity of LeY CAR T-cells

  5 years

• To assess the Progression Free Survival (PFS) of patients treated with LeY CAR T-cells

  5 years

• To assess the Overall Survival (OS) of patients treated with LeY CAR T-cells

  5 years

• To assess persistence of anti-LeY T-cells in peripheral blood

  12 months

Study Arms (1)

LeY CAR T cells

EXPERIMENTAL

One arm study consisting of "3 + 3" dose escalation study design (see below) followed by dose expansion phase at determined MTD. Dose level : Target Number LeY CART cells infused \* -1 (if needed): 1 x 10e8 1. 2 x 10e8 2. 5 x 10e8 3. 1 x 10e9 4. 5 x 10e9 * Targeted number of LeY CAR T cells (minus 40% acceptance range) for manufacture according toTGA-approved standard protocols Treatment follows a lymphodepleting, chemotherapy regimen that consists of Fludarabine (25 mg/m2 per day) and Cyclophosphamide (300mg/m2 per day) for 3 consecutive days prior to cell infusion, with chemotherapy completed at least 48 hours before the re-infusion of the LeY CAR T cells.

Biological: LeY CAR T cells

Interventions

LeY CAR T cells BIOLOGICAL

Autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-ζ vector (LeY CAR T cells)

LeY CAR T cells

Eligibility Criteria

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

You may qualify if:

• All of the following must apply at the time of enrollment:
• Patients with an advanced solid tumour (defined as incurable locally advanced or metastatic disease and excluding any haematologic malignancy).
• Tumour is positive for Lewis Y expression by immunohistochemistry - defined as a staining of ≥ 10 % of tumour cells positive for LeY expression. For the purposes of tumour screening, where possible the most recently available tumour sample should be utilised. A new biopsy is not mandatory where archival tissue is available, but may be considered.
• Patient is ≥18 years of age.
• Patient has an ECOG performance status of 0 - 1
• Patient has provided written confirmation of informed consent on participant information and consent form
• Life expectancy of ≥ 12 weeks
• Patient has adequate organ function satisfying all of the following:
• Liver: bilirubin \<1.5x upper limit of normal (ULN) unless patient has known Gilbert's syndrome;
• AST/ALT ≤2.5 x ULN except in patients with known liver metastases where AST/ALT≤5.0
• Kidney: either serum creatinine \<1.5x ULN or creatinine clearance \> 50ml/min. Creatinine clearance is either derived using the Cockcroft-Gault formula or may be measured by 24 hour urine collection or nuclear medicine assessment.
• Lung: Adequate pulmonary function defined by SaO2 \>91% on room air and ≤ grade I dyspnoea.
• Cardiac: LVEF ≥ 40% as confirmed by echocardiogram or multiple uptake gated acquisition (MUGA)
• Adequate bone marrow reserve as defined as:
• Absolute neutrophil count (ANC) ≥ 1.0 x 10e9/L

You may not qualify if:

• Patients who meet any of the following criteria will be excluded from participation in this study:
• Patients with known active central nervous system (CNS) involvement by malignancy. Patients with previous treated and/or neurologically stable disease will be eligible.
• Prior chimeric antigen receptor T (CART) cell therapy
• Patient has been given chemotherapy and/or G-CSF in the last 4 weeks or is planned to receive such therapy prior to apheresis of PBMC. Patients can only receive cytotoxic drugs as per the schedule of treatment for this protocol.
• Patient has had immunosuppressive therapy within 4 weeks of apheresis. Therapeutic doses of steroids (defined as \> 20 mg/day of Prednisolone (or equivalent) must be able to be stopped \> 7 days prior to leukapheresis and 72 hours prior to LeY CART cell infusion Physiologic doses of steroid (e.g. Prednisolone \<10mg or equivalent), topical and inhaled steroids are permitted.
• Patient who are eligible for potentially curative therapy
• Uncontrolled active or latent Hepatitis B or active Hepatitis C or HIV
• Patients with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics.
• History or presence of active clinically relevant CNS pathology such as epilepsy, aphasia, severe brain injury, dementia, Parkinson's disease, cerebellar disease or psychosis.
• Radiation therapy within 2 weeks prior to registration
• Patient has an active haematologic malignancy (any lymphoma, leukaemia, multiple myeloma or myelodysplastic syndrome)
• Patient has a history of significant pulmonary disease (including radiation pneumonitis) or known, biopsy proven autoimmune inflammatory disease of the gastrointestinal tract.
• Unstable angina or myocardial infarct within 6 months prior to screening.
• Patient has known clinically significant autoimmune disease with positive serology for RHF (\>20kU/L) or ANA (titre \>1:40).
• Women of child bearing potential (WOCBP) who are unwilling or unable to use an effective method of contraception to avoid pregnancy for the entire study period and for at least 12 months after completion of study treatment.

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (1)

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Related Publications (1)

• Meyran D, Zhu JJ, Butler J, Tantalo D, MacDonald S, Nguyen TN, Wang M, Thio N, D'Souza C, Qin VM, Slaney C, Harrison A, Sek K, Petrone P, Thia K, Giuffrida L, Scott AM, Terry RL, Tran B, Desai J, Prince HM, Harrison SJ, Beavis PA, Kershaw MH, Solomon B, Ekert PG, Trapani JA, Darcy PK, Neeson PJ. TSTEM-like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models. Sci Transl Med. 2023 Apr 5;15(690):eabk1900. doi: 10.1126/scitranslmed.abk1900. Epub 2023 Apr 5.

  PMID: 37018415 DERIVED

Study Officials

• Ben Solomon

  Peter MacCallum Cancer Centre, Australia

  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: The study will employ dose level cohorts of three patients that will be treated at each level described in Table 1, based on the number of T cells to be infused using the "3 + 3" dose-escalation strategy. If the proposed number of T cells is unable to be obtained due to technical production reasons, the available number will be infused. However, the cohort will only be escalated when a minimum of three patients have been safely treated at the planned level. The fourth cohort dose level has been set according to the maximum level considered to be feasible taking into account technical constraints. The study will be expanded to accrue additional patients at the MTD (expansion phase cohort) with an expansion cohort of upto 20 patients. For technical and logistic reasons the maximum number of patients to be enrolled on the study will be 30.

Study Record Dates

• First Submitted: February 12, 2019
• First Posted: February 22, 2019
• Study Start: November 24, 2016
• Primary Completion: April 1, 2022
• Study Completion: April 1, 2022
• Last Updated: May 3, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)