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Advanced CancerPhase 1LeY-CAR-TNCT03851146

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

A Phase 1 study testing LeY CAR T cells in people with Advanced Cancer, run by Peter MacCallum Cancer Centre, Australia at 1 site in Australia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Cancer
What is being tested?
LeY CAR T cells
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteAustralia
Study dates
24 Nov 2016to 1 Apr 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • Absolute lymphocyte count ≥ 0.5 x 10e9/L
  • Platelets ≥ 100 x 10e9/L
  • Haemoglobin >80g/L
  • WCC <30 x 10e9/L
  • Patient is deemed capable and willing to undergo the planned study procedures in the view of the principal investigator.
  • Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for one year following LeY CART therapy.
  • Patient has measurable disease as per RECIST 1.1.

Who cannot join

  • 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
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  • 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.
  • Women who are pregnant or breastfeeding.
  • Men who are unwilling or unable to use an acceptable method of contraception for the entire study period and for at least 12 months after completion of study treatment if their sexual partners are WOCBP.
  • Patient has a serious uncontrolled medical disorder, psychological or social factors that which would impair the ability to receive protocol therapy and follow up.

Trial locations and contacts

1 site in 1 country.

Australia1 site

  • Peter MacCallum Cancer Centre

    Melbourne, Victoria, 3000

Other trials in Australia

About this study

Official title: A Phase I Investigation of the Safety, Tolerability and Immunological Effects of T Lymphocytes Transduced With an Anti-Lewis Y (LeY) Chimeric Antigen Receptor Gene (LeY-CAR-T) in Patients With LeY Antigen Expressing Advanced Solid Tumours

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.

Read the detailed description

To autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-ζ vector in patients with LeY expressing advanced solid tumours. evaluate the safety and tolerability of an intravenous infusion of autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-ζ vector in patients with LeY expressing advanced solid tumours.

Aims:

To evaluate the safety and tolerability of an intravenous infusion of autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-ζ vector in patients with LeY expressing advanced solid tumours.

Primary Objectives To determine the maximum tolerated dose and rate of dose limiting toxicities of a single intravenous infusion of autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-ζ vector in patients with LeY expressing advanced solid tumours (LeY CAR T cells).

Secondary Objectives i. To assess the anti-tumour activity of the LeY CAR T cells in terms of overall response, duration of response, progression free survival and overall survival.

ii. To assess persistence in peripheral blood of the LeY CAR T cells.

The study will recruit an anticipated number of 12 patients in the dose escalation phase consisting of 4 dose levels, each with dose level cohorts of 3 patients. Following completion of the dose-escalation phase, additional patients with Le Y expressing solid tumours will be recruited to the study. These patients will be administered the maximum number of cells safely delivered in the dose escalation phase of the study. A subset comprising 5 patients in the expansion cohort will be administered Indium-111 labelled T-cells and imaged by SPECT to determine the biodistribution of reinfused T cells.

If the proposed number of T cells is unable to be obtained due to technical production reasons, the available number will be infused.

It is anticipated that up to 30 patients will be treated on this protocol.

Conditions
Advanced Cancer
Being tested
LeY CAR T cells

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LeY CAR T cellsBiological

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

Study groups in NCT03851146
Study groupRoleWhat they receive
LeY CAR T cellsExperimentalOne 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.
Receives: Biological: LeY CAR T cells

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Measured: 4 weeks

  2. 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.

    Measured: 4 weeks

Secondary outcomes (5)

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

    Overall response (OR), defined as the best response to the CAR T-cells re-infusion based on RECIST v1.1 criteria. Response will be determined by CT scan at baseline (screening), week 4 and week 8 post-infusion, every 8 weeks thereafter until 1 year has elapsed, followed by every 12 weeks until progression.

    The main analysis will occur once all patients have had 12 months follow up with the final analysis to occur once all patients have had 5 years follow-up.

    Measured: 5 years

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

    Duration of response, defined as the time from the date of first response of PR or better until the date of disease progression, for those patients who experience a PR or better as assessed by RECIST v1.1 criteria (death is a censoring event), for those patients who experience a PR or better.

    Response will be determined by CT scan at baseline (screening), week 4 and week 8 post-infusion, every 8 weeks thereafter until 1 year has elapsed, followed by every 12 weeks until progression.

    The main analysis will occur once all patients have had 12 months follow up with the final analysis to occur once all patients have had 5 years follow-up.

    Measured: 5 years

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

    Progression free survival (PFS), defined as the time from LeY CAR T cells re-infusion to the earliest of date of disease progression as assessed by RECIST v1.1criteria or death.

    Response will be determined by CT scan at baseline (screening), week 4 and week 8 post-infusion, every 8 weeks thereafter until 1 year has elapsed, followed by every 12 weeks until progression.

    The main analysis will occur once all patients have had 12 months follow up with the final analysis to occur once all patients have had 5 years follow-up.

    Measured: 5 years

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

    Overall survival (OS), defined as the time from LeY CAR T cells re-infusion to date of death.

    Response will be determined by CT scan at baseline (screening), week 4 and week 8 post-infusion, every 8 weeks thereafter until 1 year has elapsed, followed by every 12 weeks until progression.

    The main analysis will occur once all patients have had 12 months follow up with the final analysis to occur once all patients have had 5 years follow-up.

    Measured: 5 years

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

    Detection (presence/absence) and quantification of LeY CAR T-cell transgene in peripheral blood by qPCR at each of the following time points of assessment (day -7(pre-infusion), day 0 (day of infusion), days 1, 2, 3, 6, 10, 14, 21, 28, 42, 56 post-infusion and every 4 weeks thereafter until 1 year has elapsed.

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Feb 2019
  2. Study start24 Nov 2016
  3. Primary completion1 Apr 2022
  4. Study completion1 Apr 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Model description
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.
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03851146
Sponsor's protocol ID
LeYPh1-02
Other IDs
ACTRN12616001580460
Acronym
LeY-CAR-T
Status last verified
May 2022
First submitted
12 Feb 2019
Last updated
3 May 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 37018415

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing LeY CAR T cells in people with Advanced Cancer, run by Peter MacCallum Cancer Centre, Australia at 1 site in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Maximum Tolerated Dose (MTD) of LeY CAR T-cell infusion (time frame: 4 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03851146, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2022; AzTrials last refreshed its copy on 7 Nov 2026.

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