A Phase 1 interventional study of LeY CAR T cells in Advanced Cancer, sponsored by Peter MacCallum Cancer Centre, Australia. Completed at 1 site in Australia. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-05-03.
Sponsored by Peter MacCallum Cancer Centre, Australia · Phase 1, Interventional, and Treatment
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.
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.
Peter MacCallum Cancer Centre, Australia is the lead sponsor of 80 studies on the registry; 26 are open to participants now.
Counted across the registry records on this site, refreshed daily.
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 has adequate organ function satisfying all of the following:
Adequate bone marrow reserve as defined as:
Exclusion Criteria:
Patients who meet any of the following criteria will be excluded from participation in this study:
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
Autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-ζ vector (LeY CAR T cells)
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)
Time frame: 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.
Time frame: 4 weeks
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.
Time frame: 5 years
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.
Time frame: 5 years
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.
Time frame: 5 years
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.
Time frame: 5 years
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.
Time frame: 12 months
Plan to share: No
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Peter MacCallum Cancer Centre, Australia