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
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Advanced Cancer
- Sponsor
- Peter MacCallum Cancer Centre, Australia
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- The Dose-Limiting Toxicities (DLTs) associated with LeY CAR T-cell infusion
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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
Outcomes
Primary Outcomes
The Dose-Limiting Toxicities (DLTs) associated with LeY CAR T-cell infusion
Time Frame: 4 weeks
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.
The Maximum Tolerated Dose (MTD) of LeY CAR T-cell infusion
Time Frame: 4 weeks
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)
Secondary Outcomes
- To assess the Overall Response (OR) to anti-tumour activity of LeY CAR T-cells(5 years)
- To assess the Overall Survival (OS) of patients treated with 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 persistence of anti-LeY T-cells in peripheral blood(12 months)