Clinical Trials /

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

NCT03851146

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: LeYPh1-02
  • SECONDARY ID: ACTRN12616001580460
  • NCT ID: NCT03851146

Conditions

  • Advanced Cancer

Interventions

DrugSynonymsArms
LeY CAR T cellsLeY CAR T cells

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
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 2 x 10e8 5 x 10e8 1 x 10e9 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.
  • LeY CAR T cells

Eligibility Criteria

        Inclusion Criteria:

        All of the following must apply at the time of enrollment:

          1. 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.

          2. Patient is ≥18 years of age.

          3. Patient has an ECOG performance status of 0 - 1

          4. Patient has provided written confirmation of informed consent on participant
             information and consent form

          5. Life expectancy of ≥ 12 weeks

          6. 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

          7. Patient is deemed capable and willing to undergo the planned study procedures in the
             view of the principal investigator.

          8. 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.

          9. Patient has measurable disease as per RECIST 1.1.

        Exclusion Criteria:

        Patients who meet any of the following criteria will be excluded from participation in this
        study:

          1. Patients with known active central nervous system (CNS) involvement by malignancy.
             Patients with previous treated and/or neurologically stable disease will be eligible.

          2. Prior chimeric antigen receptor T (CART) cell therapy

          3. 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.

          4. 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.

          5. Patient who are eligible for potentially curative therapy

          6. Uncontrolled active or latent Hepatitis B or active Hepatitis C or HIV

          7. Patients with uncontrolled systemic fungal, bacterial, viral or other infection
             despite appropriate antibiotics.

          8. History or presence of active clinically relevant CNS pathology such as epilepsy,
             aphasia, severe brain injury, dementia, Parkinson's disease, cerebellar disease or
             psychosis.

          9. Radiation therapy within 2 weeks prior to registration

         10. Patient has an active haematologic malignancy (any lymphoma, leukaemia, multiple
             myeloma or myelodysplastic syndrome)

         11. Patient has a history of significant pulmonary disease (including radiation
             pneumonitis) or known, biopsy proven autoimmune inflammatory disease of the
             gastrointestinal tract.

         12. Unstable angina or myocardial infarct within 6 months prior to screening.

         13. Patient has known clinically significant autoimmune disease with positive serology for
             RHF (>20kU/L) or ANA (titre >1:40).

         14. 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.

         15. Women who are pregnant or breastfeeding.

         16. 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.

         17. Patient has a serious uncontrolled medical disorder, psychological or social factors
             that which would impair the ability to receive protocol therapy and follow up.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The Maximum Tolerated Dose (MTD) of LeY CAR T-cell infusion
Time Frame:4 weeks
Safety Issue:
Description: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 Outcome Measures

Measure:To assess the Overall Response (OR) to anti-tumour activity of LeY CAR T-cells
Time Frame:5 years
Safety Issue:
Description: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.
Measure:To assess the Duration of Response (PR) to anti-tumour activity of LeY CAR T-cells
Time Frame:5 years
Safety Issue:
Description: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.
Measure:To assess the Progression Free Survival (PFS) of patients treated with LeY CAR T-cells
Time Frame:5 years
Safety Issue:
Description: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.
Measure:To assess the Overall Survival (OS) of patients treated with LeY CAR T-cells
Time Frame:5 years
Safety Issue:
Description: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.
Measure:To assess persistence of anti-LeY T-cells in peripheral blood
Time Frame:12 months
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Peter MacCallum Cancer Centre, Australia

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