The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03851146




Registration number
NCT03851146
Ethics application status
Date submitted
12/02/2019
Date registered
22/02/2019
Date last updated
22/02/2019

Titles & IDs
Public title
A Study of Anti-Lewis Y Chimeric Antigen Receptor-T Cells (LeY-CAR-T) in Patients With Solid Tumours
Scientific 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
Secondary ID [1] 0 0
ACTRN12616001580460
Secondary ID [2] 0 0
LeYPh1-02
Universal Trial Number (UTN)
Trial acronym
LeY-CAR-T
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - LeY CAR T cells

Experimental: LeY CAR T cells - 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
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.


Other interventions: LeY CAR T cells
Autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-? vector (LeY CAR T cells)

Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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)
Timepoint [1] 0 0
4 weeks
Primary outcome [2] 0 0
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:
Any treatment-emergent Grade 4 or 5 (death) AEs related to LeY CAR T cells, excluding laboratory values deemed not clinically significant.
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
Any treatment-emergent Grade 3 or 4 seizure
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.
Timepoint [2] 0 0
4 weeks
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
5 years
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
5 years
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
5 years
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
12 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Peter MacCallum Cancer Centre, Australia
Address
Country

Ethics approval
Ethics application status

Summary
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-? 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.
Trial website
https://clinicaltrials.gov/show/NCT03851146
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Ben Solomon
Address 0 0
Peter MacCallum Cancer Centre, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
John P Parisot, PhD
Address 0 0
Country 0 0
Phone 0 0
61385595000
Fax 0 0
Email 0 0
john.parisot@petermac.org
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03851146