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Trial registered on ANZCTR


Registration number
ACTRN12616001580460
Ethics application status
Approved
Date submitted
2/11/2016
Date registered
16/11/2016
Date last updated
3/05/2021
Date data sharing statement initially provided
20/02/2019
Date results information initially provided
3/05/2021
Type of registration
Prospectively registered

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] 290430 0
LeYPh1-02
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
advanced solid tumors expressing LeY antigen 300780 0
Condition category
Condition code
Cancer 300610 300610 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study treatment consists in a single intravenous infusion of autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-zeta vector.
The study involves initial pre-screening of tumour tissue for Lewis Y expression to assess patient eligibility for the study protocol. If eligible, the patient will undergo leukapheresis as soon as possible, followed by lymphodepleting conditioning chemotherapy and then infusion of LeY CAR T cells. Patients will then have follow up for assessment and management of adverse events and evaluation of response.
## Leukapheresis (not less than 12 days from Infusion). Venous access is required for leukapheresis and should be determined according to institutional practice. For the MNC collection an initial apheresis cycle is to be performed to obtain sufficient quantity of PBMCs to generate LeY CAR T cells. If there is an insufficient yield of PBMC following the apheresis, initiation of the cell culture will not proceed. However, the patient may undergo further apheresis procedures. If a sufficient number of PBMC cannot be achieved with a maximum of five collections, the patient may be withdrawn from the study.The turnaround time for the transduction and manufacture of the T cells is 12 days.
## Lymphodepleting conditioning chemotherapy (within 7 days from Infusion) this is not standard of care. To increase immunosuppression and improve persistence of engineered T-cells, patients will receive fludarabine and cyclophosphamide before re-infusion of the transduced T-cells. Upon notification from the sponsor that LeY CAR T cells will be available, Lymphodepleting conditioning chemotherapy should be initiated so as to finish at least 48 hours prior to LeY CAR T cells administration. Patients will receive intravenous fludarabine (25 mg/m2 per day) and Cyclophosphamide (300mg/m2 per day) for 3 consecutive days prior to cell infusion (Note: Lymphodepleting conditioning chemotherapy was previously fludarabine alone for 2 days upto the end of cohort dose #2, ie, patient #06, but was subsequently amended in the study protocol to enable improved cell expansion). Chemotherapy should be started within 7 days of re-infusion of the T-cell product (day 0). Alternative lymphodepleting schedules may be investigated in discussion with the Data Safety Management Committee (DSMC).
## Re-Infusion of LeY CAR T cell(Day0)
After the date of infusion of the LeY CAR T cells has been determined, generation of the LeY CAR T-cell product will proceed. LeY CAR T cells are an autologous cellular immunotherapy product containing T cells that have undergone ex vivo activation, gene modification, expansion and formulation in re-infusion medium (normal saline with 5% Albumex 20). LeY CAR T cells will be administered according to the dose level to which the patient is assigned.Decisions to modify the dose increments or the number of patients in each dosing cohort may be made at the discretion of the principal investigator in conjunction with the DSMC in the event of adverse events observed among any patients during dose escalation at an unexpected high incidence or severity. It may also be possible to explore additional dose levels.

##Concomitant treatment will consist of prophylaxis of hypersensitivity reactions to the infusion of the T-cell product by intake of 10 mg of loratadine (oral tablets) or Phenergan (25mg oral or IV) and 1g of paracetamol (oral tablets) 30 minutes prior to the infusion. Whether loratadine or phenergen is administered will be in the the opinion of the treating physician.


Only one patient can be treated with the T cell product at any given time point during the dose escalation. No additional patients can progress to T cell infusion until the current patient is 2 or more weeks post infusion during the dose escalation phase.
Initially 3 patients will be enrolled into a cohort, starting at dose level cohort 1.
#If 0/3 patients report a DLT within the observation period (28 days following infusion of LeY CAR T cells) then 3 patients will be enrolled at one dose level above. If current dose is dose level -1 or dose level 4 then a further 3 patients will be enrolled at the current dose level.
# If 1/3 patients report a DLT within the observation period then a further 3 patients will be enrolled at the current dose level.
#If 1/6 patients report a DLT within the observation period:
- If current dose level was a dose reduction or if it is dose level 4 then the current dose level will be declared the Maximum Tolerated Dose (MTD).
- If current dose level was not a dose reduction nor is dose level 4 then 3 patients will be enrolled at one dose level above
#If greater than or equal to 2/6 patients report a DLT within the observation period:
- If current dose level is dose level -1, the trial will be stopped
- If 6 patients were treated at one dose level below, declare one dose below as MTD.
- If 0 or 3 patients were enrolled one dose level below, then three patients will be enrolled at one dose level below.
If greater than or equal to 2/3 patients report a DLT within the observation period:
-If current dose level is dose level -1, the trial will be stopped
- If 6 patients were treated at one dose level below, declare one dose below as MTD.
-If 0 or 3 patients were enrolled one dose level below, then three patients will be enrolled at one dose level below.
Target dose level -1 if needed 1x10e8
cohort 1: 1.2 - 2 x10e8 LeY CAR T cells infused
cohort 2: 3 - 5 x 10e8 LeY CAR T cells infused
cohort 3: 0.6 -1 x 10e9 LeY CAR T cells infused
cohort 4: 3 - 5 x 10e9 LeY CAR T cells infused
Intervention code [1] 296273 0
Treatment: Drugs
Intervention code [2] 296318 0
Treatment: Other
Comparator / control treatment
nil
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300043 0
To determine the maximum tolerated dose of a single intravenous infusion of autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-zeta vector in patients with LeY expressing advanced solid tumours (LeY CAR T cells).

This outcome will be assessed by evaluating occurrence, type, severity and relationship to treatment of adverse events (AEs) and laboratory abnormalities.
9Adverse events described according to NCI CTCAE v4.03)
Timepoint [1] 300043 0
28 days after infusion
Primary outcome [2] 300072 0
To determine the rate of dose limiting toxicities of a single intravenous infusion of autologous peripheral blood T-lymphocytes transduced with the anti-LeY-scFv-CD28-zeta vector in patients with LeY expressing advanced solid tumours (LeY CAR T cells).

This outcome will be assessed by evaluating the occurrence and type of DLTs
Timepoint [2] 300072 0
28 days after infusion
Secondary outcome [1] 328884 0
To assess the anti-tumour activity of the LeY CAR T cells in terms of overall response, defined as the best response to the CAR T-cells re-infusion based on RECIST v1.1:
Response will be determined by CT scan and response assessment, to assess disease lesions and responses.
Timepoint [1] 328884 0
The main analysis will occur once all patients have had 12 months follow up
The final analysis will occur once all patients have had 5 years follow up

Each patient is intended to have CT scan performed at baseline (screening) and then during follow up on Day 28 and 56 (+/- 2 days), every 8 weeks to 1 year (+/- 1 week), then every 12 weeks, until progression.
Secondary outcome [2] 328939 0
To assess the anti-tumour activity of the LeY CAR T cells in terms of 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 (death is a censoring event), for those patients who experience a PR or better.
Timepoint [2] 328939 0
The main analysis will occur once all patients have had 12 months follow up
The final analysis will occur once all patients have had 5 years follow up

Each patient is intended to have CT scan performed at baseline (screening) and then during follow up on Day 28 and 56 (+/- 2 days), every 8 weeks to 1 year (+/- 1 week), then every 12 weeks, until progression.
Secondary outcome [3] 328940 0
To assess the anti-tumour activity of the LeY CAR T cells in terms of progression free survival defined as the time from LeY CAR T-cells re-infusion to the earliest of date of disease progression as assessed by RECIST v1.1 or death.
Timepoint [3] 328940 0
The main analysis will occur once all patients have had 12 months follow up
The final analysis will occur once all patients have had 5 years follow up

Each patient is intended to have CT scan performed at baseline (screening) and then during follow up on Day 28 and 56 (+/- 2 days), every 8 weeks to 1 year (+/- 1 week), then every 12 weeks, until progression.
Secondary outcome [4] 328941 0
To assess the anti-tumour activity of the LeY CAR T cells in terms of overall survival, defined as the time from re-infusion to date of death.
Timepoint [4] 328941 0
The main analysis will occur once all patients have had 12 months follow up
The final analysis will occur once all patients have had 5 years follow up

Each patient is intended to have CT scan performed at baseline (screening) and then during follow up on Day 28 and 56 (+/- 2 days), every 8 weeks to 1 year (+/- 1 week), then every 12 weeks, until progression.
Secondary outcome [5] 328942 0
To assess persistence of anti-LeY T-cells in peripheral blood through the detection (presence/absence) and quantification of LeY transgene in PB by qPCR at each time point of assessment
Timepoint [5] 328942 0
The main analysis will occur once all patients have had 12 months follow up
The final analysis will occur once all patients have had 5 years follow up

Each patient is intended to have CT scan performed at baseline (screening) and then during follow up on Day 28 and 56 (+/- 2 days), every 8 weeks to 1 year (+/- 1 week), then every 12 weeks, until progression.

Eligibility
Key inclusion criteria
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 'greater than or equal to'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 'greater than or equal to'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 'greater than or equal to' 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 equal to 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-h 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-Patient is able to undergo apheresis of PBMC within 14 days following registration.

9-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 CAR T therapy.

10-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
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 the last 4 weeks. 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 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
Non-randomised trial
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
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
It is anticipated that dose level cohorts of three patients will be treated at each level based on the number of T cells to be infused using the “3 + 3” dose-escalation strategy. If four patients are attempted, and the proposed number of T cells is unable to be obtained in at least 1 of these patients, the feasibility of that dose level will be reviewed by the DSMC and enrolment at a lower dose level will be considered.
cohort 1: 1.2 - 2 x10e8 LeY CAR T cells infused
cohort 2: 3 - 5 x 10e8 LeY CAR T cells infused
cohort 3: 0.6 - 1 x 10e9 LeY CAR T cells infused
cohort 4: 3 - 5 x 10e9 LeY CAR T cells infused
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Dose escalation phase: The sample size has been determined to allow completion of the escalation phase with a minimum of 3 patients per cohort. Allowance will be made for the possibility that adequate cell numbers will not be collected so escalation to a higher dose level will not occur until 3 patients have been treated at the current dose level with the intended number of T cells. In the event of all four dose levels being tested, there could be at least 12 patients with adequate cell numbers in the dose escalation phase (3 patients at each of 4 dose levels).
If patients are treated with fewer cells than intended, they will still have all study related assessments, but will not be included in the assessment of that dose level. If the patient has greater cells than a previously tested dose level, they will be summarised as part of that dose level cohort for the statistical analysis reporting at the conclusion of the study.If 0 of 4 patients treated at a dose level is able to achieve the specified cell number the feasibility of that dose level will be reviewed by the DSMC and enrolment at a lower dose level will be considered. Dose expansion phase: Following determination of the maximum tolerated dose, further patients will be accrued. The sample size is limited by technical and logistic reasons, so the maximum number of patients to receive the T-cell product is limited to 30. If, for example, the MTD is determined from 12 patients, up to 18 patients may be in the expansion phase. It is possible that the dose escalation phase may require >12 patients, depending on the occurrence of DLTs and inadequate cell numbers being collected from some patients, therefore leaving a sample size of <18 for the expansion phase.

Recruitment
Recruitment status
Active, not recruiting
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

Funding & Sponsors
Funding source category [1] 294857 0
Commercial sector/Industry
Name [1] 294857 0
Juno Therapeutics
Address [1] 294857 0
307 Westlake Avenue N., Suite 300
Seattle, WA 98109 USA
Country [1] 294857 0
United States of America
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Center
Address
305 Grattan Street 3000 Melbourne Vic
Country
Australia
Secondary sponsor category [1] 293697 0
None
Name [1] 293697 0
Address [1] 293697 0
Country [1] 293697 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296240 0
Peter MacCallum HREC
Ethics committee address [1] 296240 0
305 Grattan street 3000 Melbourne
Ethics committee country [1] 296240 0
Australia
Date submitted for ethics approval [1] 296240 0
22/08/2016
Approval date [1] 296240 0
10/10/2016
Ethics approval number [1] 296240 0
HREC/16/PMCC/30

Summary
Brief summary
This study will test the safety, tolerability and effectiveness of an experimental treatment called “LeY CAR-T cell therapy”in treating solid tumours that carry the Lewis Y marker.
Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have an advanced solid tumour that is positive for the Lewis Y antigen.
Study details
The Lewis Y antigen is a molecule that coats the surface of a cancer cell and is not usually detected by T-cells. The “LeY CAR-T cell therapy” may help the T-cells to find and destroy the cancer cells more easily. In this study, the T-cells will first be collected using a procedure called “Apheresis” that takes part before the study treatment. Apheresis collects some of the white blood cells (also called Leukocytes) including T-Cells from the blood. The collected T-cells will then be modified in the laboratory by a viral vector, to specifically target the cancer cells that have the Lewis Y marker on their surface.
After T-cells have been modified, the viral vector will be separated from modified T-cells and removed. Modified T-cells can now be called CAR-T cells. The finished LeY CAR-T cells will then be infused back into the body, without the viral vector.
As well as the LeY CAR-T cell therapy, patients will receive by lymphodepleting conditioning chemotherapy as intravenous fludarabine and cyclophosphamide for 3 consecutive days prior to cell infusion to increase immunosuppression and improve persistence of engineered T-cells.
LeY CAR-T cell therapy is an experimental treatment. This means that it is not an approved treatment for LeY expressing solid tumours in Australia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70062 0
Prof Benjamin Solomon
Address 70062 0
Peter MacCallum Cancer Centre 305 Grattan st 3000 Melbourne
Country 70062 0
Australia
Phone 70062 0
+61 (03) 8559 5000
Fax 70062 0
Email 70062 0
Ben.Solomon@petermac.org
Contact person for public queries
Name 70063 0
Dr John Parisot
Address 70063 0
Peter MacCallum Cancer Centre 305 Grattan st 3000 Melbourne
Country 70063 0
Australia
Phone 70063 0
+61 (03) 855 95035
Fax 70063 0
Email 70063 0
John.Parisot@petermac.org
Contact person for scientific queries
Name 70064 0
Prof Benjamin Solomon
Address 70064 0
Peter MacCallum Cancer Centre 305 Grattan st 3000 Melbourne
Country 70064 0
Australia
Phone 70064 0
+61 (03) 8559 5000
Fax 70064 0
Email 70064 0
Ben.Solomon@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Clinical trial data subject to commercial agreement
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary