Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000675729
Ethics application status
Approved
Date submitted
1/03/2022
Date registered
10/05/2022
Date last updated
15/04/2024
Date data sharing statement initially provided
10/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Leveraging Chimeric Antigen Receptor-Expressing T Cells for Children with Diffuse Midline Glioma
Scientific title
A Phase I Study of the Safety of Autologous GD2-Specific Chimeric Antigen Receptor-Expressing T Cells in Children with Diffuse Midline Glioma
Secondary ID [1] 306324 0
None
Universal Trial Number (UTN)
Trial acronym
LEVI’S CATCH
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Central Nervous System Tumour 325097 0
Diffuse Midline Glioma 325098 0
High Grade Glioma 325099 0
Diffuse Intrinsic Pontine Glioma 325100 0
Condition category
Condition code
Cancer 322521 322521 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Autologous GD2-specific chimeric antigen receptor-expressing T cells (GD2-iCAR-PBT) will be used to treat children (less than or equal to 21 years of age) with a diagnosis of diffuse midline glioma.

The study will be performed in two parts:

Part I: Manufacture of GD2-iCAR-PBT

In Part I, patients with diffuse midline glioma will be consented and screened (history and physical examination, cellular therapy donor questionnaire, blood tests including pregnancy test). Patients who meet eligibility criteria for Part I will consent for collection of peripheral T cells by apheresis. Collection of peripheral T cells by apheresis is performed by a haematologist and takes approximately 3 hours. If collection of peripheral T cells and subsequent generation of GD2-iCAR-PBT is successful, patients may then consent to Part II, which will allow for treatment with the manufactured product. Ideally patients should be enrolled in Part I prior to radiation therapy, although this is not essential.

Part II: Treatment with GD2-iCAR-PBT

In Part II, patients will be consented and screened (physical examination, safety and research blood tests, pregnancy test, urine test, ECG and echocardiogram, and brain MRI). Part II of the study will commence at least 4 weeks after Part I.

Patients may be treated with radiation therapy as per standard of care. Radiation therapy must be completed at least 4 weeks before the GD2-iCAR-PBT infusion. As patients are at significant risk of pseudoprogression, a ventriculo-peritoneal shunt or ventricular reservoir must be inserted at least one week prior to initiation of lymphodepleting chemotherapy. At the discretion of the treating neurologist, the ventriculo-peritoneal shunt or ventricular reservoir will be inserted by a neurosurgeon. This procedure takes about an hour.

Lymphodepleting chemotherapy will be given prior to infusion of GD2-iCAR-PBT, and will consist of fludarabine and cyclophosphamide, along with bevacizumab to prevent tumour pseudoprogression. Fludarabine 30mg/m^2 will be given intravenously on Days -6, -5, -4 and -3, and cyclophosphamide 500 mg/m^2 will be given intravenously on Days -6 and -5, prior to the GD2-iCAR-PBT injection. Each dose of fludarabine and/or cyclophosphamide takes approximately 1 hour to administer. Up to three doses of bevacizumab 10mg/kg will be administered intravenously every two weeks to cover the period surrounding the injection of GD2-iCAR-PBT. The first dose will be given one week prior to the GD2-iCAR-PBT injection, with subsequent doses every two weeks. The third dose is optional and will be given at the discretion of the treating oncologist.

The starting dose level of GD2-iCAR-PBT is 1 x 10^7 cells/m^2. A single ascending dose-escalation design and rolling six dose-finding method will be applied to find a safe dose of GD2-iCAR-PBT. Dose Level -1: 1 x10^6 cells/m^2, Dose Level 1a: 5 x 10^7 cells/m^2, Dose Level 2: 1 x 10^8 cells/m^2.

Patients will be treated with the first dose of GD2-iCAR-PBT given intravenously. The dose-limiting toxicity (DLT) evaluation period is 6 weeks. In the absence of a dose-limiting toxicity, patients with evidence of clinical benefit at the 6-week evaluation or at subsequent evaluations will be eligible to receive additional doses of GD2-iCAR-PBT at least 6 weeks apart. Additional doses of GD2-iCAR-PBT will be given intravenously at the same dose level, or intracerebroventricularly at a fixed dose level (30 x 10^6 cells). GD2-iCAR-PBT must be infused as an inpatient.

After the GD2-iCAR-PBT infusion, patients will be closely monitored as an inpatient for a minimum of 21 days. Follow-up assessments after the GD2-iCAR-PBT infusion will include physical examination, safety and research blood tests, pregnancy test, urine test, ECG and echocardiogram, and brain MRI. Follow-up will be weekly in the first month, then study visits will be 2-3 months apart until 2 years after the infusion. Annual follow-up shall continue for 5 years after the infusion.

The study will be of open-label, single ascending dose-escalation design, and will employ a rolling six dose-finding method to determine a safe dose of an intravenous injection of GD2-iCAR-PBT in patients with GD2-positive diffuse midline glioma. There will be no intra-patient dose escalation. The recommended phase 2 dose (RP2D) will be based on the findings of the toxicity, immune effects, and activity profile in the patients enrolled to this phase I study.
Intervention code [1] 322753 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330311 0
'Dose-limiting toxicity assessed as adverse events (e.g. rash, fever, vomiting) assessed by participant self-report and physical examination in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0)
Timepoint [1] 330311 0
Monitored continuously for 6 weeks post-infusion, after each infusion.
Secondary outcome [1] 405738 0
Tumour response assessed using brain MRI in accordance with the RAPNO criteria.
Timepoint [1] 405738 0
6 weeks post-infusion, after each infusion.
Secondary outcome [2] 405739 0
Progression free survival assessed using brain MRI in accordance with the RAPNO criteria.
Timepoint [2] 405739 0
Assessed every 6 months for up to 5 years after the final infusion.
Secondary outcome [3] 405740 0
Overall survival assessed using follow-up visits and patient electronic medical records.
Timepoint [3] 405740 0
Assessed every 6 months for up to 5 years after the final infusion.
Secondary outcome [4] 408727 0
Tumour response assessed using brain MRI in accordance with the iRANO criteria.
Timepoint [4] 408727 0
6 weeks post-infusion, after each infusion.

Eligibility
Key inclusion criteria
PART I Inclusion Criteria
- Written informed consent;
- Age less than or equal to 21 years old at the time of study enrolment;
- Diffuse Intrinsic Pontine Glioma (DIPG) diagnosed by MRI and/or histological diagnosis of Diffuse Midline Glioma (DMG) with an H3K27M mutation or loss of H3K27 trimethylation;
- Lansky / Karnofsky score greater than or equal to 50%;
- Absolute lymphocyte count greater than or equal to 0.1x10^9/L;
- No evidence of tumour progression following any form of anti-tumour treatment;
- Life expectancy of greater than or equal to 12 weeks.

PART II Inclusion Criteria
- At least 4 weeks since completion of treatment with radiation therapy of at least 50Gy to the primary tumour;
- Previously enrolled on Part I with availability of T cell product that has met batch release criteria including greater than or equal to 20% expression of GD2-iCAR (by flow cytometry) on the autologous peripheral blood T cells (PBT);
- Karnofsky greater than or equal to 50% for patients greater than 16 years of age and Lansky greater than or equal to 50% for patients less than or equal to 16 years of age;
- Recovered to less than or equal to Grade 1 from the acute toxic effects of all prior anti-cancer treatment at least a week before entering this study;
- Life expectancy of greater than or equal to 6 weeks;
- At least 4 weeks since major surgery, and recovered adequately from the toxicity and/or complications from surgery;
- Adequate cardiac function, defined as fractional shortening greater than or equal to 27% or ejection fraction of greater than or equal to 50%, measured by echocardiography;
- Females of childbearing potential and fertile male patients must use an effective method of contraception starting with the first dose of study therapy through 4 months after the last dose of study therapy;
- For females of childbearing potential, the patient must have a negative serum pregnancy test at screening, and a negative urine pregnancy test, prior to dosing at each treatment course.
Minimum age
No limit
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
PART I Exclusion Criteria
- Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count less than or equal to 1.0 x 10^9/L or platelet count less than or equal to 100 x 10^9/L (cannot be post-transfusion) or haemoglobin less than 105 g/L (can be post-transfusion);
- Patient weight less than 5kg;
- Patient is not medically fit for apheresis procedure;
- Participation in a trial of an investigational agent within the 7 days prior to enrolment;
- Pregnant or breast-feeding females;
- Evidence of active infection with HIV, hepatitis B, or hepatitis C;
- Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents;
- Patients with an underlying diagnosis of immunodeficiency;
- Evidence of severe or uncontrolled systemic diseases;
- Any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in this trial or which would jeopardise compliance with the protocol.

PART II Exclusion Criteria
- Has clinical or radiological evidence of pseudoprogression after standard of care radiation therapy;
- Disease progression following treatment with radiation therapy or other anti-cancer therapy;
- Clinical or radiological evidence of brain herniation;
- Progressive neurological symptoms within 2 weeks prior to enrolment;
- Patient is on greater than 0.1mg/kg dexamethasone (or other corticosteroid equivalent) total daily dose;
- Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count less than or equal to 1.0 x 10^9/L or platelet count less than or equal to 100 x 10^9/L (cannot be post-transfusion) or haemoglobin less than 105 g/L (can be post-transfusion);
- International Normalised Ratio (INR) or Prothombin Time (PT) or Activated Partial Thromboplastic Time (aPTT) greater than 1.5 times the upper limit of normal (x ULN) unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants;
- Serum bilirubin greater than 3 x institutional ULN unless patient has Gilbert’s syndrome;
- Liver transaminase levels greater than 5 x institutional ULN;
- Creatinine clearance or radioisotope GFR less than or equal to 70ml/min/1.73 m^2 or serum creatinine level based on age/gender:
- Participation in a trial of an investigational agent within the 7 days prior to enrolment;
- Pregnant or breast-feeding females;
- Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents;
- Has a diagnosis of immunodeficiency;
- Evidence of severe or uncontrolled systemic diseases;
- Any concurrent condition which in the investigator’s opinion makes it undesirable for the patient to participate in this trial or which would jeopardise compliance with the protocol.

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2023
Actual
23/05/2023
Date of last participant enrolment
Anticipated
1/04/2025
Actual
Date of last data collection
Anticipated
1/04/2030
Actual
Sample size
Target
18
Accrual to date
7
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21612 0
Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 36538 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 310672 0
Charities/Societies/Foundations
Name [1] 310672 0
Levi's Project
Country [1] 310672 0
Australia
Funding source category [2] 310694 0
Charities/Societies/Foundations
Name [2] 310694 0
Australian Philanthropic Services
Country [2] 310694 0
Australia
Funding source category [3] 310695 0
Government body
Name [3] 310695 0
Cancer Institute NSW
Country [3] 310695 0
Australia
Funding source category [4] 310705 0
Government body
Name [4] 310705 0
Medical Research Future Fund, Australian Government Department of Health
Country [4] 310705 0
Australia
Funding source category [5] 310736 0
Charities/Societies/Foundations
Name [5] 310736 0
Cure Cancer Australia Foundation
Country [5] 310736 0
Australia
Primary sponsor type
Government body
Name
Sydney Children's Hospitals Network
Address
Corner Hawkesbury Road & Hainsworth Street
Westmead NSW 2145
Country
Australia
Secondary sponsor category [1] 311895 0
None
Name [1] 311895 0
Address [1] 311895 0
Country [1] 311895 0
Other collaborator category [1] 282148 0
Hospital
Name [1] 282148 0
Royal Adelaide Hospital (operating as Central Adelaide Local Health Network Incorporated)
Address [1] 282148 0
Port Road
Adelaide SA 5000
Country [1] 282148 0
Australia
Other collaborator category [2] 282149 0
Other Collaborative groups
Name [2] 282149 0
Children's Cancer Institute Australia
Address [2] 282149 0
Lowy Cancer Research Centre
C25/9 High Street
Kensington NSW 2750
Country [2] 282149 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310263 0
Sydney Children's Hospitals Network HREC
Ethics committee address [1] 310263 0
Ethics committee country [1] 310263 0
Australia
Date submitted for ethics approval [1] 310263 0
24/01/2022
Approval date [1] 310263 0
25/02/2022
Ethics approval number [1] 310263 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117046 0
Prof David Ziegler
Address 117046 0
Kids Cancer Centre
Sydney Children’s Hospital
High Street
Randwick NSW 2031
Country 117046 0
Australia
Phone 117046 0
+61 2 9382 3122
Fax 117046 0
Email 117046 0
[email protected]
Contact person for public queries
Name 117047 0
Prof David Ziegler
Address 117047 0
Kids Cancer Centre
Sydney Children’s Hospital
High Street
Randwick NSW 2031
Country 117047 0
Australia
Phone 117047 0
+61 2 9382 3122
Fax 117047 0
Email 117047 0
[email protected]
Contact person for scientific queries
Name 117048 0
Prof David Ziegler
Address 117048 0
Kids Cancer Centre
Sydney Children’s Hospital
High Street
Randwick NSW 2031
Country 117048 0
Australia
Phone 117048 0
+61 2 9382 3122
Fax 117048 0
Email 117048 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Aggregate results will be made available publicly.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AICAR T cell therapies for diffuse midline glioma2023https://doi.org/10.1016/j.trecan.2023.07.007
N.B. These documents automatically identified may not have been verified by the study sponsor.