Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001514796
Ethics application status
Approved
Date submitted
17/11/2022
Date registered
6/12/2022
Date last updated
17/04/2023
Date data sharing statement initially provided
6/12/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
KARPOS - A Phase 1, Single-Centre, Non-randomised, Open-labelled, Escalating Dose Study of Autologous GD2-Specific Chimeric Antigen Receptor-expressing Peripheral Blood T cells in Patients with Recurrent GD2-positive Glioblastoma Multiforme
Scientific title
KARPOS - A Phase 1, Single-Centre, Non-randomised, Open-labelled, Escalating Dose Study of Autologous GD2-Specific Chimeric Antigen Receptor-expressing Peripheral Blood T cells in Patients with Recurrent GD2-positive Glioblastoma Multiforme
Secondary ID [1] 308434 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
KARPOS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Glioblastoma Multiforme 328232 0
Condition category
Condition code
Cancer 325283 325283 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study: KARPOS
Drug Name: GD2-iCAR-PBT (CAR-T Cells)

i. Cell collection for CAR-T manufacturing
Peripheral blood mononuclear cells (PBMC) will be collected via apheresis from each patient. Apheresis will be performed at the Apheresis Unit, Cancer Day Centre on level 3E of the Royal Adelaide Hospital (RAH) and will take approximately 3 hours.

The target for collection will be 5 x 10^8 total nucleated cells to yield 1.5 x 10^8 CD3+ cells. Apheresis will ensure adequate numbers of cells for manufacturing given that glioblastoma patients are frequently lymphopenic. From the apheresis product, peripheral blood T cells (PBT) will be selected.

ii. Planned cohort
Up to 3 patients will be treated at each dose level and observed for dose limiting toxicities (DLTs) for 4 weeks. If none of the 3 patients experiences a DLT, then a further 3 patients will be treated. If 1 of 3 patients experiences a DLT, then 3 more patients will be treated at the same dose level. If the incidence of DLT among those 6 patients is 1 in 6, then the MTD and thus the recommended dose of GD2-iCAR-PBT will have been determined. In the absence of DLT, patients in each cohort will be replaced if the 4-week observation period is not completed. If 2 or more of the 3 patients experience a DLT, then the study will be placed on hold while the investigators confer with the Medical Monitor and the Safety Review Committee (SRC) on the appropriate next course of action. In general, if 2 or more of the 6 patients treated at a dose level experience a DLT, then the MTD is considered to have been exceeded. In which case, and in consultation with the Independent Medical Monitor and the Investigators, who will provide this

iii. Dosing Schedule
A standard 3+3 dose-escalation method will be employed with cohorts of size 3 per dose level. Each patient will receive one injection of one dose of GD2-iCAR-PBT.

iv. Cell Administration
GD2-iCAR-PBT will be given by intravenous injection over 5-10 minutes into a peripheral vein and the IV flushed with saline. The infusion will be delivered by a volumetrically controlled delivery system.
- Between 2 and 30mL of cells will be infused
The volume of infusion will depend upon the concentration of the cells when frozen, the dose level, and the size of the patient

v. Dosing levels
Dose level 0 – 1 x10^7 cells/m^2 without lymphodepletion chemotherapy
Dose level 1 – 1 x10^7 cells/m^2 with lymphodepletion chemotherapy
Dose level 2 – 3 x10^7 cells/m^2 with lymphodepletion chemotherapy
Dose level 3 - 1 x10^8 cells/m^2 with lymphodepletion chemotherapy

vi. Determination of dose escalation
For this trial, the maximum tolerated dose (MTD) is defined as the highest dose studied for which the incidence of DLT is less than 33%. Patients in a cohort can be enrolled concurrently but patients within a dose cohort should have completed the 4-week window after the PBT infusion for assessment of DLT before enrolment of patients into the next recommended dose level. To increase safety, patients enrolled in the same dose cohort will not be treated within the same week.

vii. Concurrent anti-cancer therapies
Patients may receive intravenous administration of GD2-iCAR-PBT cells concurrently with bevacizumab used in the control of disease progression as per standard of care (SOC) and at the discretion of treating neuro-oncologist.

From dose level 1 (1x10^7 cells/m^2), all participants will receive lymphodepletion chemotherapy consisting of fludarabine (30 mg/m^2 IV on Days -4, -3 and -2) and cyclophosphamide (500 mg/m^2 IV on Days -4 and -3).

viii. Re-biopsy/resection
Where biopsy or resection is undertaken as SOC, pre- and post-treatment biopsies will be analysed by immunohistochemistry and immunofluorescence for tumour cell GD2 expression and various types of non-tumour cell. Findings from pre- and post-treatment tumour biopsy samples will be summarised.

ix. Monitoring adherence
Safety - Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, electrocardiograms and traces, physical examinations including Neurological Assessment in Neuro-Oncology, and clinical laboratory tests. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance. Adverse Events will be graded according to the NCI Common Terminology Criteria for Adverse Events.

Efficacy - Tumour response will be determined for all patients with at least a single supratentorial lesion in two dimensions using the international Immunotherapy Assessment in Neuro-Oncology (iRANO) criteria. The first assessment will be made at 3 months after the GD2-iCAR-PBT infusion. Repeat imaging will be performed earlier if the patient complained of new or worsening neurological deficits, worsening headaches, or if indicated for any other reason.
Intervention code [1] 324881 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 333145 0
Feasibility of GD2-specific chimeric antigen receptor (CAR) T cells preparation at the time of diagnosis of recurrent glioblastoma multiforme (rGBM) for intravenous administration at the time of recurrence. Measured by T-cell products generated, participant blood collection and urine collection.
Timepoint [1] 333145 0
GD2-iCAR-PBT generation for this trial takes approximately 3 weeks
Primary outcome [2] 333146 0
To determine the safety profile and dose limiting toxicities of intravenous administration of GD2-CAR T cells in patients with rGBM. Measured by medical review of adverse event reports and the results of vital sign measurements (Blood pressure via digital sphygmomanometer, heart rate and oxygen saturation via pulse oximeter, respiratory rate by direct observation of breaths per minute), electrocardiograms and traces, physical examinations including Neurological Assessment in Neuro-Oncology, and clinical laboratory tests. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance. Adverse Events will be graded according to the NCI Common Terminology Criteria for Adverse Events.
Timepoint [2] 333146 0
In-patient monitoring includes observations (such as vital signs) pre-dose, then every 15 mins post-administration for 1 h, then every 30 mins up to 4 h post-administration, then hourly until 8 h post-administration and then every 4 h until 24 h post-administration (except when sleeping). Blood samples (16.5 mL) will be drawn at 6 h and 24 h post-administration for routine biochemistry, CRP, ferritin, and serum cytokines. Safety assessment follow ups weekly for first month, then every 3 months for a year, then yearly for 14 years.
Secondary outcome [1] 415936 0
To assess the in vivo persistence and immunophenotype of the infused GD2 CAR T cells and the associated serum cytokine profile via blood samples.
Timepoint [1] 415936 0
Blood samples (16.5 mL) will be drawn at 6 h and 24 h post-administration for routine biochemistry, CRP, ferritin, and serum cytokines. Then at safety assessment follow ups weekly for first month, then every 3 months for a year, then yearly for 14 years.
Secondary outcome [2] 415937 0
To determine tumour response as measured by Immunotherapy Response Assessment in Neuro-Oncology criteria (iRANO) criteria.
Timepoint [2] 415937 0
Once every 12 weeks for 6 months post-infusion and then as per standard of care.
Secondary outcome [3] 416153 0
To measure progression free survival via in-person visits or telephone follow up and data linkage to medical records where in-person visits are not feasible to participant.
Timepoint [3] 416153 0
6 months post infusion.
Secondary outcome [4] 416154 0
To measure overall survival via in-person visits or telephone follow up and data linkage to medical records where in-person visits are not feasible to participant.
Timepoint [4] 416154 0
12 weekly for first year and then yearly for an additional 13 years.

Eligibility
Key inclusion criteria
Procurement inclusion criteria:
1., Must be able and willing to provide written informed consent
2. 18 years of age or above
3. Histologically confirmed glioblastoma (World Health Organization grade IV) with greater than or equal to 10% GD2-positive tumour cells by 14g2a immunohistochemistry (IHC) and supratentorial tumour location
4. Evidence of first or subsequent recurrence of GBM (rGBM) radiologically by brain perfusion MRI after completion of the standard Stupp regimen, which includes completion of 6 cycles of consolidation temozolomide chemotherapy. Clinically indicated neurosurgical intervention including biopsy and tumour re-resection will be considered for rGBM patients after discussion in a neuro-oncology multidisciplinary meeting.
5. ECOG performance status of at least 2 expected at infusion
6. Stable dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day
7. Measurable disease on at least 2 dimensions on MRI

Treatment Inclusion criteria
1. Availability of CAR-T-cell product that has met batch release criteria including greater than or equal to 10% expression of GD2-iCAR (by flow cytometry) on autologous peripheral blood T cells
2. Evidence of first or subsequent recurrence of GBM (rGBM) radiologically by brain perfusion MRI after completion of the standard Stupp regimen, which includes completion of 6 cycles of consolidation temozolomide chemotherapy. Clinically indicated neurosurgical intervention including biopsy and tumour re-resection will be considered for rGBM patients after discussion in a neuro-oncology multidisciplinary meeting.
3. Measurable disease on at least 2 dimensions on MRI brain
4. ECOG performance status of at least 2
5. Stable dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day
6. Neurological deficits in patients must have been stable for at least 7 days
7. At least 2 weeks since prior cytotoxic chemotherapy and 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 except for pre-GD2-iCAR-PBT infusion fludarabine-cyclophosphamide where recovery from any acute related toxicity to less than or equal to grade 2 is allowed; another exception is temozolomide (TMZ), which has an extremely short half-life and can be received until two days before the T-cell infusion
8. May receive intravenous administration of GD2-iCAR-PBT cells concurrently with bevacizumab used in the control of disease progression
9. Life expectancy of greater than or equal to 12 weeks
10. 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

11. Female patients are eligible to enter and participate in the study if they meet the following inclusion criteria:
a. Hysterectomised, or
b. Bilateral oophorectomy (ovariectomy), or
c. Bilateral tubal ligation, or
d. Post-menopausal (demonstrated total cessation of menses for greater than or equal to 1 year).

12. For females of childbearing potential, the patient must:
a. Have a negative serum pregnancy test at screening, and a negative urine pregnancy test, prior to dosing at each treatment course.
The female patient must also agree to the use of the one of the following contraceptive methods:
b. An intrauterine device (IUD) with a documented failure rate of less than 1% per year
c. Vasectomized partner who is sterile prior to the patient’s entry and is the sole sexual partner for that woman
d. Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm
e. Complete abstinence from sexual intercourse where the lifestyle of the patient ensures compliance
f. Continue these methods of contraception starting with the first dose of study therapy through 4 months after the last dose of study therapy
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Procurement Exclusion Criteria
1. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count less than or equal to 1.0 x 109/L or platelet count less than or equal to 100 x 109/L (cannot be post-transfusion) or haemoglobin less than 100 g/L (can be post-transfusion)
2. Participation in a trial of an investigational agent within the 7 days before enrolment
3. Pregnant or breast-feeding females
4. Evidence of active infection with HIV, hepatitis B, or hepatitis C
5. 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. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
6. Patients with an underlying diagnosis of immunodeficiency
7. Evidence of severe or uncontrolled systemic diseases (e.g., infection requiring treatment with intravenous (IV) antibiotics, unstable or uncompensated respiratory, cardiac, hepatic, or renal disease; thromboembolic stroke with marked residual deficits
8. 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.

Treatment Exclusion Criteria
1. Has evidence clinically or radiologically by brain perfusion MRI or MR spectroscopy of pseudo-progression or radiation necrosis during or after treatment, not considered to be true progression after discussion in neuro-oncology multi-disciplinary meeting
2. Has tumour localised below the tentorium
3. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count less than or equal to 1.5 x 109/L or platelet count less than or equal to 100 x 109/L (cannot be post-transfusion) or haemoglobin less than 100 g/L (can be post-transfusion)
4. 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 subject is receiving anticoagulant therapy if PT or aPTT is within therapeutic range of intended use of anticoagulants
5. Serum bilirubin greater than 1.5 x ULN
6. Liver transaminase levels greater than 5 x ULN
7. Creatinine clearance of less than or equal to 50mL/min calculated by Cockcroft-Gault
8. Unresolved toxicity greater than or equal to CTC grade 2 from previous anti-cancer therapy except alopecia and less than or equal to grade 2 neuropathy (if applicable) unless agreed that the patient can be entered after discussion with the Medical Monitor. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
9. Participation in a trial of an investigational agent within the 30 days prior to day 0
10. Pregnant or breast-feeding females
11. Evidence of active infection with HIV, hepatitis B, or hepatitis C
12. 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. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
13. Refractory seizure disorder
14. Evidence of severe or uncontrolled systemic diseases (e.g., infection requiring treatment with intravenous (IV) antibiotics, unstable or uncompensated respiratory, cardiac, hepatic, or renal disease; thromboembolic stroke with marked residual deficits
15. 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.
16. Participants who have another cancer diagnosis with history of visceral metastases at the time of pre-entry evaluation except for the following diagnoses:
• squamous cell cancer of the skin without known metastases
• basal cell cancer of the skin without known metastases
• carcinoma in situ of the breast (DCIS or LCIS)
• carcinoma in situ of the cervix
• prostate cancer with only PSA elevation and no radiological evidence of distant metastases
• melanoma in situ

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
25/04/2023
Actual
Date of last participant enrolment
Anticipated
1/03/2025
Actual
Date of last data collection
Anticipated
1/03/2037
Actual
Sample size
Target
18
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 23591 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 39011 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 312682 0
Charities/Societies/Foundations
Name [1] 312682 0
Neurosurgical Research Foundation
Country [1] 312682 0
Australia
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital
Address
Port Road, Adelaide, South Australia, 5000
Country
Australia
Secondary sponsor category [1] 314293 0
None
Name [1] 314293 0
Address [1] 314293 0
Country [1] 314293 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311984 0
Central Adelaide Local Health Network
Ethics committee address [1] 311984 0
Port Road, Adelaide, South Australia, 5000
Ethics committee country [1] 311984 0
Australia
Date submitted for ethics approval [1] 311984 0
21/11/2022
Approval date [1] 311984 0
07/02/2023
Ethics approval number [1] 311984 0

Summary
Brief summary
The aim of this study is to assess the feasibility, safety, and efficacy of autologous GD2-specific chimeric antigen receptor-expressing peripheral T cells (GD2-CAR T cells, a blood transfusion derived from the patient’s own cells) in patients with recurrent GD2-positive glioblastoma multiforme.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, you have histologically confirmed glioblastoma that is recurrent, and your tumour stains positively for the marker GD2 on biopsy.

Study details
All participants will undergo collection of peripheral T cells by apheresis (i.e. removing whole blood from a vein) to manufacture the GD-2 CAR T cells. If manufacture of the therapy is successful, the participant will receive a single treatment of GD2-iCAR-PBT intravenously at an initial dose of 1 x 10^8 cells/m^2.

For 8 weeks following the GD2-CAR T cell infusion, participants will be assessed for any toxicities from the treatment, and at 8 weeks post-injection their initial tumour response will be assessed using brain MRI. If determined to be safe and effective, subsequent participants enrolled into the study may receive a higher starting dose of GD2-iCAR-PBT, to determine the maximum safe dose of administration. All participants will be monitored for up to 1 year post-enrolment for efficacy of the treatment using brain MRI.

It is hoped that this study may help us find the dose of administration of GD2-CAR T cell therapy that produces the greatest tumour response with the least toxicities for the treatment of glioblastoma multiforme. This may help to direct treatment of other patients with this tumour in future.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123062 0
Prof Michael P Brown
Address 123062 0
Medical oncology, Royal Adelaide Hospital, Port Road, Adelaide, South Australia, 5000
Country 123062 0
Australia
Phone 123062 0
+61 0870742426
Fax 123062 0
Email 123062 0
michaelp.brown@sa.gov.au
Contact person for public queries
Name 123063 0
Ms Jes Logan
Address 123063 0
Cancer Clinical Trials, Royal Adelaide Hospital, Port Road, Adelaide, South Australia, 5000
Country 123063 0
Australia
Phone 123063 0
+61 0870742341
Fax 123063 0
Email 123063 0
Jesikah.Logan@sa.gov.au
Contact person for scientific queries
Name 123064 0
Dr Tessa Gargett
Address 123064 0
Centre for Cancer Biology, Port Road, Adelaide, South Australia, 5000
Country 123064 0
Australia
Phone 123064 0
+61 0882223271
Fax 123064 0
Email 123064 0
tessa.gargett@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
EmbaseGene Targets of CAR-T Cell Therapy for Glioblastoma.2023https://dx.doi.org/10.3390/cancers15082351
N.B. These documents automatically identified may not have been verified by the study sponsor.