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

ACTRN 12622001514796

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 cellsthe basic structural and functional unit of all living things (GD2-CAR T cells, a bloodthe red bodily fluid that transports oxygen and other nutrients around the body transfusion derived from the patient’s own cells) in patients with recurrent GD2-positive glioblastoma multiforme.

Intervention/Treatment

• Drug: GD2-iCAR-PBT.

Inclusion Criteria

Procurement Inclusion Criteria

1. 18 years of age or above.
2. Must be able and willing to provide written informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment..
3. Must be able and willing to reside within 100km of site where GD2-iCAR-PBT infusionto slowly introduce/give fluid into a vein is administered for entire duration of safety follow-up period (up to 30 days post GD2-iCAR-PBT infusion).
4. Patient must be able to nominate an in-residence carer for at least 7 days post GD2-iCAR-PBT infusion.
5. Adult-type diffuse glioma in a supratentorial tumoura tissue mass that forms from groups of unhealthy cells location, histologically confirmed as WHO gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells 4 IDH-wildtype glioblastoma with lack of MGMT promoter methylation, and which has been treated with maximally safe debulkingremoval of as much of the tumour as possible when complete tumour removal is not possible, also known as cytoreduction and has been or is proposed to be treated with standard post-operative radiotherapy without either concurrent or consolidation temozolomide chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells.
6. Adult-type diffuse glioma, which is histologically confirmed as WHO grade 4 IDH-wildtype glioblastoma or IDH-mutant astrocytoma (2021 WHO Classification of Tumours of the CNS), or previously histologically confirmed WHO grade 2 or grade 3 glioma (i.e., astrocytoma or oligodendroglioma) clinically and/or radiologically behaving as recurrent grade 4 glioma, together with greater than or equal to 10% GD2-positive tumour cells by 14g2a immunohistochemistry (IHC), and a supratentorial tumour location.
7. Evidence of first or subsequent recurrenceto occur or happen again of GBM (rGBM) radiologically by brain perfusion MRI after completion of the standard Stupp regimen, which includes maximal or subtotal resectionsurgical removal of tissue or part/all of an organ as defined by the surgeon and completion of 6 cycles of consolidation temozolomide chemotherapy, or other standard treatment that includes surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence, radiotherapy, and chemotherapy e.g., for WHO grade 2 or grade 3 glioma (i.e., astrocytoma or oligodendroglioma). Clinically indicated neurosurgical intervention including biopsyremoval of a section of tissue to analyse for cancer cells and tumour re-resection will be considered for rGBM patients after discussion in a neuro-oncology multidisciplinary meeting.
8. ECOG performance status of at least 2 expected at infusion.
9. Stable dosethe amount of medication taken of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day.

Treatment Inclusion criteria

1. Must be able and willing to reside within 100km of site where GD2-iCAR-PBT infusion is administered for entire duration of safety follow-up period (up to 30 days post GD2-iCAR-PBT infusion).
2. Patient must be able to nominate an in-residence carer for at least 7 days post GD2-iCAR-PBT infusion.
3. 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.
4. Evidence of first or subsequent recurrence of GBM (rGBM) radiologically by brain perfusion MRI after completion of the standard Stupp regimen, which includes maximal or subtotal resection as defined by the surgeon and completion of 6 cycles of consolidation temozolomide chemotherapy, or other standard treatment that includes surgery, radiotherapy, and chemotherapy e.g., for WHO grade 2 or grade 3 glioma (i.e., astrocytoma or oligodendroglioma). 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. Measurable disease on at least 2 dimensions on MRI brain scan.
6. ECOG performance status of at least 2.
7. Pulse oximetry greater than or equal to 90% in room air.
8. Stable dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day excepting pre-medication for lymphodepletion chemotherapy.
9. Neurological deficits in patients must have been stable for at least 7 days.
10. At least 2 weeks since prior cytotoxic chemotherapy and recovered to less than or equal to Grade 1 from the acutenew, recent, comes with an urgent or significant sense, is sudden, sharp 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 non-laboratory-related toxicity to lesser 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.
11. May receive intravenousinto or within a vein administration of GD2-iCAR-PBT cells concurrently with bevacizumab used in the control of disease progression.
12. Life expectancy of greater than or equal to 12 weeks.
13. Fertile male patients must use an effective method of contraception starting with the first dose of study therapy through 4 months after the last CAR-T cell infusion.
14. Female patients are eligible to enter and participate in the study if they meet the following inclusion criteria:
    • Hysterectomised, or
    • Bilateralaffecting both sides oophorectomyremoval of one (unilateral) or both (bilateral) ovaries (ovariectomy), or
    • Bilateral tubal ligation, or
    • Post-menopausal (demonstrated total cessation of menses for greater than or equal to 1 year).
    • For females of childbearing potential, the patient must:
      1. Have a negative serum pregnancy test at screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening before the CAR-T cell infusion.
    • The female patient must also agree to the use of the following contraceptive methods:
      1. An intrauterine device (IUD) with a documented failure rate of less than 1% per year.
      2. Vasectomized partner who is sterile prior to the patient’s entry and is the sole sexual partner for that woman.
      3. Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm.
      4. Complete abstinence from sexual intercourse where the lifestyle of the patient ensures compliance.
      5. Continue these methods of contraception during treatment and for 4 months after the CAR-T cell infusion.