None listed
Conditions
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.
Interventions
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 manu
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.
Sponsors
Royal Adelaide Hospital
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Procurement Inclusion Criteria 1. 18 years of age or above 2. Must be able and willing to provide written informed consent 3. 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) 4. Patient must be able to nominate an in-residence carer for at least 7 days post GD2-iCAR-PBT infusion 5. , Histologically adult-type diffuse glioma 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 25% GD2-positive tumour cells by 14g2a immunohistochemistry (IHC), and a supratentorial tumour location except for a diffuse intrinsic pontine glioma 6. Participant meets either of the following: - Evidence of first or subsequent recurrence of GBM (rGBM) radiologically by brain perfusion MRI after completion of a standard treatment regimen, which includes surgery, radiotherapy, and completion of 6 cycles of consolidation temozolomide chemotherapy, unless partly or wholly declined by the patient, 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, OR, - Evidence of first or subsequent recurrence of GBM (rGBM) radiologically by brain perfusion MRI in adult-type diffuse glioma in a supratentorial tumour location, histologically confirmed as WHO grade 4 IDH-wildtype glioblastoma with lack of MGMT promoter methylation, and which has been surgically treated and has been or is proposed to be treated with standard post-operative radiotherapy without either concurrent or consolidation temozolomide chemotherapy, or an inoperable radiologically diagnosed and H3K27-altered diffuse midline glioma that has been or is proposed to be treated with palliative radiotherapy only. 7. ECOG performance status of at least 2 expected at infusion 8. Stable dose 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 25% 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 (unless partly or wholly declined by the patient), 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 >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 equal to or less than 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 non-laboratory-related toxicity to equal to or less than 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 intravenous administration of GD2-iCAR-PBT cells concurrently with bevacizumab used in the control of disease progression 12. Life expectancy of less than 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 - Bilateral oophorectomy (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: - Have a negative serum pregnancy test at screening before the CAR-T cell infusion. - The female patient must also agree to the use of the following contraceptive methods: - An intrauterine device (IUD) with a documented failure rate of less than 1% per year - Vasectomized partner who is sterile prior to the patient’s entry and is the sole sexual partner for that woman - Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm - Complete abstinence from sexual intercourse where the lifestyle of the patient ensures compliance - Continue these methods of contraception during treatment and for 4 months after the CAR-T cell infusion.
Exclusion criteria
Procurement Exclusion Criteria 1. Inability to comply with study and follow-up procedures (including, but not limited to geographical or administrative reasons such as lack of ambulance insurance or residence more than 100km away from trial site for up to 30 days post GD2-iCAR-PBT infusion) 2. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count less than 1.0 x 10^9/L or platelet count less than 100 x 10^9/L (cannot be post-transfusion) or haemoglobin < 100 g/L (can be post-transfusion) 3. Participation in a trial of an investigational agent within the 7 days before enrolment 4. Pregnant or breast-feeding females 5. Evidence of active infection with HIV, hepatitis B, or hepatitis C 6. 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 7. Evidence of severe or uncontrolled systemic diseases (e.g., infection requiring treatment with intravenous (IV) antibiotics, unstable or uncompensated respiratory, cardiac [including life-threatening arrhythmias], hepatic, or renal disease 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. Inability to comply with study and follow-up procedures (including, but not limited to geographical or administrative reasons such as lack of ambulance insurance or residence more than 100km away from trial site for up to 30 days post GD2-iCAR-PBT infusion) 2. 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 3. Has tumour localised below the tentorium except for a diffuse intrinsic pontine glioma 4. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count less than 1.5 x 10^9/L or platelet count less than 100 x 10^9/L (cannot be post-transfusion) or haemoglobin < 100 g/L (can be post-transfusion) unless lymphodepletion chemotherapy has been administered 5. International Normalised Ratio (INR) or Prothombin Time (PT) or Activated Partial Thromboplastic Time (aPTT) > 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 6. Serum bilirubin > 1.5 x ULN 7. Liver transaminase levels > 5 x ULN 8. Creatinine clearance of less than or equal to 50mL/min calculated by Cockcroft-Gault 9. Pregnant or breast-feeding females 10. History of hypersensitivity to reactions to murine protein-containing products 11. Evidence of active infection with HIV, hepatitis B, or hepatitis C 12. Has a documented history of a clinically severe autoimmune disease or syndrome that required systemic steroids or immunosuppressive agents within the past month. 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 [including life-threatening arrhythmias], hepatic, or renal disease 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.
Outcome results
None listed