A CAR T study for paediatric-type diffuse high-grade gliomas including diffuse midline glioma

Trial ID: ISRCTN15356845

Other - Phase 1 - Recruiting

Background and study aims Of childhood brain tumours, about 10% are high-grade gliomas. Paediatric high-grade gliomas (pHGG) account for 40% of deaths due to brain tumours in children. Treatment is limited with surgery only possible if the tumour is not in delicate parts of the brain. Radiotherapy can stop tumour growth but tumour will inevitably grow again. Chimeric antigen receptor (CAR) T cells are blood cells genetically engineered to recognize and kill tumour cells. Sustained complete remissions have been achieved in leukaemia and encouraging results in non-blood cancers are emerging. Early clinical data suggests CAR T therapy can be effective in glioma. Researchers have developed CAR T cells that recognize IL13RA2 (Interleukin 13 receptor subunit alpha 2) present on glioma cells. The CAR T cells have been engineered to secrete interleukin15 to help the CAR T cells persist in the body. The study aims to test whether giving CAR T cells to pHGG patients is safe, what is the best dose and the optimal way to give the cells. Who can participate? Patients aged between 2 and 16 years with pHGG What does the study involve? T cells are collected from the participant’s blood to make the CAR T cells. New genes are put into the T cells so they recognise and kill the glioma cells and help the CAR T cells persist in the body to stop tumour regrowth. To allow careful monitoring, participants have an Ommaya Reservoir placed under the skin of the scalp so the pressure in the brain can be measured. They are given two chemotherapy drugs to help the CAR T cells persist in the body. The CAR T cells are given into the vein. Participants are closely monitored in hospital for at least 2 weeks. MRI scans are used to look at the effect on the tumour. If the tumour is still present 1 month after the CAR T cells and the cells did not cause severe side effects, a 2nd CAR T cell dose may be given via the Ommaya reservoir into the fluid around the brain. What are the possible benefits and risks of participating? There may be no benefit in taking part in this study. If the CAR T cells ‘work’, which is not yet known, this may help decrease the pHGG tumour or stop it from growing. The information collected may help improve our knowledge of treating pHGG, which may benefit the treatment of patients with high-grade glioma in the future. Leukapheresis is required to obtain participants’ T cells (a type of white blood cell) for the manufacture of CAR T cells. The T cells are collected using a catheter inserted into a large vein. Pain, bruising and a small amount of bleeding can occur at the insertion site. Pain medication and application of a pressure dressing may be used. The small risk of fainting is prevented by having the participant sit or lie down during the procedure. Muscle cramps are prevented by giving calcium supplements if needed. Fludarabine and cyclophosphamide are used as a standard regimen to prepare for CAR T cell administration referred to as lymphodepletion. Common side effects of fludarabine are lymphopenia and infection. Neurotoxicity is generally only observed in higher doses. Cyclophosphamide can cause irritation and bleeding from the bladder. To minimize this risk, it is administered with excess fluids and mesna. Cyclophosphamide may cause transient nausea and cytopenias. Participants have anti-emetic prophylaxis and transfusion support as needed. Participants will have an Ommaya reservoir placed before lymphodepletion in order to monitor, and if necessary treat, raised intracranial pressure (ICP). The researchers will also test if delivery of CAR T cells with an Ommaya reservoir is safe and benefits participants whose disease persists or regrows after CAR T cells are given into a vein. An Ommaya reservoir is a catheter placed in one of the fluid-filled spaces in the brain (ventricle) attached to a reservoir implanted under the scalp. Insertion is a surgical procedure performed under general anaesthesia. The risk of serious complications due to implanting this device is <2%. Complications include infection, bleeding or swelling in the brain causing loss of function, such as weakness, pain, numbness, speech, swallowing or visual problems, difficulties with memory and cognition, and epilepsy. This is usually temporary and mild but can be serious and sustained in rare cases. The Ommaya reservoir will be inserted by an experienced neurosurgeon. Antibiotics will be given to prevent infection. Post-procedure observation is at least 6 hours and supportive care will be provided as required if a complication occurs. Infusion of CAR T cells via the Ommaya reservoir will be performed by a practitioner experienced in the administration of medications via this device. Participants will be closely monitored for 4 hours after infusion and then daily for at least 14 days in hospital. Cytokine release syndrome (CRS) is characterised by fever, hypotension, and in severe cases hypoxia and/or neurological disturbance. Severe CRS requires high-dependency supportive care and is usually self-limiting but may be fatal. Treatment with Tocilizumab is highly effective. Other agents are available for the management of CRS that is unresponsive to tocilizumab. Participants will be monitored for at least 14 days post CAR T cell infusion with daily review/regular blood tests. Participants developing CRS will receive supportive care including intravenous fluids, supplementary oxygen and if needed ventilatory/inotropic support on the intensive care unit. Immune effector cell-associated neurotoxicity syndrome (ICANS) is a type of neurotoxicity which can occur in participants after receiving CAR T cells. It is of variable severity, mild and reversible in most cases. Severe cases present with aphasia, obtundation, delirium and seizures. In rare cases, fatalities have been reported. Participants will receive supportive treatment with anticonvulsants, corticosteroids, and if required intensive care including sedation and ventilation. Neurotoxicity can occur due to activation of CAR T cells and associated swelling at the tumour site when - as in pHGG - the tumour is located in the brain or spine (tumour inflammation associated neurotoxicity or TIAN). TIAN can result in transient worsening of pre-existing neurological symptoms (e.g. cranial nerve deficits or ataxia in brainstem tumours; or back pain in spinal cord tumours). In severe cases, TIAN can cause raised ICP resulting in headache and vomiting or, impending herniation syndromes which are life-threatening and need urgent intervention. Participants with spinal cord tumours may develop urinary retention or reduced power or sensation in extremities. Participants will have daily assessments including neurological examination for at least 14 days after CAR T cell administration, with increased frequency as clinically indicated. Patients with spinal cord tumours will be monitored daily for spinal cord dysfunction. The Ommaya reservoir allows regular measurement of ICP to ensure early detection of raised ICP and drainage of CSF to rapidly normalise ICP. Management also includes Anakinra and corticosteroids. With the listed monitoring and management of TIAN, experience to date in patients with DMG treated with CAR T cells indicates that symptoms of TIAN are transient and fully reversible. Where is the study run from? Cancer Research UK & University College London Cancer Trials Centre (UK) When is the study starting and how long is it expected to run for? May 2024 to December 2041 Who is funding the study? 1. Jon Moulton Charity Trust (UK) 2. Abbie's Army (UK) Who is the main contact? GLIMPS Trial Manager, ctc.glimps@ucl.ac.uk Plain English summary under review with external organisation

Conditions

• Paediatric-type diffuse high-grade glioma (pHGG)
• Cancer

Interventions

• Autologous IL-15/06B5 CAR T cells

Eligibility

Inclusion criteria

• 1. Age ≥2 and ≤16 years 2. Tissue diagnosis of paediatric-type diffuse high-grade glioma 3. Expression of IL-13RA2 in the tumour 4. Radiographically evident tumour 5. At least 6 weeks following completion of standard of care treatment. 6. At least 3 weeks or 5 half-lives, whichever is shorter, after treatment with chemotherapy or other agents on other early phase clinical trial 7. Performance status: Karnofsky (age ≥10 years) or Lansky (age <10) score ≥40% allowing for stable neurological deficit due to pHGG 8. Absolute neutrophil count ≥1.0 x 10e9/L and platelet count ≥50 x 10e9/L 9. Total bilirubin <1.5 ULN and ALT <2.5 ULN 10. Serum creatine <1.5 ULN for age, if higher, an estimated (calculated) creatinine clearance must be ≥60 ml/min/1.73m² 11. Women of childbearing potential must have a negative pregnancy test and agree to comply with the pregnancy reporting requirements of the protocol (if applicable) 12. Written informed consent

Exclusion criteria

• 1. Systemic corticosteroid therapy ≥0.05 mg/kg dexamethasone daily (or equivalent) at the time of IL-15/06B5 CAR T cell infusion 2. Asthma or atopic dermatitis requiring inhaled steroids or topical steroids respectively 3. Tissue diagnosis of Infant-type hemispheric glioma 4. Tumour involvement of the thalamus or cerebellar vermis or hemispheres (pontocerebellar peduncle involvement is allowed) 5. Clinical or radiological evidence of significant and rapid tumour progression 6. Active hepatitis B, C or HIV infection 7. Active helminth or parasite infection 8. Inability to tolerate leukapheresis 9. Pre-existing significant neurological disorder not related to pHGG 10. Clinically significant systemic illness or medical condition (e.g., significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the investigator is likely to interfere with the assessment of safety or efficacy of the investigational regimen and its requirements 11. Any contraindication to lymphodepletion or to the use of Cyclophosphamide or Fludarabine as per the local SmPC 12. Any contraindication to the use of Anticoagulant Citrate Dextrose Solution 13. Any contraindication to Ommaya reservoir (or similar catheter) insertion 14. Known allergy to albumin, DMSO or EDTA 15. Primary immunodeficiency or history of autoimmune disease (e.g., Crohn’s, rheumatoid arthritis, systemic lupus) or inflammatory bowel disease requiring systemic immunosuppression/systemic disease-modifying agents within the last 2 years 16. Prior treatment with investigational or approved gene therapy or cell therapy products 17. Life expectancy <3 months 18. Women who are pregnant or breastfeeding Exclusion criteria for IL-15/06B5 CAR T cell infusion (IV Theme 1 and ICV Theme 2): 1. Uncontrolled fungal, bacterial, viral, or other infection. 2. Previously diagnosed infection for which the patient continues to receive antimicrobial therapy is permitted (with the exception of ongoing treatment for helminth of parasite infection) if responding to treatment and clinically stable at the time of scheduled IL-15/06B5 CAR T cell infusion. 3. Systemic corticosteroid therapy ≥ 0.05 mg/kg dexamethasone daily (or equivalent) at the time of IL-15/06B5 CAR T cell infusion Additional exclusion criteria for dose 2 IL-15/06B5 CAR T cell infusion (ICV – Theme 2): 1. Presence of grade 4 neurotoxicity (ICANS and/or TIAN) following infusion of Theme 1 dose 2. Presence of grade 1, 2 or 3 neurotoxicity (ICANS and/or TIAN) following the infusion of Theme 1 (Dose 1/IV IL-15/06B5 CAR T cell dose) that has not fully resolved prior to proposed administration of Theme 2 (Dose 2/ICV IL-15/06B5 CAR T cell dose), or if the investigators consider that the risk/benefit balance does not support proceeding with Theme 2 (Dose 2/ICV) 3. Presence of grade 4 CRS following infusion of Theme 1 (Dose 1/IV IL-15/06B5 CAR T cell dose) 4. Presence of grade 1, 2 or 3 CRS following infusion of Theme 1 (Dose 1/IV IL-15/06B5 CAR T cell dose) that has not fully resolved prior to proposed administration of Theme 2 (Dose 2/ICV IL-15/06B5 CAR T cell dose), or if the investigators consider that the risk/benefit balance does not support proceeding with Theme 2 (Dose 2/ICV)

Sponsor

University College London

Source: https://www.isrctn.com/

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