Paediatric-type diffuse high-grade glioma (pHGG) Cancer
Conditions
Interventions
1. Leukapheresis: following registration, patients will undergo an unstimulated leukapheresis which will be sent to the Centre for Cell, Gene & Tissue Therapeutics (CCGTT) at the Royal Free Hospital f
Sponsors
University College London
Eligibility
Sex/Gender
All
Inclusion criteria
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
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Safety: toxicity of IL-15/06B5 CAR T cells as assessed by the incidence of grade 3-5 toxicity causally related to the ATIMP (particularly severe cytokine release syndrome and severe neurotoxicity) occurring within 28 days of IL-15/06B5 CAR T cell infusion. 2. Feasibility of generation of the ATIMP as evaluated by the number of therapeutic products generated and the number of ATIMPs infused (as an intravenous agent (Theme 1) and as an intracerebroventricular agent (Theme 2) after successful manufacture. Measured 28 days after the ATIMP infusion. | — |
Secondary
| Measure | Time frame |
|---|---|
| Measured 1 year after ATIMP infusion: 1. Overall survival (OS): the proportion of patients alive at 1 year will be tabulated. If numbers are sufficient, overall survival will also be analysed using Kaplan-Meier survival analyses. Survival times will be measured from the date of IL15/06B5 CAR T infusion until the date of death from any cause. 2. Progression Free Survival (PFS): the proportion of patients alive and progression-free at 1 year will be tabulated. Progression-free survival will be analysed using Kaplan-Meier survival analyses with the median survival time reported. Survival times will be measured from the date of the IL15/06B5 CAR T infusion until the date of progression or death. 3. Time to Progression (TTP): TTP will be summarised as a median and range. If numbers are sufficient, this will also be analysed using Kaplan-Meier survival analyses with the duration calculated as the time from first response (=PR) until progression. 4. Best objective response rate (ORR): this will be taken as the best response as defined by both iRANO and RAPNO criteria observed at any time point following CAR T infusion. The number and proportion of patients achieving a response =PR will be presented for all patients as well as by dose level. | — |
Countries
England, United Kingdom
Outcome results
None listed