RecruitingACTRN12622000675729

Leveraging Chimeric Antigen Receptor-Expressing T Cells for Children with Diffuse Midline Glioma

A Phase I Study of the Safety of Autologous GD2-Specific Chimeric Antigen Receptor-Expressing T Cells in Children with Diffuse Midline Glioma

Sponsor

Sydney Children's Hospitals Network

Enrollment

18 participants

Start Date

May 23, 2023

Study Type

Interventional

Conditions

Central Nervous System Tumour High Grade Glioma Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma

Summary

The aim of this study is to assess the toxicity, efficacy, and optimum dosing of autologous GD2-specific chimeric antigen receptor-expressing T cells (GD2-iCAR-PBT, a cell product infusion derived from the patient’s own T cells) in paediatric patients with Diffuse Midline Glioma. Who is it for? You may be eligible for this study if you are aged 21 years or younger, and have diffuse intrinsic pontine glioma diagnosed by MRI and/or a histological diagnosis of diffuse midline glioma with an H3K27M mutation or loss of H3K27 trimethylation. Study details All participants will undergo collection of peripheral T cells by apheresis (i.e. removing whole blood from a vein and separating out T cells) to manufacture the study therapy GD2-iCAR-PBT. The therapy will take approximately 3 weeks to manufacture, during which time participants may receive radiotherapy as part of standard care. If manufacture of the therapy is successful, the participant will receive a single treatment of GD2-iCAR-PBT intravenously at an starting dose of 1 x 10^7 cells/m^2. Participants will also receive up to three doses of bevacizumab intravenously at a dose of 10mg/kg in the period surrounding the injection of GD2-iCAR-PBT. The first dose will be given one week prior to the GD2-iCAR-PBT injection, with subsequent doses every two weeks, with the third dose being optional. For 6 weeks following the GD2-iCAR-PBT injection, participants will be assessed for any toxicities from the treatment, and at 6 weeks post-injection their tumour response will be assessed using brain MRI. If responding to the treatment and experiencing minimal toxicities, participants will be eligible to receive additional treatments of GD2-iCAR-PBT at least 6 weeks apart. The additional doses will be given intravenously at the same dose level or intracerebroventricularly at a fixed dose of 30 x 10^6 cells. 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 5 years post-infusion for efficacy of the treatment using brain MRI. It is hoped that this study may help us find the dose of administration of GD2-iCAR-PBT that produces the greatest tumour response with the least toxicities, for the treatment of Diffuse Midline Glioma. This may help to direct treatment of other paediatric patients with this tumour in future.

Eligibility

Sex: Both males and femalesMax Age: 21 Yearss

Plain Language Summary

Simplified for easier understanding

Diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG), is one of the most devastating brain tumours in children. It grows in the brainstem or other deep parts of the brain that control breathing and movement, making surgery impossible. Standard radiotherapy can temporarily slow the tumour but rarely controls it long-term, and there are very few effective treatments. This study tests a cutting-edge approach called CAR T-cell therapy — using the patient's own immune cells, specifically engineered in the laboratory to recognise and attack the tumour. The patient's T cells are collected, genetically modified to target a protein called GD2 that is found on the surface of these tumours, and then infused back into the body. The study tests different doses to find the safest and most effective level, and also evaluates giving the therapy directly into the brain's fluid spaces. Participants are monitored closely for toxicity and tumour response. You may be eligible if your child is 21 years of age or younger, has a confirmed diagnosis of DIPG by MRI or a diffuse midline glioma with specific genetic markers, has adequate bone marrow and organ function, and has a life expectancy of at least 12 weeks. Children who have already experienced tumour progression after radiation or who have active autoimmune disease are not eligible for the treatment phase.

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Interventions

Autologous GD2-specific chimeric antigen receptor-expressing T cells (GD2-iCAR-PBT) will be used to treat children (less than or equal to 21 years of age) with a diagnosis of diffuse midline glioma.

Autologous GD2-specific chimeric antigen receptor-expressing T cells (GD2-iCAR-PBT) will be used to treat children (less than or equal to 21 years of age) with a diagnosis of diffuse midline glioma. The study will be performed in two parts: Part I: Manufacture of GD2-iCAR-PBT In Part I, patients with diffuse midline glioma will be consented and screened (history and physical examination, cellular therapy donor questionnaire, blood tests including pregnancy test). Patients who meet eligibility criteria for Part I will consent for collection of peripheral T cells by apheresis. Collection of peripheral T cells by apheresis is performed by a haematologist and takes approximately 3 hours. If collection of peripheral T cells and subsequent generation of GD2-iCAR-PBT is successful, patients may then consent to Part II, which will allow for treatment with the manufactured product. Ideally patients should be enrolled in Part I prior to radiation therapy, although this is not essential. Part II: Treatment with GD2-iCAR-PBT In Part II, patients will be consented and screened (physical examination, safety and research blood tests, pregnancy test, urine test, ECG and echocardiogram, and brain MRI). Part II of the study will commence at least 4 weeks after Part I. Patients may be treated with radiation therapy as per standard of care. Radiation therapy must be completed at least 4 weeks before the GD2-iCAR-PBT infusion. As patients are at significant risk of pseudoprogression, a ventriculo-peritoneal shunt or ventricular reservoir must be inserted at least one week prior to initiation of lymphodepleting chemotherapy. At the discretion of the treating neurologist, the ventriculo-peritoneal shunt or ventricular reservoir will be inserted by a neurosurgeon. This procedure takes about an hour. Lymphodepleting chemotherapy will be given prior to infusion of GD2-iCAR-PBT, and will consist of fludarabine and cyclophosphamide, along with bevacizumab to prevent tumour pseudoprogression. Fludarabine 30mg/m^2 will be given intravenously on Days -6, -5, -4 and -3, and cyclophosphamide 500 mg/m^2 will be given intravenously on Days -6 and -5, prior to the GD2-iCAR-PBT injection. Each dose of fludarabine and/or cyclophosphamide takes approximately 1 hour to administer. Up to three doses of bevacizumab 10mg/kg will be administered intravenously every two weeks to cover the period surrounding the injection of GD2-iCAR-PBT. The first dose will be given one week prior to the GD2-iCAR-PBT injection, with subsequent doses every two weeks. The third dose is optional and will be given at the discretion of the treating oncologist. The starting dose level of GD2-iCAR-PBT is 1 x 10^7 cells/m^2. A single ascending dose-escalation design and rolling six dose-finding method will be applied to find a safe dose of GD2-iCAR-PBT. Dose Level -1: 1 x10^6 cells/m^2, Dose Level 1a: 5 x 10^7 cells/m^2, Dose Level 2: 1 x 10^8 cells/m^2. Patients will be treated with the first dose of GD2-iCAR-PBT given intravenously. The dose-limiting toxicity (DLT) evaluation period is 6 weeks. In the absence of a dose-limiting toxicity, patients with evidence of clinical benefit at the 6-week evaluation or at subsequent evaluations will be eligible to receive additional doses of GD2-iCAR-PBT at least 6 weeks apart. Additional doses of GD2-iCAR-PBT will be given intravenously at the same dose level, or intracerebroventricularly at a fixed dose level (30 x 10^6 cells). GD2-iCAR-PBT must be infused as an inpatient. After the GD2-iCAR-PBT infusion, patients will be closely monitored as an inpatient for a minimum of 21 days. Follow-up assessments after the GD2-iCAR-PBT infusion will include physical examination, safety and research blood tests, pregnancy test, urine test, ECG and echocardiogram, and brain MRI. Follow-up will be weekly in the first month, then study visits will be 2-3 months apart until 2 years after the infusion. Annual follow-up shall continue for 5 years after the infusion. The study will be of open-label, single ascending dose-escalation design, and will employ a rolling six dose-finding method to determine a safe dose of an intravenous injection of GD2-iCAR-PBT in patients with GD2-positive diffuse midline glioma. There will be no intra-patient dose escalation. The recommended phase 2 dose (RP2D) will be based on the findings of the toxicity, immune effects, and activity profile in the patients enrolled to this phase I study.