Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioma

Diffuse Intrinsic Pontine Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Stem Neoplasms

Infratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Gaucher Disease Type 2

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Rolling-6 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG.

GD2CART will be administered in escalating doses on Day 0 in hospitalized subjects with either DIPG or spinal DMG

Intravenously

* Dose Level -1: 3x10\^5 transduced T cells/kg(± 20%)
* Dose Level 1: 1x10\^6 transduced T cells/kg (± 20%)
* Dose Level 2: 3x10\^6 transduced T cells/kg (± 20%)

Intracerebroventricularly, without conditioning lymphodepletion chemotherapy

* Dose Level -1: 10x10\^6 transduced T cells (±20%)
* Dose Level 1: 30x10\^6 transduced T cells (±20%)
* Dose Level 2: 50x10\^6 transduced T cells (±20%)
* Dose Level 3: 100x10\^6 transduced T cells (±20%)

Intracerebroventricularly after administration of conditioning lymphodepletion chemotherapy regimen with cyclophosphamide and fludarabine

* Dose Level -1: 10x10\^6 transduced T cells (±20%)
* Dose Level 1: 30x10\^6 transduced T cells (±20%)
* Dose Level 2: 50x10\^6 transduced T cells (±20%)

Autologous T-Cells transduced with retroviral vector (14g2a-CD8.BB.z.iCasp9) expressing GD2-chimeric antigen receptor

GD2 CAR T cells

Fludarabine 25 mg/m2 per day IV for days -4, -3, -2

Cyclophosphamide 500 mg/m2 per day IV for days -4, -3, -2

Courtney Erickson, RN, BSN

Ashley Jacobs, RN, BSN

Ashley Jacobs

Michelle Monje, MD, PHD

Liora Schultz, MD

Kara Davis, D.O.

Robbie Majzner, MD

Crystal Mackall, MD

Laura Prolo, M.D

Sneha Ramakrishna, MD

Cynthia Campen, MD

Sonia Partap, MD

Paul Fisher, MD

Lindsey Rasmussen, MD

Timothy Cornell, MD

Susan Hiniker, MD

Kristen Yeom, MD

Jasia Mahdi, MD

Brian Scott, MD

Michelle Monje

The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.

Primary Objectives:

* Determine the feasibility of manufacturing autologous T cells transduced with 14g2a-CD8-BBz-iCasp9 retroviral vector expressing GD2 Chimeric Antigen Receptor (GD2CART) for administration in subjects with H3K27M+ diffuse intrinsic pontine glioma (DIPG) or subjects with spinal H3 K27M-mutant diffuse midline glioma (DMG) using a retroviral vector and dasatinib in the Miltenyi CliniMACS Prodigy® system.
* Assess the safety and identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of GD2CART in subjects with H3K27M+ DIPG administered after cyclophosphamide/fludarabine-based lymphodepletion regimen using the following dose escalation schedule: DL1: 1e6 transduced T cells/kg; DL2: 3e6 transduced T cells/kg; DL3: 10e6 transduced T cells/kg.
* Assess the safety of the MTD/RP2D of GD2CART in subjects with spinal H3K27M mutant DMG.

Secondary Objectives:

* In a preliminary manner, assess clinical benefit of GD2CART at the RP2D in subjects with H3K27M DIPG or spinal H3 K27M-mutant DMG.
* If unacceptable toxicity occurs that is possibly, probably or likely related to GD2CART, assess the capacity for AP1903, a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity.

GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)

Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR) T Cells (GD2CART) for Diffuse Intrinsic Pontine Gliomas (DIPG) and Spinal Diffuse Midline Glioma (DMG)

The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.

Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2CART cells, will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at each dose level tested in subjects with H3K27M-mutant DIPG following standard upfront radiation therapy.

Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2CART cells will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 in subjects with spinal H3K27M-mutant DMG following standard upfront radiation therapy

Radiographic Response will be evaluated using tumor response criteria:

Complete Response (CR): disappearance on MR of all evaluable tumor and mass effect; stable or improving neurologic examination. If CSF was positive, it must be negative.

Partial Response (PR): ≥ to 50% reduction in tumor size; stable or improving neurologic examination.

Stable Disease (SD): at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither PR nor PD Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression; OR a \> 25% increase in the bi-dimensional measurement, OR the appearance of a new tumor lesion.

OS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of death from any cause

PFS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of radiographic progression or death from any cause.

PPS is measured for each subject with DIPG as OS minus PFS, and for each patient with recorded progression as OS minus Time to Progression (TTP)

Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2CART cells within 72 hours

California Institute for Regenerative Medicine (CIRM)

CureSearch

National Institutes of Health (NIH)

Professor of Pediatrics and of Medicine

Treatment with the ATIMP: GD2 CAR T-cells

CARMIGO Trial Coordinator

Karin Straathof

Darren Hargrave

The CARMIGO Trial is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children and young adults aged 2-16 years with Diffuse Midline Glioma (DMG).

The study will evaluate the feasibility of generating the ATIMP, the safety and tolerability of the GD2CAR T-cell therapy and how effectively GD2CAR T-cells engraft, expand and persist following administration in patients with DMG.

The CARMIGO Trial is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children and young adults aged 2-16 years with Diffuse Midline Glioma (DMG).

The ATIMP for this study is cryopreserved autologous patient-derived T-cells transduced with GD2CAR vector to generate GD2CAR T-cells.

Patients will undergo an unstimulated leucapheresis for the generation of the ATIMP which will take approximately 15 days to generate.

Patients will have an intraventricular catheter (Ommaya catheter) placed following enrolment and prior to GD2 CAR T cell infusion to allow monitoring, and treatment if necessary, of increased intracranial pressure (ICP).

Patients will receive lymphodepleting (LD) chemotherapy with fludarabine 30mg/m2 administered over 4 days (Day -6 to Day -3) and cyclophosphamide 60mg/kg administered over 2 days (Day -4 and Day-3).

All patients will be treated on Theme 1 of the study (intravenous CAR T administration) at one of the three dose levels (Dose Level 1: 3 x10\^7 GD2 CAR T cells/m2; Dose Level 2: 10 x10\^7 GD2 CAR T cells/m2; Dose Level 3: 30 x10\^7 GD2 CAR T cells/m2) following LD chemotherapy as described above. Patients with no/partial response at Day 28 (or disease progression after initial CR beyond Day 28) and in the absence of severe/persisting toxicity related to the ATIMP, will be potentially eligible for Theme 2 of the study where they can receive Dose 2, a single dose of 30 x 10\^6 CD19CAR T-cells intraventricularly via an Ommaya reservoir following LD chemotherapy as described above.

The study will evaluate the feasibility of generating the ATIMP, the safety of administering GD2CAR T-cell therapy, the tolerability of the GD2CAR T cell in patients and how effectively GD2CAR T-cells engraft, expand and persist following administration in patients with DMG.

Following infusion of GD2CAR T-cell therapy patients will be monitored for between 2-4 weeks as an inpatient. Following discharge, patients will enter the interventional follow up phase and be followed up for 1 year. Patients will be seen at 6 weeks post infusion then 3 monthly until 1 year post GD2CAR T-cell infusion.

If patients relapse within the first year post last GD2CAR T-cell infusion they will come off the interventional follow up and will be followed up annually until the end of trial is declared.

After completing the 1 year interventional phase of the study all patients, irrespective of whether they progressed or responded to treatment, will enter long term follow up until the end of trial is declared.

CAR T Cells to Target GD2 for DMG

Chimeric Antigen Receptor (CAR)-T Cells to Target GD2 for Diffuse Midline Glioma

Toxicity of GD2 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).

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 intraventricular agent (Theme 2) after successful manufacture.

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 GD2 CAR T infusion until the date of death from any cause.

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 GD2 CAR T infusion until the date of progression or death.

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

This will be taken as the best response as defined by 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.

University College, London

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

The GD2 CAR T cells target GD2 positive cells. The cells also express transgenes that aim to increase their resistance within the tumour microenvironment.

MAGNETO Trial Coordinator

Giuseppe Barone

MAGNETO is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children and teenagers aged 1-16 years with relapsed or refractory neuroblastoma.

The study will assess the feasibility of generating the ATIMP (GD2 CAR T cells) and the safety of administering the ATIMP in patients with relapsed or refractory neuroblastoma.

MAGNETO is a single-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in children and teenagers aged 1-16 years with neuroblastoma.

The ATIMP for this study (GD2 CAR T cells) are autologous T cells, modified to express GD2 CAR (targeting GD2 on the neuroblastoma cells) and additional transgenes aiming to confer resistance to inhibition in the tumour microenvironment and to support CAR T cell function and persistence.

Patients will undergo an unstimulated leucapheresis for the generation of the ATIMP which will take approximately 15 days to generate.

Patients will receive lymphodepleting (LD) chemotherapy with fludarabine 30 mg/m2 administered over 4 days (Day -6 to Day -3) and cyclophosphamide 500 mg/m2 administered over 2 days (Day -4 and Day-3).

Patients will be treated at one of three dose levels following LD chemotherapy as described above.

The study will evaluate the feasibility of generating the ATIMP, the safety of administering ATIMP, the tolerability of the ATIMP and how effectively the CAR T cells engraft, expand and persist following administration in patients with neuroblastoma.

Following infusion of the CAR T cells, patients will be monitored for between 2-4 weeks as an inpatient. Following discharge, patients will enter the interventional follow up phase and be followed up for 1 year. Patients will be seen at 6 weeks post infusion then 3 monthly until 1 year post CAR T cells infusion.

If patients relapse within the first-year post CAR T cell infusion, they will come off the interventional follow up and will be followed up annually until 15 years after the CAR T infusion.

After completing the 1-year interventional phase of the study, all patients, irrespective of whether they progressed or responded to treatment, will enter long term follow up until 15 years post CAR T infusion.

Multi-modular Chimeric Antigen Receptor Targeting GD2 in Neuroblastoma

Incidence of grade 3-5 toxicity causally related to the ATIMP, particularly severe cytokine release syndrome and severe neurotoxicity.

Feasibility of generation of the ATIMP as evaluated by the number of therapeutic products generated and the number of ATIMPs infused after successful manufacture.

Based on cross-sectional imaging and semi-quantitative assessment on 123I-MIBG after the ATIMP intravenous administration

Progression Free Survival (PFS) after the ATIMP intravenous administration

Time to Progression (TTP) after the ATIMP intravenous administration

Overall Survival after the ATIMP intravenous administration

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)	NCT04196413	Glioma of Spina... Glioma of Brain...	GD2 CAR T cells Fludarabine Cyclophosphamid...	2 Years - 50 Years	Stanford University
CAR T Cells to Target GD2 for DMG	NCT05544526	Diffuse Midline...	GD2 CAR T cells	- 16 Years	University College, London
Multi-modular Chimeric Antigen Receptor Targeting GD2 in Neuroblastoma	NCT05990751	Neuroblastoma	GD2 CAR T cells	1 Year - 16 Years	University College, London

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