Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioblastoma

Glioma

Diffuse Intrinsic Pontine Glioma

Astrocytoma

Oligodendroglioma

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

Anaplastic Astrocytoma

Oligoastrocytoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Cetuximab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Superselective Intraarterial Cerebral Infusion (SIACI) of Erbitux (200 mg/m\^2) and Bevacizumab (15 mg/kg)

Subjects will receive a single intra-arterial dose of Cetuximab (200 mg/m\^2) and Bevacizumab (15 mg/kg) via Superselective Intraarterial Cerebral Infusion (SIACI).

SIACI of Erbitux and Bevacizumab

Jeffery Greenfield, MD PhD

Central nervous system (CNS) malignancies are the second most common malignancy and the most common solid tumor of childhood, including adolescence. Annually in the United States, approximately 2,200 children are diagnosed with CNS malignancy and rates appear to be increasing. CNS tumors are the leading cause of death from solid tumors in children. Survival duration after diagnosis in children is highly variable depending in part on age at diagnosis, location of tumor, and extent of resection; however, most children with high grade glioma die within 3 years of diagnosis. All patients with high grade glioma experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). We have shown in previous phase I trials that a single Superselective Intra-arterial Cerebral Infusion (SIACI) of Cetuximab and/or Bevacizumab is safe for the treatment of recurrent glioblastoma multiforme (GBM) in adults, and we are currently evaluating the efficacy of this treatment. Therefore, this phase I/II clinical research trial is an extension of that trial in that we seek to test the hypothesis that intra-arterial Cetuximab and Bevacizumab is safe and effective in the treatment of relapsed/refractory glioma in patients \<22 years of age. We expect that this project will provide important information regarding the utility of SIACI Cetuximab and Bevacizumab therapy for malignant glioma in patients \<22 years of age and may alter the way these drugs are delivered to our patients in the near future.

The experimental aspects of this treatment plan will include:

1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 25%; 10 mL over 2 minutes) in order to disrupt the blood brain barrier. This technique has been used in several thousand patients in previous studies for the IA delivery of chemotherapy for malignant glioma. We have used this without complication in our patients from our Phase I protocols as well.
2. To treat patients \<22 years of age with recurring or relapsing glioma with a single intraarterial delivery (SIACI) of Cetuximab and Bevacizumab. Our Phase I trials have demonstrated the safety of SIACI delivery of these drugs in adults. This trial will focus on the safety and efficacy in patients \<22 years of age.

Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22

Phase I/II Trial Of Super-Selective Intraarterial Infusion Of Erbitux (Cetuximab) And Avastin (Bevacizumab)For Treatment Of Relapsed/Refractory Intracranial Glioma In Patients Under 22 Years Of Age

Overall Survival (OS) will be measured from the date of the first dose of SIACI Cetuximab/Avastin to the date of death.

The overall response proportion along with a 95% confidence interval will be estimated via binomial proportions. The investigator will define "evaluable" patients as patients who met eligibility requirements and have initiated therapy.

All treatment emergent adverse events will be assessed and graded according to Common Terminology Criteria for Adverse Events (CTCAE)v. 4.0 terminology for severity, duration, and relationship to research protocol treatment.

PFS will be assessed by Kaplan-Meier survival analysis, assuming adequate follow-up time. PFS will be measured from the date of the first dose of SIACI Cetuximab/Avastin to the date of progression.

Weill Medical College of Cornell University

Patients were closely monitored for toxicity. The primary observation period after IA therapy was 28 days. After the 28 day period, the patient started treatment as recommended by patient's neurooncologist. Toxicities were monitored by history, physical examination, blood tests, and chest x-ray as outlined in the protocol. Within the 28 day period, AEs were assessed on day 0, day 1, and 1 month post-procedure. Participants were followed for grade 5 AEs (death) for 2 years.

Superselective Intraarterial Cerebral Infusion (SIACI) of Erbitux (200 m/m\^2) and Bevacizumab (15 mg/kg)

SIACI of Erbitux and Bevacizumab: Subjects will receive a single intra-arterial dose of Cetuximab (200 m/m\^2) and Bevacizumab (15 mg/kg) via Superselective Intraarterial Cerebral Infusion (SIACI).

Superselective Intraarterial Cerebral Infusion (SIACI) of Erbitux (200 mg/m\^2) and Bevacizumab (15 mg/kg)

SIACI of Erbitux and Bevacizumab: Subjects will receive a single intra-arterial dose of Cetuximab (200 mg/m\^2) and Bevacizumab (15 mg/kg) via Superselective Intraarterial Cerebral Infusion (SIACI).

Age, Categorical

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United States

Region of Enrollment

This study was terminated early and participant enrollment was low, resulting in a small sample size (N=13). Having a small sample size may reduce statistical reliability and generalizability of results.

Median Overall Survival (OS)

The data for this outcome was not collected.

Composite Overall Response Rate (CORR)

Grade 1

Grade 2

Grade 3

Grade 4

Number of Treatment Emergent Adverse Events

Median Progression-free Survival (PFS)

Overall Study

Gaucher Disease Type 2

Antirheumatic Agents

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

Molgramostim

Sargramostim

Adjuvants, Immunologic

Patients with malignant gliomas will receive combined immune adjuvants (GM-CSF, TLR ligands) and radiation. The safety and efficacy will be analyzed.

24 hours before the radiation, patients will be administrated poly I:C or CAR-T or TCR-T intratumorally and receive granulocyte macrophage colony stimulating factor 5 days after the radiation.

Combined immune adjuvants and radiation

Song Lin, M.D.

Chun Zeng, M.D.

Peijuan Ren, M.D.

You-Wen He, M.D. Ph.D.

The study will investigate combined radiotherapy and immunotherapy on malignant gliomas. Immune adjuvants will be injected intratumorally and systemically to induce antitumor-specific immunity after radiation induced immunological tumor cell death (ICD). With radiation, tumor cells release tumor antigens that are captured by antigen presenting dendritic cells. Immune adjuvants promote the presentation of tumor antigens and the priming of antitumor T lymphocytes. The combined treatment induces and amplifies the specific antitumor immunity in patients with malignant gliomas, prolonging survivals of patients.

High grade gliomas, such as glioblatoma (GBM) is an aggressive malignancy with a poor prognosis. The current strategy for newly diagnosed GBM patients includes surgery, chemotherapy and radiotherapy. Unfortunately, after the standard treatmetn,the median survival of GBM is only about one year. Once relapsed, there is no standard therapy and survival is less than 9 months. Recently, personalized cancer immunotherapy has shown great promise in treating different types of cancers. However, effective immunotherapies for high grade gliomas, especially after progression, have yet to be established. Newly diagnosed GBM patients experience recurrence in five or seven months after standard treatment. We will investigate whether combining radiotherapy with intratumoral and systemic administration of immune adjuvants will improve the treatment outcome of high grade gliomas. We will use several immune adjuvants that activate innate and adaptive immunity.

Combination of Immunization and Radiotherapy for Malignant Gliomas (InSituVac1)

Adverse events during and after the combined treatment

Disease progression free survival time after combined treatment

Overall survival time after the combined treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22	NCT01884740	Glioblastoma Mu... Fibrillary Astr... Glioma of Brain... Anaplastic Astr... Pilomyxoid Astr... Mixed Oligodend... Brain Stem Glio... Diffuse Intrins...	SIACI of Erbitu...	1 Year - 21 Years	Weill Medical College of Cornell University
Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22	NCT01884740	Glioblastoma Mu... Fibrillary Astr... Glioma of Brain... Anaplastic Astr... Pilomyxoid Astr... Mixed Oligodend... Brain Stem Glio... Diffuse Intrins...	SIACI of Erbitu...	1 Year - 21 Years	Weill Medical College of Cornell University
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
Combination of Immunization and Radiotherapy for Malignant Gliomas (InSituVac1)	NCT03392545	High Grade Glio... Glioblastoma Glioma of Brain... Glioma, Maligna...	Combined immune...	18 Years - 65 Years	Beijing Tiantan Hospital

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