Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Glioma

Disease Attributes

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Immunomodulating Agents

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

NEOADJUVANT: Patients receive nivolumab IV over 30 minutes 14 days before undergoing standard of care surgical resection.

ADJUVANT MAINTENANCE: After completion of neoadjuvant infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Ancillary studies, given in person or online

Quality-of-Life Assessment

Questionnaire Administration

Jannerfer An

Sabine Mueller, MD, PhD

Girish Dhall, MD

Katie Metrock, MD

Tom Davidson, MD

Megan Paul, MD

Sabine Mueller, MD, Phd

Sabine Mueller, MD

Lindsay Kilburn, MD

Elias Sayour, MD, PhD

Scott Coven, DO, MPH

Runco Daniel, MD, MS

Kenneth Cohen, MD, MBA

Eric Raabe, MD

Susan Chi, MD

Mohamed Abdelbaki, MD

Derek Hanson, MD

Linda Stork, MD

Matthew Miller, MD

Nicholas Whipple, MD

Priya Chan

David Ziegler, BSc (Med), MBBS, FRACP, MD/PhD

Regienald Gayaman

Dinisha Govender, MBChB, FRACP

Natasha Brown

Karen Clements

Tim Hassall, MBBS, FRACP

Callie Ayles

James Kirby

Maria Kirby, MBBS FRACP

Yun Y Tu

Kanika Bhatia, MD

Nick Gottardo, MB,ChB,FRACP,PhD

Michal Yalon

Nicolas Gerber, MD

Tom Davidson (tdavidson@chla.usc.edu), MD

This phase I trial studies the side effects of nivolumab before and after surgery in treating children and young adults with high grade glioma that has come back (recurrent) or is increasing in scope or severity (progressive). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVES:

I. To measure the relative changes in cell cycle-related genetic signature of the tumor microenvironment post administration of neoadjuvant nivolumab in children and young adults with recurrent or progressive HGG when compared to a cohort of archived non-treated recurrent pediatric HGG samples.

II. To characterize the safety and tolerability of neoadjuvant nivolumab followed by adjuvant nivolumab in children and young adults with recurrent or progressive HGG.

SECONDARY OBJECTIVES:

I. To determine the 6 month and 12 month overall survival (OS) in children and young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab followed by adjuvant nivolumab.

II. To determine the 6 month and 12 month progression-free survival (PFS) in children and young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab followed by adjuvant nivolumab.

EXPLORATORY OBJECTIVES:

I. To measure relative changes in interferon gamma associated genetic signature within the tumor microenvironment post administration of neoadjuvant nivolumab in children and young adults with recurrent or progressive HGG compared to archived non-treated recurrent pediatric HGG samples.

II. To explore the correlation of interferon-gamma-associated genetic signature, cell cycle-related genetic signature and infiltrating T lymphocyte (TIL) density and clonality with clinical responses.

III. To measure TIL density post administration of neoadjuvant nivolumab in children and young adults with recurrent or progressive HGG.

IV. To estimate the objective response rate (ORR) in children and young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab followed by adjuvant nivolumab.

V. To evaluate the association between advanced MRI parameters (ADC on DWI, rCBV on dynamic susceptibility contrast (DSC) perfusion MRI, pre-contrast T1 shortening on T1-weighed images, and/or MTRasym on pH-Weighted Amine CEST-EPI) and tumor and peripheral blood immune responses.

VI. To measure relative change in peripheral T-cell response and post administration of neo-adjuvant nivolumab in children and young adults with recurrent or progressive HGG.

VII. To measure PD-1 and PDL-1 expression by immunohistochemistry for children and young adults with recurrent or progressive HGG post neoadjuvant nivolumab and evaluate the differences between the treatment cohort and archived non-treated recurrent pediatric HGG samples.

VIII. To explore the correlation of tumor mutational load with clinical response for children and young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab followed by adjuvant nivolumab.

IX. To assess Quality of Life (QOL) and cognitive measures in children and young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab followed by adjuvant nivolumab.

X. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures in the context of race ethnicity and other health related social risks.

XI. To assess on therapy toxicity in the context of race, ethnicity and other health related social risks.

OUTLINE: Neoadjuvant nivolumab followed by adjuvant nivolumab evaluation.

NEOADJUVANT TREATMENT: Participants will receive a single infusion of nivolumab of 3 mg/kg 14± 5 days prior to surgery. When scheduling, please keep in mind that the two pre-surgical plasma samples (day of neoadjuvant dose and day of surgery) should be drawn greater than 10 days apart.

Tumor samples will be obtained at time of surgery. The tissue from this surgery (fresh, frozen and FFPE) and the archived tissue (FFPE) from the most recent surgery prior to registration revealing HGG will be processed so as to best achieve the primary, secondary and exploratory objectives.

ADJUVANT TREATMENT: Infusion Cycle #1 should begin as soon as participant has recovered from surgery and has been tapered off of steroids. A maximum dexamethasone dose of 0.1 mg/kg/day is allowed, but preferably have been discontinued (inhaled or topical use of steroids is allowed).

Maintenance Cycle 1+ Day 1 \& 15: Participants will receive nivolumab (3mg/kg) IV every 2 weeks until progression or development of unacceptable toxicities or withdrawal. Blood samples will be obtained as pharmacodynamic markers throughout the study (Day 1 of every other cycle). Dose interruptions and symptomatic management will occur based upon preset adverse event determination.

After completion of study treatment, patients are followed up at 30 days and then every 2 months for up to 5 years.

Immunotherapy Before and After Surgery for Treatment of Recurrent or Progressive High Grade Glioma in Children and Young Adults

A Single Arm, Pilot of Neoadjuvant Checkpoint Inhibition Followed by Adjuvant Checkpoint Inhibition in Children and Young Adults With Recurrent or Progressive High Grade Glioma (HGG)

Will assess the percentage change in cell cycle-related genetic signature post administration of neoadjuvant treatments when compared to archived recurrent pediatric HGG group. The number of participants with high cell cycle gene signature (positive median gene set variation analysis (GSVA) score) will be tabulated. Variables involved in the primary analyses will be examined graphically and summarized by descriptive statistics.

Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 from initiation of study treatment until 2 years after treatment discontinuation or until study treatment related adverse events resolve or return to baseline, Adverse experiences (specific terms as well as system organ class terms) and predefined limits of change in laboratory, and vital sign parameters that are not pre-specified as events of interest will be summarized with descriptive statistics (counts, percentage, mean, standard deviation, etc.).

Survival will be assessed at 6 months and 12 months from the time of enrollment until the time of death. Kaplan-Meier survival analyses will be performed. Medians together with 2-sided 95% confidence intervals will be computed using a log-log transformation.

PFS is defined as the time of enrollment until the time of progressive disease or death. Kaplan-Meier survival analyses will be performed. Medians together with 2-sided 95% confidence intervals will be computed using a log-log transformation.

Pacific Pediatric Neuro-Oncology Consortium

Principal Investigator

Nervous System Diseases

Brain Neoplasms

Oligodendroglioma

Gliosarcoma

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Brain Tumor, Adult

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Oligoastrocytoma

Anaplastic Oligoastrocytoma

Anti-Infective Agents

Flucytosine

Clotrimazole

Miconazole

Antifungal Agents

Antimetabolites

Patients undergo debulking craniotomy and receive injections of HB1.F3.CD neural stem cells directly into brain tissue on day 0. Patients then receive oral 5-fluorocytosine every 6 hours on days 4-10 in the absence of disease progression or unacceptable toxicity.

flucytosine

polymerase chain reaction

immunohistochemistry staining method

Injected at the time of the surgery to resect the tumor

gene therapy

pharmacological study

3-Tesla magnetic resonance imaging

laboratory biomarker analysis

therapeutic conventional surgery

E. coli CD-expressing genetically modified neural stem cells

Jana Portnow

RATIONALE: Genetically-modified neural stem cells (NSCs) that convert 5-fluorocytosine (5-FC) into the chemotherapy agent 5-FU (fluorouracil) at sites of tumor in the brain may be an effective treatment for glioma.

PURPOSE: This clinical trial studies genetically-modified NSCs and 5-FC in patients undergoing surgery for recurrent high-grade gliomas.

PRIMARY OBJECTIVES:

I. To determine the safety and feasibility of intracerebral administration of NSCs in combination with oral 5-FC in patients with recurrent high-grade gliomas.

SECONDARY OBJECTIVES:

I. To characterize the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU with increasing NSC dose level.

II. To non-invasively assess the presence of 5-FU in the brain with the use of fluorine (19F)-magnetic resonance spectroscopy (MRS)(no longer in effect as of 5/1/2012).

III. To assess for the possible development of immunogenicity against the NSCs.

IV. To assess the intracerebral distribution of NSCs using iron-labeling as a cellular tracker.

V. To gather preliminary imaging data regarding perfusion permeability parameters and imaging characteristics as shown on magnetic resonance imaging (MRI) studies due to the presence of NSCs in the brain.

VI. To determine, at time of autopsy, the fate of the NSCs.

OUTLINE:

This is a dose-escalation study.

After biopsy or surgery to resect tumor, study patients receive injections of genetically modified NSCs directly into brain tissue on day 0. Patients then take oral 5-FC every 6 hours during days 4-10 which is converted to 5-FU in the brain by the NSCs.

Follow-up MRIs of the brain are performed on days 32, 60, and every 2 months thereafter to assess for response and side effects.

A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

Measures of feasibility include the incidence of clinically symptomatic intratumoral hemorrhage, CNS infection, seizures, altered mental status, development of focal neurologic deficits, as well as chemotherapy-associated toxicities. All toxicities at each dose level will be summarized using descriptive statistics. Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Summarized by NSC dose cohort using descriptive statistics and graphs. The Macdonald Criteria will be used to assess response. As of 11/30/2012 patients will no longer undergo these tests.

As of 5/1/2012, study patients will no longer undergo 19F-MRS.

As of 11/30/2012 patients will no longer undergo these tests.

City of Hope Medical Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy Before and After Surgery for Treatment of Recurrent or Progressive High Grade Glioma in Children and Young Adults	NCT04323046	Glioblastoma Malignant Gliom... Recurrent Gliob... Recurrent Malig... Recurrent Grade... Grade III Gliom...	Nivolumab Quality-of-Life... Questionnaire A...	6 Months - 25 Years	University of California, San Francisco
A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas	NCT01172964	Adult Anaplasti... Recurrent Grade... Recurrent Grade... Adult Anaplasti... Adult Brain Tum... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Adult Mixed Gli... Recurrent Adult... Adult Anaplasti... Recurrent High ...	flucytosine polymerase chai... immunohistochem... gene therapy pharmacological... 3-Tesla magneti... laboratory biom... therapeutic con... E. coli CD-expr...	13 Years -	City of Hope Medical Center
A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas	NCT01172964	Adult Anaplasti... Recurrent Grade... Recurrent Grade... Adult Anaplasti... Adult Brain Tum... Adult Giant Cel... Adult Glioblast... Adult Gliosarco... Adult Mixed Gli... Recurrent Adult... Adult Anaplasti... Recurrent High ...	flucytosine polymerase chai... immunohistochem... gene therapy pharmacological... 3-Tesla magneti... laboratory biom... therapeutic con... E. coli CD-expr...	13 Years -	City of Hope Medical Center

Spots Global Cancer Trial Database for recurrent grade iii glioma