Symptoms and General Pathology

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Nutritional and Metabolic Diseases

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Glioblastoma

Glioma

Brain Neoplasms

Diphtheria

Medulloblastoma

Tetanus

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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

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Brain Tumor, Childhood

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Vaccines

Molgramostim

Sargramostim

Immunologic Factors

CMV-DCs are autologous dendritic cells derived from peripheral blood mononuclear cells (PBMCs) loaded with ribonucleic acid (RNA) encoding the human CMV matrix protein pp65 as a fusion protein with the full-length LAMP protein (pp65-flLAMP) plus GM-CSF and Td vaccine as adjuvants.

CMV-DCs are autologous dendritic cells derived from PBMCs loaded with RNA encoding the human CMV matrix protein pp65 as a fusion protein with the full-length LAMP protein (pp65-flLAMP) plus GM-CSF.

CMV-DCs with GM-CSF

Patients will receive preconditioning with Td in the right groin, and approximately 6-24 hours later, they will receive their first CMV-DC vaccination. Patients will also receive Td preconditioning approximately 6-24 hours prior to their 4th vaccine and subsequent vaccines, if any.

Td (tetanus toxoid)

Daniel Landi, MD

The purpose of this study is to determine the feasibility and safety of administering CMV RNA-pulsed dendritic cells (DCs), also known as CMV-DCs, to children and young adults up to 35 years old with nWHO Grade IV glioma, recurrent malignant glioma, or recurrent medulloblastoma. Evidence for efficacy will also be sought. This will be a phase 1 study evaluating CMV-DC administration with tetanus toxoid (Td) preconditioning and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) adjuvant in children and young adults up to 35 years old with WHO grade IV glioma, recurrent malignant glioma, or recurrent medulloblastoma. This safety study will enroll a maximum of 10 patients.

Participants in this study will undergo a leukapheresis procedure in which blood is collected into a machine that removes white blood cells and then returns the remainder of the blood back to the individual. The white blood cells removed from the blood are used to make the participant's study vaccine. Newly diagnosed patients will undergo standard radiation therapy (RT) with or without temozolomide after leukapheresis. If a patient has been diagnosed with a Grade IV glioma or recurrence of either malignant glioma or medulloblastoma, the study doctor may recommend "bridge therapy" after leukapheresis. Bridge therapy is approved or standard therapy for the tumor intended to bridge the time without the study drugs, dose-intensified temozolomide (DI-TMZ) or CMV-DC vaccine. All participants will undergo a cycle of "dose-intensified" temozolomide. Participants will receive Td pre-conditioning given as a shot in the right leg, six to 24 hours before receiving their 1st vaccine, which is also given as shots in the legs. If more than one vaccine is made, vaccines #2 and #3 will occur at 2-week intervals after the 1st vaccine. After the 3rd vaccine, there will be 4 weeks between vaccines for as many vaccines as the study team can prepare from the participant's leukapheresis.

Please note data collection will continue to occur outside of the defined primary outcomes for 2 exploratory objectives- describing changes in T cell response to CMV-DC vaccination and describing overall and progression-free survival of patients enrolled on the study. The percent change in pp65-specific T cell responses will be calculated from a pre-chemotherapy baseline, post-chemotherapy baseline, 1 week after Vaccine #3, and 1 week after final vaccine. Progression-free survival is defined as the time between starting DI TMZ and disease progression. Patients will be followed for overall survival for up to 3 years.

Cytomegalovirus (CMV) RNA-Pulsed Dendritic Cells for Pediatric Patients and Young Adults With WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent Medulloblastoma

A Phase 1 Trial of CMV RNA-Pulsed Dendritic Cells With Tetanus-Diphtheria Toxoid Vaccine in Pediatric Patients and Young Adults With WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent Medulloblastoma

Percentage of patients for whom three or more vaccines can be generated from the pre-treatment leukapheresis

Percentage of patients who experience unacceptable toxicity from CMV-DC administration

Gary Archer Ph.D.

Assistant Professor of Neurosurgery

CMV-DCs With GM-CSF and Td (Tetanus Toxoid)

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Principal Investigator

Percentage of Patients for Whom 3 or More Vaccines Can be Made

One eligible patient had a leukapheresis (evaluable for feasibility), but was withdrawn from the study due to clinical decline prior to receiving any treatment (not evaluable for safety).

Percentage of Patients Who Experience Unacceptable Toxicity

Overall Study

Medulloblastoma, Childhood

Participants will receive an individualized treatment recommendation including a combination of up to four FDA-approved drugs within 21 business days of tissue acquisition using the results of real-time high-throughput drug screening, whole exome sequencing (WES), and RNA sequencing.

Specialized Treatment Plan of up to four FDA approved drugs based on participant's screening results will be assigned by PNOC specialized tumor board

Specialized Tumor Board Treatment Plan

Aubrie Drechsler

Ashley Margol, MD

Tom Davidson, MD

John Crawford, MD, MS

Jennifer Elster, MD

Krystal Pryor

Sabine Mueller, MD, PhD

Alyssa Reddy, MD

Lindsay Kilburn, MD

Roger Packer, MD

Mohamed AbdelBaki, MD

Margaret Shatara, MD

Cassie Kline, MD, MAS

Jane Minturn, MD, PhD

Sabine Mueller, MD, PhD, MAS

Joshua Rubin, MD, PhD

Robert Wechsler-Reya, PhD

Megan Paul, MD

The current study will use a new treatment approach based on the molecular characteristics of each participant's tumor. The study will test the feasibility of performing real-time drug screening on tissue taken during surgery, and of having a specialized tumor board assign a treatment plan based on the results of this screening and genomic sequencing. The aim of this trial is to allow every child and young adult with medulloblastoma to receive the most effective and least toxic therapies currently available, and will pave the way for improved understanding and treatment of these tumors in the future.

This is a single arm multi-center pilot trial within the Pacific Pediatric Neuro-Oncology Consortium (PNOC). Relapsed participants will receive an individualized treatment recommendation including up to four FDA-approved drugs based on the results of real-time high-throughput drug screening, whole exome sequencing (WES), and RNA sequencing.

PRIMARY OBJECTIVE:

I. To determine the feasibility of using the results of real-time in vitro drug screening, whole exome sequencing, and RNA sequencing of participant-derived specimens to guide treatment recommendations by a specialized tumor board, in a clinically-actionable timeframe, for children and young adults with recurrent medulloblastoma.

SECONDARY OBJECTIVE:

I. To determine the safety and describe the toxicity of treating children and young adults with relapsed medulloblastoma according to a specialized tumor board that makes treatment recommendations based on real-time drug screening and genomic sequencing.

EXPLORATORY OBJECTIVES:

I. To estimate the objective response rate, progression free survival at 6 months (PFS-6) and overall survival (OS) of relapsed medulloblastoma in children and young adults treated with an individualized treatment regimen.

II. To assess Quality of Life (QOL) measures in participants with relapsed medulloblastoma treated with an individualized regimen.

III. To archive tumor and normal DNA from each participant along with serial blood draw following therapies as biospecimens for later studies to determine whether circulating tumor DNA (ctDNA) sequences in the participant's blood serve as biomarkers of tumor burden, response to therapy, or development of drug resistance.

Participants may continue treatment as tolerated for up to two years or until disease progression. Participants will be followed until progression, death, or up to 5 years from start of therapy.

Individualized Treatment Plan in Children and Young Adults With Relapsed Medulloblastoma

A Pilot Trial of Real Time Drug Screening and Genomic Testing to Determine an Individualized Treatment Plan in Children and Young Adults With Relapsed Medulloblastoma

Individual participant data after de-identification.

Time to tissue collection will be used to determine the feasibility of using the results of real-time in vitro drug screening, WES and RNAseq of participant-derived specimens to guide treatment recommendations by a specialized tumor board, in a clinically-actionable timeframe, for children and young adults with recurrent medulloblastoma. Participants are expected to receive treatment plan within 21 business days

Proportion of participants with grade 3 or higher toxicities classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Adverse events and clinically significant laboratory abnormalities (meeting Grade 3 or higher criteria will be summarized by maximum grade and relationship to study drug(s).

Washington University School of Medicine

St. Baldrick's Foundation

Ashion Analytics

University of Washington

Pacific Pediatric Neuro-Oncology Consortium

University of California, San Francisco

Ependymoma

Anti-Infective Agents

Antirheumatic Agents

Anti-Inflammatory Agents

Analgesics

Lipid Regulating Agents

Etoposide

Cytarabine

Cyclophosphamide

Bevacizumab

Angiogenesis Inhibitors

Etoposide phosphate

Thalidomide

Celecoxib

Fenofibric acid

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Growth Inhibitors

Enzyme Inhibitors

Antimetabolites

Antiviral Agents

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Anti-Bacterial Agents

Anticholesteremic Agents

Hypolipidemic Agents

10mg/kg, intravenous (iv), biweekly, 1 year

35-50 mg/m2, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year

2.5mg/kg, oral, alternating 21-day cycles of daily oral etoposide and cyclophosphamide, 1 year

0.5mg, intrathecal, day 1-5, every four weeks, alternating with intrathecal liposomal cytarabine, 1 year

16-30mg, intrathecal, twice weekly for two weeks out of every four weeks, alternating with intrathecal etoposide phosphate, 1 year

Andreas Peyrl, MD

Irene Slavc, MD

Rebecca Loret de Mola

Rebecca Loret De Mola, MD

Ashley Ratcliffe

Virginia Harrod, MD

Elisabeth Hulla-Gumbsch

Martin Benesch, MD

Yvonne Ennemoser, MSc

Roman Crazzolara, MD

Martina Winkler

Georg Ebetsberger, MD

Neil Jones, MD

Agnes Gamper, MD

Alexandra Martincekova, MD

Jaroslav Sterba, MD

Zdenek Pavelka, MD

Klara Hruba

David Sumerauer, MD

Karsten Nysom, MD

Pierre Leblond, MD

Ingrid Torsvik

Ingrid Torsvik, MD

Alvaro Lassaletta, MD, PhD

Karin Fritzson

Anna Schröder- Håkansson

Magnus Sabel, MD

Birgitta Lannering, Prof

Birgitta Hellström

Pernilla Augustsson

Irene Devenney, MD

Yvonne Håkansson

Simon Johansson

Helena Mörse, MD

Carina Rinaldo

Yvonne Copeland

Stefan Holm, MD

Marita Wikström-Larsson

Mattias Mattsson

Katarina Vallin

Anders Öberg, MD

Monika Chocholous, MD

Patients with relapsed medulloblastoma, ependymoma and ATRT have a very poor prognosis whether treated with conventional chemotherapy, high-dose chemotherapy with stem cell rescue, irradiation or combinations of these modalities. Antiangiogenetic therapy has emerged as new treatment option in solid malignancies. The frequent, metronomic schedule targets both proliferating tumor cells and endothelial cells, and minimizes toxicity. In this study the investigators will evaluate the use of biweekly intravenous bevacizumab in combination with five oral drugs (thalidomide, celecoxib, fenofibrate, and alternating cycles of daily low-dose oral etoposide and cyclophosphamide), augmented with alternating courses of intrathecal etoposide and cytarabine. The aim of the study is to extend therapy options for children with recurrent or progressive medulloblastoma, ependymoma and ATRT, for whom no known curative therapy exists, by prolonging survival while maintaining good quality of life. The primary objective of the MEMMAT trial is to evaluate the activity of this multidrug antiangiogenic approach in these heavily pretreated children and young adults. Additionally, progression-free survival (PFS), overall survival (OS), as well as feasibility and toxicity will be examined.

3 Strata (medulloblastoma - 40 patients; ependymoma - 30 patients; ATRT - 30 patients)

Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma and ATRT

A Phase II Study of Metronomic and Targeted Anti-angiogenesis Therapy for Children With Recurrent/Progressive Medulloblastoma, Ependymoma and ATRT

Response rate (Complete remission, partial response, stable disease =\[CR+PR+SD\]/n) 6 months after start of antiangiogenic treatment

The percentage of patients in the study who are alive for a certain period of time (6, 12, 24, and 36 months) after start of treatment with an antiangiogenic multidrug-regime

The percentage of patients in the study who are alive with a non-progressive disease for a certain period of time (6, 12, 24, and 36 months) after start of treatment with an antiangiogenic multidrug-regime.

To evaluate and document toxicities from chronic administration of these drugs at the doses prescribed in this protocol in patients with recurrent or progressive medulloblastoma. These will be descriptive in nature.

To evaluate the feasibility of achieving the prescribed drug doses given the reduced bone marrow tolerance after multiple relapses.

Quality of Life (QoL) will be evaluated by a generic quality of life instrument for children (the KINDL®-questionnaire).

To evaluate the influence of tumor biology(histologic subgroups, metastatic stage, age at first diagnosis \[\<3 years, \>3 years\]), age at start of antiangiogenic therapy, sex, duration of remission prior to antiangiogenic therapy, number of recurrences.

To evaluate serum markers for in-vitro correlative studies of tumor response.

Medical University of Vienna

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cytomegalovirus (CMV) RNA-Pulsed Dendritic Cells for Pediatric Patients and Young Adults With WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent Medulloblastoma	NCT03615404	Glioblastoma Malignant Gliom... Medulloblastoma... Pediatric Gliob... Pediatric Brain... Pediatric Brain...	CMV-DCs with GM... Td (tetanus tox...	0 Years - 35 Years	Duke University
Cytomegalovirus (CMV) RNA-Pulsed Dendritic Cells for Pediatric Patients and Young Adults With WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent Medulloblastoma	NCT03615404	Glioblastoma Malignant Gliom... Medulloblastoma... Pediatric Gliob... Pediatric Brain... Pediatric Brain...	CMV-DCs with GM... Td (tetanus tox...	0 Years - 35 Years	Duke University
Individualized Treatment Plan in Children and Young Adults With Relapsed Medulloblastoma	NCT05057702	Medulloblastoma Medulloblastoma... Medulloblastoma...	Specialized Tum...	12 Months - 39 Years	University of California, San Francisco
Cytomegalovirus (CMV) RNA-Pulsed Dendritic Cells for Pediatric Patients and Young Adults With WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent Medulloblastoma	NCT03615404	Glioblastoma Malignant Gliom... Medulloblastoma... Pediatric Gliob... Pediatric Brain... Pediatric Brain...	CMV-DCs with GM... Td (tetanus tox...	0 Years - 35 Years	Duke University
Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma and ATRT	NCT01356290	Medulloblastoma... Ependymoma Recu... ATRT Recurrent	Bevacizumab Thalidomide Celecoxib Fenofibric acid Etoposide Cyclophosphamid... Etoposide phosp... Cytarabine	- 19 Years	Medical University of Vienna
Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma and ATRT	NCT01356290	Medulloblastoma... Ependymoma Recu... ATRT Recurrent	Bevacizumab Thalidomide Celecoxib Fenofibric acid Etoposide Cyclophosphamid... Etoposide phosp... Cytarabine	- 19 Years	Medical University of Vienna
Cytomegalovirus (CMV) RNA-Pulsed Dendritic Cells for Pediatric Patients and Young Adults With WHO Grade IV Glioma, Recurrent Malignant Glioma, or Recurrent Medulloblastoma	NCT03615404	Glioblastoma Malignant Gliom... Medulloblastoma... Pediatric Gliob... Pediatric Brain... Pediatric Brain...	CMV-DCs with GM... Td (tetanus tox...	0 Years - 35 Years	Duke University

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