Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

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Glioma

Diffuse Intrinsic Pontine Glioma

Brain Neoplasms

Gliosarcoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

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Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Central Nervous System Neoplasms

Nervous System Neoplasms

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Central Nervous System Diseases

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Infratentorial Neoplasms

Brain Tumor, Childhood

Childhood Brain Stem Glioma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Panobinostat

Histone Deacetylase Inhibitors

Enzyme Inhibitors

All patients will initially receive marizomib (MRZ) alone (Course A1) The dose escalation and de-escalation for single agent and combination will be guided using the Bayesian optimal interval (BOIN) design

-Intravenously initially given every other week over a 28 day course but may go to weekly x 3 and weekly x 4 as the dose levels increase. Up to 26 courses.

If tolerated,combination of Marizomib: and panobinostat on subsequent cycles. The dose escalation and de-escalation for single agent and combination will be guided using the Bayesian optimal interval (BOIN) design.

* Intravenously initially given every other week over a 28 day course but may go to weekly x 3 and weekly x 4 as the dose levels increase. Up to 26 courses.
* Panobinostat: Oral dosage is given 3 times weekly, every other week over a 28 day course

- Intravenously initially given every other week over a 28 day course but will go to weekly x 3 and weekly x 4 as the dose levels increase Up to 26 courses.

Marizomib

- Panobinostat: Oral dosage is given 3 times weekly, every other week over a 28 day course

Katherine Warren, MD

This research study is evaluating the safety, tolerability and preliminary efficacy of the drugs marizomib and panobinostat in pediatric patients with diffuse intrinsic pontine glioma (DIPG).

The names of the study drugs involved in this study are:

* Marizomib
* Panobinostat

This research study involves chemotherapy as a possible treatment for pediatric patients with Diffuse intrinsic pontine glioma (DIPG)

* The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.
* The names of the study drugs involved in this study are:

  * Marizomib
  * Panobinostat

This study consists of 2 parts:

* Part A : The investigators are looking at the highest dose (up to a targeted maximum dose) of the study drug Marizomib that can be administered safely without severe or unmanageable side effects in participants that have DIPG, not everyone who participates in this research study will receive the same dose of the study intervention. The dose given will depend on the number of participants who have been enrolled prior and how well the dose was tolerated.
* Part B: Participants who tolerate Marizomib alone will be treated with Marizomib and panobinostat, but at lower dose of marizomib than the dose of marizomib when given alone.

Participants are expected to be on study treatment for up to 2 years followed for up to 5 years.

It is expected that up to 45 people will take part in this research study. This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied.

* Marizomib has not been approved by the U.S. Food and Drug Administration (FDA) as a treatment for any disease.

  -- This is the first time Marizomib will be given to children.
* Panobinostat has not approved by the U.S. Food and Drug Administration (FDA) for the treatment of diffuse intrinsic pontine glioma but it has been approved for other uses.

Phase I Study of Marizomib + Panobinostat for Children With DIPG

Phase 1 Trial of Marizomib Alone and in Combination With Panobinostat for Children With Diffuse Intrinsic Pontine Glioma

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

To determine the toxicity profile and any dose-limiting toxicity (DLT) of marizomib as a single agent at doses up to 0.8 mg/m2 , in children with DIPG

To determine the toxicity profile and any DLT of marizomib at doses up to 0.8 mg/m2 when administered in combination with panobinostat to children with DIPG

To estimate the maximum-tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of marizomib when administered as a single agent in children with DIPG

To estimate the MTD or RP2D of marizomib when administered in combination with panobinostat in children with DIPG

Estimated using compartmental methods. Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form

Estimated using compartmental methods Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form

Kaplan-Meier method will be used to summarize the time-to-event endpoints, i.e. OS

determined by combination of radiographic assessment, symptoms (patient/parent-reported), clinical (physician or NP) assessment, steroid use, ability to walk, and quality of life (QOL) measure

Celgene

Secura Bio, Inc.

Dana-Farber Cancer Institute

Principal Investigator

Fresh-frozen and fixed tumor samples, correspondent normal brain tissue samples, cerebrospinal fluid, urine, and serum samples from patients affected with diffuse intrinsic pontine glioma or brainstem glioma

Javad Nazarian, PhD

Madhuri Kambhampati, MS

Roger Packer, MD

Suresh Magge, MD

Amanda L Muhs, MD

The purpose of this study is to prospectively collect specimens from pediatric patients with diffuse intrinsic pontine glioma or brainstem glioma, either during therapy or at autopsy, in order to characterize the molecular abnormalities of this tumor.

High grade diffuse intrinsic pontine glioma (DIPG) accounts for approximately 80% of pediatric brainstem tumors and 10% of pediatric brain tumors, and is the most lethal form of brainstem gliomas in children. There is currently no effective therapy to treat these tumors. We hypothesize that this tumor exhibits unique molecular abnormalities leading to altered RNA and protein expression. The aim of this trial is to collect specimens from pediatric patients with diffuse intrinsic pontine glioma including serum, cerebrospinal fluid, urine, brain tumor and other constitutional tissue, during therapy and/or at autopsy. Our goal is to study this tissue to characterize the genetic abnormalities that lead to tumor formation in order to identify key molecules as biomarkers which we can target to design and test new and more effective treatments.

Cerebrospinal fluid, serum, urine, brainstem tumor and constitutional tissue from patients with diffuse intrinsic pontine glioma or brainstem glioma will be collected.

Molecular Analysis of Samples From Patients With Diffuse Intrinsic Pontine Glioma and Brainstem Glioma

Collected tumor and normal samples will potentially be used for RNA genome-wide expression pattern profiling.

The molecular analysis done on collected samples will be validated through whole genome sequencing.

To obtain full characterization of collected samples, proteomic profiling will be done on tumor and normal samples collected.

Collected tumor and normal samples will have the immunochemistry and western blot compared to assess protein expression variation.

To obtain full characterization of collected samples, whole genome sequencing will be done on tumor and normal samples collected.

Collected samples will potentially be used for in vitro analysis and generation of animal models of this tumor.

In an effort to continue to draw knowledge from samples collected, potential benefits and drawbacks from specimen acquisition will be continuously accessed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Study of Marizomib + Panobinostat for Children With DIPG	NCT04341311	Diffuse Intrins... Pediatric Brain... Pediatric Brain... Pediatric Cance... Pediatric Brain... Diffuse Glioma	Marizomib Panobinostat	- 21 Years	Dana-Farber Cancer Institute
Molecular Analysis of Samples From Patients With Diffuse Intrinsic Pontine Glioma and Brainstem Glioma	NCT01106794	Diffuse Intrins... Brainstem Gliom...		- 21 Years	Children's National Research Institute

Spots Global Cancer Trial Database for pediatric brainstem glioma