Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Disease Progression

Ependymoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Anaplastic Ependymoma

Neuroepithelioma

All Drugs and Chemicals

Proteasome Inhibitors

Marizomib at days 1, 8, and 15 of each 28-day cycle

Data collection on pregnancy, birth and Health of Child

0.8mg/m(2) intravenous (IV) on days 1, 8, and 15 of each 28-day cycle, 24 cycles total.

Marizomib

Mark R Gilbert, M.D.

Background:

Ependymomas are rare tumors that arise from the ependyma. That is a tissue of the central nervous system. They can develop in the brain or the spine. They are usually treated with surgery, radiation, and/or chemotherapy. Researchers want to see if the new drug marizomib can help people with a certain kind of ependymoma.

Objective:

To see if marizomib stops tumor growth and prolongs the time that the tumor is controlled.

Eligibility:

Adults age 18 and older who have been diagnosed with ependymomas and have already been treated with standard therapies

Design:

Participants will be screened with the following tests or recent results from similar tests:

* Medical history
* Physical exam
* Neurological assessment
* Electrocardiogram (EKG) to evaluate the heart
* Review of symptoms and ability to perform normal activities
* Computed tomographic scan (CT) or magnetic resonance imaging (MRI) to produce an image of the brain or spine.
* Blood and urine tests
* Tests of tumor samples. Participants may have to have new tumor samples taken.

Participants will get the study drug in cycles. Each cycle is 4 weeks. Participants will have up to 24 cycles.

Participants will get the study drug through a small plastic tube in a vein on days 1, 8, and 15 of each cycle.

During each cycle, some screening tests will be repeated.

Participants will answer questions about their general well-being and functioning.

About 4 5 weeks after finishing the study drug, participants will have a follow-up visit. They will answer questions about their health, get a physical and a neurological exam, and have blood tests. They may have an MRI or CT scan.

...

Background:

* Ependymomas are rare primary brain tumors arising from radial glial stem cells. They comprise 5.2% of all pediatric primary brain tumors and 1.9% of all adult primary brain tumors.
* The standard therapy for newly diagnosed ependymoma is gross total resection followed by radiation therapy. For anaplastic ependymoma, recurrence rate is high with a median progression free survival (PFS) of 2.3 years.
* There are limited chemotherapy options for recurrent ependymomas, which have already been irradiated. Therefore, there is an unmet need to target novel pathways for treatment of ependymomas.
* About 70% of supratentorial ependymomas have a characteristic signature C11 orf95-V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA) fusion which drives tumorigenesis in ependymomas by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) transcription pathway.
* Marizomib is a second-generation irreversible proteasome inhibitor which penetrates across the blood-brain-barrier (BBB). It inhibits the activity of 20S proteasome in glioma cells, activates caspases, builds up reactive oxygen species and thus induces apoptosis. Marizomib blocks the NF-pathway by proteasome inhibition. Thus, it may have an additional targeted therapeutic effect in the RELA-fusion molecular subgroup of ependymomas.

Objective:

-To evaluate the efficacy of treatment with marizomib in RELA-fusion recurrent ependymoma and non RELA-fusion recurrent ependymoma as measured by progression-free survival at 6 months (PFS6).

Eligibility:

* Histologically proven intra-cranial or spinal ependymoma.
* Radiographic evidence of tumor progression
* Patients must be greater than or equal to 18 years old.

Patients must have had prior radiotherapy.

Design:

* This is a phase II study to determine the efficacy of marizomib in recurrent ependymoma.
* A novel 2-stage sequential design will be employed to conduct the trial for recurrent ependymoma.
* In the first stage, we will enroll 18 patients with RELA-fusion ependymoma and if 4 or more patients in Cohort 1 are progression free at 6 months, we will proceed to stage 2; otherwise, we will terminate the trial and conclude that marizomib is not effective.
* In the second stage, we will enroll 32 patients with non RELA-fusion ependymoma.
* Patients will be treated with marizomib in cycles consistent of 28 days until disease progression or a maximum of 24 cycles.

Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma

Phase II Clinical Trial of Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma

1. Biomedical Translational Research Information System (BTRIS): All IPD recorded in the medical record will be shared with intramural investigators upon request.
2. Database of Genotypes and Phenotypes (dbGaP): All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Progression was assessed by the Response assessment in neuro-oncology criteria (RANO) and is defined as a 25% increase in the sum of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline. Appearance of new lesions, or clear worsening of any evaluable disease. Failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

To determine the safety of marizomib in recurrent ependymoma patients and in a subset of patients with more than 2 prior chemotherapies (RELA-fusion Cohort 2 and non-RELA-fusion Cohort 4).

To estimate the efficacy of marizomib in recurrent ependymoma patients (RELA- fusion Cohort 2 and non RELA-fusion Cohort 4) with more than 2 prior chemotherapies as measured by progression free disease after 6 months. Progression was assessed by the Response Assessment in Neuro-oncology (RANO) criteria and is defined as a 25% increase in the sum of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline. Appearance of new lesions, or clear worsening of any evaluable disease. Failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Progression was assessed by the Response Assessment in Neuro-oncology criteria (RANO) and is defined as a 25% increase in the sum of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline. Appearance of new lesions, or clear worsening of any evaluable disease. Failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Changes in quality of life using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) instrument was used to determine symptom severity.To longitudinally evaluate participant reported outcome measures using self-reported symptom severity with daily activities using the MDASI-BT and/or MDASI-SP instrument.

To estimate the efficacy of marizomib in recurrent ependymoma patients (RELA- fusion Cohort 2 and non RELA-fusion Cohort 4) with more than 2 prior chemotherapies as measured by objective response. Complete Response is complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. Partial Response is greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions.

Median amount of time subject survives 12 months after therapy

OS is defined as the time from treatment start date until date of death or date last known alive.

Changes in quality of life using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) instrument was used to determine symptom interference.To longitudinally evaluate participant reported outcome measures using self-reported symptom interference with daily activities using the MDASI-BT and/or MDASI-SP instrument.

National Cancer Institute (NCI)

Principal Investigator

Marizomib at days 1, 8, and 15 of each 28-day cycle

Marizomib: 0.8mg/m(2) intravenous (IV) on days 1, 8, and 15 of each 28-day cycle, 24 cycles total.

Participants with Intra-cranial or Spinal V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA)-fusion Ependymoma who have had none, 1 or 2 prior chemotherapies.

1/Cohort 1 - Participants With Ependymoma Who Had None, One or Two Prior Chemotherapies

Participants with intra-cranial or spinal RELA-fusion ependymoma who had more than two prior chemotherapies.

2/Cohort 2 - Participants With Ependymoma Who Had More Than Two Prior Chemotherapies

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Mark Gilbert

Number of Participants That Are Progression-free at 6 Months Time Point After Initiation of Treatment

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Toxicities by Grade Using the Common CTCAE Version 5.0.

The one participant in Cohort 2 had progressive disease prior to 6 month mark and we did not enroll in Cohort 4 due to early study termination.

Number of Participants That Have Progressive Disease After 6 Months

Number of Participants With 12-month Progression-free Survival (PFS12)

This outcome measure was not done because we were unable to determine due to low accrual and few data timepoints for which meaningful data could be extracted.

Symptom Severity Using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) Instrument

We did not enroll to Cohort 4 due to early termination of the study.

Number of Participants Assessed Using the Response Assessment in Neuro-oncology Criteria (RANO) for Complete Response (CR) + Partial Response (PR)

This outcome measure was not done. We were unable to determine as participants were taken off study for early study termination prior to the 12 months post therapy timepoint.

Median Amount of Time Subject Survives 12 Months After Therapy

This outcome measure was not done. We were unable to determine for non RELA-fusion recurrent ependymoma patients since we did not enroll in those cohorts due to early study termination. And for the 4 participants with RELA-fusion recurrent ependymoma enrolled, the study was prematurely terminated pharmaceutical sponsor.

Overall Survival (OS) of RELAfusion and Non RELA-fusion Recurrent Ependymoma Patients Treated With Marizomib.

Symptom Interference Using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) Instrument

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