Clinical trial NCT03727841: Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
Official title: Phase II Clinical Trial of Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial and Spinal Cord Ependymoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Anaplastic Ependymoma
Ependymoma
Ependymomas
Keywords: Proteasome Inhibitor
Penetration Across the Blood-Brain-Barrier (BBB)
Apoptosis Induction
Targeted Therapeutic Effect
Tumor Progression
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-11-01
Enrollment: 4
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

...

Detailed description: 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.

Eligibility criteria: * INCLUSION CRITERIA:
* Stage 1 Eligibility (Cohort 1 and 2)

Cohort 1

* Histologically confirmed by National Cancer Institute (NCI) Laboratory of Pathology intra-cranial or spinal V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A (RELA)- fusion ependymoma of grade I, II or III.
* Has received two or fewer prior chemotherapy regimens

Cohort 2

* Histologically confirmed by NCI Laboratory of Pathology intra-cranial or spinal RELA-fusion ependymoma of grade I, II or III.
* Has received more than two prior chemotherapy regimens

  * Stage 2 Eligibility (Cohorts 3 and 4)

Cohort 3

* Histologically confirmed by NCI Laboratory of Pathology intra-cranial or spinal non RELA-fusion ependymoma of grade I, II or III.
* Has received two or fewer prior chemotherapy regimens

Cohort 4

* Histologically confirmed by NCI Laboratory of Pathology intra-cranial or spinal non RELA-fusion ependymoma of grade I, II or III.
* Has received more than two prior chemotherapy regimens.

  * Patients must have an evidence of tumor progression.
  * Patients must have had prior radiation therapy.
  * Patients must be greater than or equal to 18 years old. Currently, no dosing or adverse event data is available on the use of marizomib in patients \< 18 years of age; therefore, only adults are included in this study. Patients \< 18 years of age will be eligible for future pediatric trials.
  * Patients must have a Karnofsky performance status of greater than or equal to 60.
  * Patients must have adequate organ and marrow function as defined below:
  * leukocytes: greater than or equal to 3,000/microliters
  * absolute neutrophil count: greater than or equal to 1,500/microliters
  * platelets: greater than or equal to 100,000/microliters
  * hemoglobin: greater than or equal to 10 gm/dL (can be achieved by transfusion)
  * Aspartate aminotransferase (AST) Serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT): less than or equal to 2.5 X institutional upper limit of normal
  * Bilirubin: \<1.5 mg/dL
  * Creatinine up to 1.5-times upper institutional limits OR estimated glomerular filtration rate (eGFR) within normal as predicted by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (greater than or equal to 60 mL/min/1.73m(2).
  * Negative urine protein or urine protein concentration less than or equal to 60 mg/dL
  * The effects of marizomib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and up to 30 days after the last dose of the drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  * Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

* Anticancer treatment within designated period of time before enrollment including:

  * surgery within 14 days
  * needle or core biopsy within 7 days
  * prior cytotoxic therapy within 28 days,
  * vincristine within 14 days
  * nitrosoureas within 42 days,
  * procarbazine administration within 21 days
  * non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid (radiosensitizer does not count) within 7 days; Avastin within 21 days. Any questions related to the definition of non-cytotoxic agents should be directed to the NCI Principal Investigator.
* Treatment with any investigational agent within 28 days before enrollment.
* History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless patient is in complete remission and off all therapy for that disease for a minimum of 3 years.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to marizomib.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Inadequately controlled hypertension (defined as systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg).
* Current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment).
* New York Heart Association (NYHA) Grade II heart failure or greater or history of hospitalization for congestive heart failure diagnosis within 12 months prior to enrollment.
* History of myocardial infarction or unstable angina within 3 months prior to enrollment.
* A marked baseline prolongation of QT interval (QT)/corrected QT interval (QTc) (e.g., repeated demonstration of a QTc interval \>480 milliseconds (ms) (CTCAE grade 1) using Frederica's QT correction

formula.

* A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
* Current use of concomitant medications that prolong the QT/QTc interval
* History of stroke or transient ischemic attack within 3 months prior to enrollment.
* Pregnant women are excluded from this study because marizomibs potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with marizomib, breastfeeding should be discontinued if the mother is treated with marizomib.
* Patients receiving combination antiretroviral therapy for treatment of Human Immunodeficiency Virus (HIV) or active anti-viral treatment for Hepatitis A, B or C infection. Anti-viral therapy, when combined with marizomib, poses a potential for pharmacokinetic interactions. Marizomib also increases immunosuppression, placing patients at an increased risk of acquiring lethal infections. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
* Inclusion Criteria for Pregnancy Cohort (P)

Because the drug manufacturer would like to study the effect of the study therapy on pregnancy, and because the required information cannot be collected unless a subject is enrolled per ruling of the OGC, the following additional groups of subjects may be enrolled if necessary.

-A child whose parent (male or female) is/was an active participant in the study at any time during the childs gestation. Active participant is defined as having received at least one dose of study therapy through 6 months after the last dose of study therapy.

OR

* An expectant mother of child whose father is/was an active participant in the study at any time during the childs gestation. The father must have received at least one dose of study therapy. Active participant is defined as having received at least one dose of study therapy through 6 months after the last dose of study therapy.
* The expectant mother must be age 18 or older and must have the capacity to provide informed consent.

Primary outcomes:
measure: Number of Participants That Are Progression-free at 6 Months Time Point After Initiation of Treatment
timeFrame: 6 months
Secondary outcomes:
measure: Number of Toxicities by Grade Using the Common CTCAE Version 5.0.
timeFrame: At end of study, up to 16 months
measure: Number of Participants That Have Progressive Disease After 6 Months
timeFrame: 6 months
measure: Number of Participants With 12-month Progression-free Survival (PFS12)
timeFrame: 12 months
measure: Symptom Severity Using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) Instrument
timeFrame: End of study
measure: Number of Participants Assessed Using the Response Assessment in Neuro-oncology Criteria (RANO) for Complete Response (CR) + Partial Response (PR)
timeFrame: Up to 16 months
measure: Median Amount of Time Subject Survives 12 Months After Therapy
timeFrame: 12 months after therapy
measure: Overall Survival (OS) of RELAfusion and Non RELA-fusion Recurrent Ependymoma Patients Treated With Marizomib.
timeFrame: Start of treatment until end of study
measure: Symptom Interference Using the MD Anderson Symptom Inventory- Brain Tumor (MDASI-BT) and/or MD Anderson Symptom Inventory - Spine Tumor Module (MDASI-SP) Instrument
timeFrame: End of study
Other outcomes:
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
timeFrame: Date treatment consent signed to date off study, approximately 14 months and 27 days, and 7 months and 22 days for the first and second group respectively.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Mark R Gilbert, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wu J, Armstrong TS, Gilbert MR. Biology and management of ependymomas. Neuro Oncol. 2016 Jul;18(7):902-13. doi: 10.1093/neuonc/now016. Epub 2016 Mar 28.
citation: Harrison SJ, Mainwaring P, Price T, Millward MJ, Padrik P, Underhill CR, Cannell PK, Reich SD, Trikha M, Spencer A. Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results. Clin Cancer Res. 2016 Sep 15;22(18):4559-66. doi: 10.1158/1078-0432.CCR-15-2616. Epub 2016 Apr 26.
citation: Di K, Lloyd GK, Abraham V, MacLaren A, Burrows FJ, Desjardins A, Trikha M, Bota DA. Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier. Neuro Oncol. 2016 Jun;18(6):840-8. doi: 10.1093/neuonc/nov299. Epub 2015 Dec 17.