Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
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 prlongs 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 C11orf95-RELA
 fusion which drives tumorigenesis in ependymomas by activating the 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.
-  INCLUSION CRITERIA:

 -  Stage 1 Eligibility (Cohort 1 and 2)

 Cohort 1

 -  Histologically confirmed by NCI Laboratory of Pathology intra-cranial or spinal 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)

 -  AST(SGOT)/ALT(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 eGFR within normal as
 predicted by the 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/QTc interval (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 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 marizomib s potential
 forteratogenic 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 child s 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 child s 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.