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

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 9 patients with RELA-fusion ependymoma and if 4 or
more patients 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 41 patients with RELA-fusion and 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)

- 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

- Stage 2 Eligibility (Cohorts 2 - 4)

- Histologically confirmed by NCI Laboratory of Pathology intra-cranial or spinal
RELA- fusion ependymoma (Cohort 2), or non RELA-fusion ependymoma (Cohorts 3, 4)
of grade I, II or III.

- Patients with 2 or fewer prior chemotherapy regimens will be enrolled in Cohort
3, patients with more than 2 prior chemotherapy regimens will be enrolled in
Cohorts 2 and 4.

- 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).

- urine protein on reagent strip

- 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. 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.