Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
Condition: Anaplastic Ependymoma; Ependymoma; Ependymomas
MeSH terms: Ependymoma
Intervention: Marizomib
Intervention description: 0.8mg/m(2) intravenous (IV) on days 1, 8, and 15 of each 28-day cycle, 24 cycles total.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Healthy volunteers: No
Keywords: Proteasome Inhibitor; Penetration Across the Blood-Brain-Barrier (BBB); Apoptosis Induction; Targeted Therapeutic Effect; Tumor Progression

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.

      ...
    

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.