Clinical Trials /

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

NCT03727841

Description:

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. ...

Related Conditions:
  • Ependymoma
  • Ependymoma, RELA Fusion-Positive
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 190011
  • SECONDARY ID: 19-C-0011
  • NCT ID: NCT03727841

Conditions

  • Anaplastic Ependymoma
  • Ependymoma
  • Ependymomas

Interventions

DrugSynonymsArms
Marizomib1/Arm 1

Purpose

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. ...

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm 1ExperimentalMarizomib at days 1, 8, and 15 of each 28-day cycle
  • Marizomib

Eligibility Criteria

        -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:6 months
Safety Issue:
Description:Proportion of patients that are progression-free at 6 months time point after initiation of treatment

Secondary Outcome Measures

Measure:Number of toxicities by grade and type scored using CTCAE version 5.0.
Time Frame:end of study
Safety Issue:
Description: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).
Measure:Proportion of patients that have progressive disease after 6, 12 months. Median amount of time subject survives after therapy
Time Frame:6 month, 12 month and end of study
Safety Issue:
Description: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 PFS6, PFS12, median PFS and OS.
Measure:Median amount of time subject survives without disease progression after treatment and Median amount of time subject survives 12 months after therapy
Time Frame:12 month and end of study
Safety Issue:
Description:To estimate the 12-month progression-free survival (PFS12), median progressionfree survival (PFS) and overall survival (OS) of RELAfusion and non RELA-fusion recurrent ependymoma patients treated with marizomib.
Measure:Proportion of patients that have changes in quality of life
Time Frame:end of study
Safety Issue:
Description:To longitudinally evaluate patient reported outcome measures using self-reported symptom severity and interference with daily activities using the MDASI-BT and/or MDASI-SP instrument.
Measure:Proportion of patients assessed using the RANO Criteria for Response
Time Frame:end of study
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Proteasome Inhibitor
  • Penetration Across the Blood-Brain-Barrier (BBB)
  • Apoptosis Induction
  • Targeted Therapeutic Effect
  • Tumor Progression

Last Updated

March 6, 2020