Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
Condition: Anaplastic Astrocytoma; Anaplastic Ependymoma; Astrocytoma, Grade II; Ependymoma; Giant Cell Glioblastoma; Glioblastoma; Gliosarcoma; Oligodendroglioma; Brainstem Tumors
MeSH terms: Glioblastoma; Astrocytoma; Ependymoma; Gliosarcoma; Oligodendroglioma; Brain Stem Neoplasms
Intervention: imetelstat sodium
Intervention description: Given IV
Intervention MeSH terms: Imetelstat; Motesanib diphosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 12 Months
Maximum age: 21 Years
Healthy volunteers: No

Summary:

      This molecular biology and phase II trial studies how well imetelstat sodium works in
      treating younger patients with recurrent or refractory brain tumors. Imetelstat sodium may
      stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
    

Eligibility criteria:

        INCLUSION CRITERIA:

          -  MOLECULAR BIOLOGY STUDY

               -  Tumor: Histologically confirmed Dx of ependymoma or HGG (such as anaplastic
                  astrocytoma, glioblastoma, gliosarcoma, or anaplastic oligodendroglioma) that is
                  recurrent or refractory to conventional therapy.

               -  Subjects must have clinical indications for surgical resection and be amenable to
                  receiving imetelstat prior to tumor resection. Subjects who require emergent
                  surgery are not eligible for the Molecular Biology study.

               -  Subjects must provide, fresh flash frozen tumor samples (target 50 mg tissue; as
                  low as 20 mg is adequate) from the time of diagnosis or previous recurrence for
                  the assessment of tumor telomerase activity by the TRAP assay.

          -  PHASE II STUDY

               -  Tumor: Subjects must have recurrent or refractory disease with a histological Dx
                  from either the initial presentation or at the time of recurrence. The
                  requirement for histologic verification is waived for subjects with DIPG (stratum
                  D). The following diagnoses are eligible and will be treated in separate strata
                  (B-D): (B) recurrent or refractory high-grade glioma, (such as anaplastic
                  astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic oligodendroglioma);
                  (C) recurrent or refractory ependymoma; (D) recurrent or refractory DIPG
                  (diagnosis by imaging characteristics acceptable; no histologic confirmation
                  required)

               -  Slides from either initial Dx or relapse must be available for central pathology
                  review for Strata B-C. Tissue slides must be sent per Section 10.1. If tissue
                  slides are unavailable, the study chair must be notified prior to study
                  enrollment.

               -  All subjects must have bi-dimensionally measurable disease in the brain and/or
                  spine, defined as at least one lesion that can be accurately measured in at least
                  two planes in order to be eligible for this study. Subjects who are enrolled on
                  the Molecular Biology trial and who have measurable disease after the surgical
                  resection and meet all other eligibility criteria for the Phase II study will be
                  counted towards the accrual of the Phase II study.

          -  FOR BOTH MOLECULAR BIOLOGY AND PHASE II STUDIES

               -  Subjects with neurological deficits should have deficits that are stable for a
                  minimum of 1 week prior to registration; a baseline detailed neurological exam
                  should clearly document the neurological status of the subject at the time of
                  registration on the study

               -  Karnofsky >= 50% for > 16 years of age; Lansky >= 50% for children < 16 years of
                  age documented within 14 days of study registration and within 7 days of the
                  start of study drug administration

               -  Hemoglobin >= 8 g/dL (may receive blood transfusions)

               -  Absolute neutrophil count > 1,000/ul

               -  Platelet count >= 100,000/ul (transfusion independent defined as no platelet
                  transfusions with a 4 week period prior to enrollment)

               -  Serum bilirubin < 2.0 mg/dL (patients with Gilbert syndrome, serum bilirubin <
                  3.0 x upper limit of normal [ULN])

               -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
                  =< 3 x institutional ULN

               -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =<
                  3 x institutional ULN

               -  Alkaline phosphatase < 2.5 x institutional ULN

               -  Albumin >= 2 g/dL

               -  Adequate coagulation defined as activated partial thromboplastin time (aPTT) <
                  1.2 x ULN

               -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
                  ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

          -  Age 1 to < 2 years: maximum serum creatinine (mg/mL) 0.6 for males and 0.6 for females

          -  Age 2 to < 6 years: maximum serum creatinine (mg/mL) 0.8 for males and 0.8 for females

          -  Age 6 to < 10 years: maximum serum creatinine (mg/mL) 1 for males and 1 for females

          -  Age 10 to < 13 years: maximum serum creatinine (mg/mL) 1.2 for males and 1.2 for
             females

          -  Age 13 to < 16 years: maximum serum creatinine (mg/mL) 1.5 for males and 1.4 for
             females

          -  Age >= 16 years: maximum serum creatinine (mg/mL) 1.7 for males and 1.4 for females

          -  The threshold creatinine values were derived from the Schwartz formula for estimating
             GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data
             published by the Centers for Disease and Control (CDC)

               -  Subjects on systemic anticoagulants are excluded from this study as the drug can
                  cause minor, transient changes in aPTT

               -  Female subjects of childbearing potential must not be pregnant or breast-feeding;
                  female subjects of childbearing potential must have a negative serum or urine
                  pregnancy test; (pregnancy test must be repeated within 48 hours prior to the
                  start of therapy)

               -  Subjects of childbearing or child fathering potential must be willing to use a
                  medically acceptable form of birth control, which includes abstinence, while
                  being treated on this study

               -  Subjects must have recovered from the acute toxicities of all prior therapy
                  before entering this study; for those acute baseline adverse events attributable
                  to prior therapy, recovery is defined as a toxicity grade =< 2, using Common
                  Terminology Criteria for Adverse Events (CTCAE) v.4.0, unless otherwise specified
                  in the Inclusion and Exclusion Criteria

               -  Subjects must have received their last dose of known myelosuppressive anticancer
                  chemotherapy at least three (3) weeks prior to study registration or at least six
                  (6) weeks if nitrosourea

               -  Subjects must have received their last dose of investigational or biologic agent
                  >= 7 days prior to study registration; in the event that a subject has received
                  an investigational or biologic agent and has experienced >= grade 2
                  myelosuppression, then at least three (3) weeks must have elapsed prior to
                  registration; if the investigational or biologic agent has a prolonged half-life
                  (>= 7 days) then at least three (3) weeks must have elapsed prior to registration

               -  Subjects must have completed at least 3 half-life periods from the last dose of
                  monoclonal antibody prior to registration; Note: A list of half-lives of commonly
                  used monoclonal antibodies is available on the Pediatric Brain Tumor Consortium
                  (PBTC) website under Generic Forms and Templates

               -  Subjects must have received their last dose of radiation (XRT):

          -  2 weeks prior to study registration for local palliative XRT (small volume)

          -  3 months prior to study registration for craniospinal XRT

          -  6 weeks (wks) prior to study registration for other substantial bone marrow
             irradiation

               -  Subject must be >= 3 months since autologous bone marrow/stem cell
                  transplantation prior to registration

               -  Subjects who are receiving a corticosteroid, such as dexamethasone, must be on a
                  stable or decreasing dosage for at least 1 week prior to registration

               -  At least 7 days since the completion of therapy with a hematopoietic growth agent
                  (filgrastim, sargramostim, and erythropoietin) and 14 days for long-acting
                  formulations

               -  Ability to understand and the willingness to sign a written informed consent
                  document

        EXCLUSION CRITERIA:

          -  Subjects must not be receiving any other investigational agents

          -  Subjects with inability to return for follow-up visits or obtain follow-up studies
             required to assess toxicity to therapy

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to imetelstat

          -  Known coagulopathy or bleeding diathesis

          -  Subjects with imaging evidence of CNS hemorrhage on baseline MRI obtained within 14
             days prior to study enrollment are not eligible; Note: The presence of small punctate
             areas consistent with hemorrhage will not exclude subjects from participation

          -  Use of systemic anticoagulant medications

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             serious infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, cirrhosis or psychiatric illness/social situations that would
             limit compliance with study requirements