Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors

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.

PRIMARY OBJECTIVES:

\* Molecular Biology:

I. To test the ability of imetelstat (GRN163L) to inhibit telomerase activity by Telomere Repeat Amplification Protocol (TRAP) in tumor and peripheral blood mononuclear cells (PBMNCs) of children with recurrent or refractory HGG or ependymoma.

II. To characterize the pharmacokinetics of imetelstat in plasma, cerebrospinal fluid (CSF), and tumor tissue of children with recurrent or refractory HGG or ependymoma.

\* Phase II:

I. To estimate the sustained objective response rates (complete response (CR) plus partial response (PR), sustained for at least 6 weeks) to imetelstat administered intravenously on Days 1 and 8 of a 21-day course at the recommended Phase II pediatric dose, 285mg/m2, in children with recurrent or refractory HGG, ependymoma or DIPG. Independent estimates of the objective response rates will be made for each of the three strata, two of which are histologically defined.

SECONDARY OBJECTIVES:

\* Phase II only:

I. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and telomerase activity by TRAP in archival tumor tissue (for HGG, and ependymoma strata) and to explore association of telomerase positivity with objective response and progression-free survival (PFS).

II. To estimate the stratum-specific PFS distributions of children with recurrent or refractory HGG, ependymoma or DIPG treated with imetelstat.

\* Molecular Biology and Phase II:

I. To characterize the plasma and CSF pharmacokinetics of imetelstat in children with recurrent or refractory HGG, ependymoma or DIPG.

II. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR, telomerase activity by TRAP, and telomere length by telomere terminal restriction fragment (TRF) analysis in PBMNCs prior to treatment with imetelstat and to assess evidence of telomerase inhibition by TRAP and telomere shortening by TRF analysis serially on treatment with imetelstat.

III. To compare incidence of Alternative Lengthening of Telomeres (ALT) mechanism in pediatric HGG, or ependymoma as determined by four different assays 1) ATRX/DAXX nuclear localization by immunofluorescence (IF) assay; 2) telomere-specific signal by fluorescence in situ hybridization (FISH); 3) telomeric terminal restriction fragment (TRF) analysis by Southern blot; and 4) by C circle assay and to assess correlation of these methods for ALT detection.

IV. To assess whether ALT status is associated with objective response rates for children with recurrent or refractory HGG, or ependymoma treated with imetelstat.

V. To describe MRI characteristics and diffusion changes of recurrent or refractory HGG, ependymoma and DIPG tumors prior to and after treatment with imetelstat to assess for an early diffusion indicator of response.

VI. To measure telomere length of tumors in children with recurrent or refractory HGG, or ependymoma and to assess association of tumor length with tumor response to imetelstat treatment.

VII. To assess hTERT promoter mutations and methylation, H3F3A, ATRX, and DAXX mutations, and examine the effects of these modifications in children with recurrent brain tumors using targeted gene, exome, RNA sequencing and methylation arrays of targeted genomic regions.

OUTLINE:

Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery. Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue to receive therapy on the same schedule as the Phase II patients starting 14-21 days after surgery.

Phase II: Patients receive imetelstat sodium IV over 2 hours on days 1 and 8. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

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