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Imetelstat

Motesanib diphosphate

Enzyme Inhibitors

Protein Kinase Inhibitors

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.

imetelstat sodium

Maryam Fouladi

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.

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

A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma and Diffuse Intrinsic Pontine Glioma

Other PBTC investigators can develop a concept proposal and submit it to the PBTC Scientific Committee for a decision to share data and to what extent to share it.

This outcome measure is for the Molecular biology study only. The assessment was done to identify cases with at least 50% reduction in telomerase activity.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR sustained for at least 6 weeks.

For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions.

This outcome measure is applicable only for the Molecular biology study arm. Telomerase inhibition was assessed in PBMCs and summarised as 'yes-inhibited' vs. 'no inhibition'

Kaplan-Meier estimates of distributions of survival and PFS for all eligible subjects who received at least one dose of imetelstat will be provided separately.

This secondary objective is for Stratum-B and C only, which enroll HGG and ependymoma patients. We will describe the evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR and telomerase activity by TRAP in archival tumor tissue; Association of telomerase positivity with objective response and PFS will not be able to be conducted as the study was terminated early and there was no objective response.

This outcome measure was for both Molecular biology and Phase II studies. We will not be able to present the results of this objective as the study was terminated early.

National Cancer Institute (NCI)

Pediatric Brain Tumor Consortium

The AEs we report were experienced while the participants were on study.

Molecular Study arm for Recurrent or Refractory Medulloblastoma/PNET Patients

Molecular Study-A

Molecular Study arm for Recurrent or refractory high-grade glioma patients

Molecular Study-B

This is the Phase-II stratum for Recurrent or Refractory Medulloblastoma/PNET Patients

Stratum-A

This is the Phase-II stratum for Recurrent or refractory high-grade glioma patients

Stratum-B

This is the Phase-II stratum for Recurrent or refractory ependymoma patients

Stratum-C

This is the Phase-II stratum for Recurrent or refractory diffuse intrinsic pontine gliomas (DIPG) patients

Stratum-D

This is the Molecular Biology arm for Medulloblastoma/PNET Patients

Molecular Biology Stratum-A

This is the Molecular Biology arm for High-Grade Glioma Patients

Molecular Biology Stratum-B

Total

Age, Continuous

Sex: Female, Male

Dr. Mehmet Kocak

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.

imetelstat sodium: Given IV

Molecular Biology Study

This outcome measure is only for the molecular biology study. Telomerase inhibition was assessed and the inhibition level was compared with the baseline level to identify increased inhibition.

Numver of Patients With Telomerase-positive Archival Tumors Who Demonstrate at Least 50% Reduction

This is the Phase-II stratum for Recurrent or refractory diffuse intrinsic pontine glioma patients

This is the Phase-II study cohort, excluding the molecular study patients.

Phase II: Stratum-specific Objective Response (CR+PR) Rate

Samples from six patients were consequently considered evaluable and were analyzed.

Number of Participants With Telomerase Inhibition

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Stratum-specific Progression-free Survival (PFS) (Phase II)

TRAP

TERT

TERC

This objective is for HGG and ependymoma patients only.

This objective is for STRATUM-C patients only, having only 4 patients with TRAP, TERT and TERC levels measured. Due to small sample and having no objective response, association studies of these markers with Objective Reponse and PFS were not possible. Therefore, we only report the the percentage of cases with at least weak TRAP activity.

Number of Patients With Telomerase Expression Data by Detection of hTERT mRNA and TERC RNA Levels by qRT-PCR and Telomerase Activity by TRAP in Archival Tumor Tissue and to Explore Association of Telomerase Positivity With Objective Response and PFS

Treatment (Imetelstat Sodium)

This study has been terminated early and the study team decided not to pursue this aim as the results would be inconclusive due to small sample size. Neither the neuroimaging, nor the biology data are available for these patients.

Quantitative MRI Parameters of Tumors Prior to and After Treatment With Imetelstat (Molecular Biology and Phase II Studies)

This is the Molecular Biology arm for Ependymoma Patients

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors	NCT01836549	Anaplastic Astr... Anaplastic Epen... Astrocytoma, Gr... Ependymoma Giant Cell Glio... Glioblastoma Gliosarcoma Oligodendroglio... Brainstem Tumor...	imetelstat sodi...	12 Months - 21 Years	Pediatric Brain Tumor Consortium
Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors	NCT01836549	Anaplastic Astr... Anaplastic Epen... Astrocytoma, Gr... Ependymoma Giant Cell Glio... Glioblastoma Gliosarcoma Oligodendroglio... Brainstem Tumor...	imetelstat sodi...	12 Months - 21 Years	Pediatric Brain Tumor Consortium

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