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Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma

2014-08-27 03:15:09 | BioPortfolio

Summary

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating young patients with recurrent or refractory low grade glioma. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) or recommend a Phase II dose of AZD6244 (selumetinib) in children with recurrent or refractory low-grade glioma (phase I completed as of April 29, 2013). (Phase I) II. To describe the toxicity profile and define the dose limiting toxicity of AZD6244 in children with recurrent or refractory low-grade glioma (phase I completed as of April 29, 2013). (Phase I) III. To study the safety of the maximum tolerated dose (MTD) or recommended a Phase II dose (RP2D) of AZD6244 as determined based on safety data from children >= 12 years of age in children < 12 years of age. If the MTD/RP2D of the older children is too toxic for the younger children, we will de-escalate to one dose level below and study the safety of that dose in the younger age cohort (phase I completed as of April 29, 2013). (Phase I) IV. To assess the sustained response rate of AZD6244 administered at 25 mg/m^2/dose twice daily (BID), in patients assigned to strata based on NF-1 status and presence or absence of BRAF aberrations, specifically BRAF V600E mutations and/or BRAF KIAA1549 fusion identified by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. (Phase II)

SECONDARY OBJECTIVES:

I. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics administered on this schedule and to assess the influence of patient specific covariates (including concomitant drug therapy) on AZD6244 pharmacokinetics (phase I completed as of April 29, 2013). (Phase I) II. To evaluate the feasibility of collecting pre-trial tumor samples and the feasibility of using in situ hybridization assay to identify BRAF aberrations in available tumor specimens (phase I completed as of April 29, 2013). (Phase I) III. To determine if pre-trial tumor samples show the biochemical signature that indicates activation of the MAPK pathway (phase I completed as of April 29, 2013). (Phase I) IV. To describe magnetic resonance imaging (MRI) characteristics of the tumors before and after treatment and to explore the diffusion changes in the tumors before and after treatment to determine if there is an early diffusion indicator of response (phase I completed as of April 29, 2013). (Phase I) V. Within the constraints of a Phase I trial, to document antitumor activity of treatment with AZD6244, as measured by objective responses and progression-free survival (PFS) (phase I completed as of April 29, 2013). (Phase I) VI. To explore the pharmacogenetic polymorphisms in AZD6244 metabolizing enzymes and transporters and relate these polymorphisms to AZD6244 pharmacokinetics (phase I completed as of April 29, 2013). (Phase I) VII. To estimate the PFS distributions associated with AZD6244 treatment separately in patients assigned to the four strata and for strata 1, 3 and 4 combined. (Phase II) VIII. To explore correlations between BRAF aberrations and treatment response and PFS in patients for whom relevant biology data is available. (Phase II) IX. To assess mitogen-activated protein kinases (MAPK) aberrations by a combination of whole-exome and ribonucleic acid (RNA) sequencing. (Phase II) X. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics administered on this schedule at the MTD/RP2D. (Phase II)

OUTLINE: This is a phase I dose-escalation study (completed as of April 29, 2013) followed by a phase II study.

Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Childhood Low-grade Cerebellar Astrocytoma

Intervention

selumetinib, laboratory biomarker analysis, pharmacological study, pharmacogenomic studies

Location

Children's Hospital Los Angeles
Los Angeles
California
United States
90027

Status

Recruiting

Source

National Cancer Institute (NCI)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:15:09-0400

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