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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

Brief Summary: This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Summary:

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) 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) 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) IV. To assess the sustained response rate of AZD6244 administered at 25 mg/m^2/dose twice daily (BID), in a single arm Phase II setting in patients assigned to strata based on neurofibromatosis (NF)-1 status and presence or absence of v-raf murine sarcoma viral oncogene homolog B (BRAF) aberrations, specifically BRAF V600E mutations and/or BRAF KIAA1549 fusion identified by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. (Phase II) V. To estimate the sustained response rate and prolonged disease stabilization rate (defined as lack of disease progression for >= 12 courses) associated with AZD6244 in patients with recurrent and/or progressive low-grade gliomas who previously received treatment on PBTC-029 or PBTC-029B for a minimum of 12 courses, with at least stable disease or patients who had a sustained response but remained on treatment < 12 courses. (Re-treatment Study)

SECONDARY OBJECTIVES:

I. To characterize the inter- and intra-patient variability in AZ
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

• Disease stabilization rates (re-treatment study) [ Time Frame: At 1 year ]
• Maximum tolerated dose and recommended phase 2 dose of selumetinib determined by dose-limiting toxicities (phase I) [ Time Frame: 28 days ]
  Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
• Objective response (OR=CR+PR) (re-treatment study) [ Time Frame: Up to 48 weeks ]
  Exact confidence interval estimates will be provided.
• Stratum-specific objective response (CR+PR) rate sustained for 8 weeks (phase II) [ Time Frame: 40 weeks ]
  For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. In addition, the confirmed sustained objective response rate observed during treatment by cumulative incidence functions will be estimated. This provides not only an overall estimate of the response rate but also an estimate of the timing of responses as a function of number of months of treatment.

Original Primary Outcome:

• Maximum-tolerated dose or recommended phase II dose of AZD6244
• Toxicity profile

Current Secondary Outcome:

• PFS (retreatment study) [ Time Frame: From the date of re-treatment initiation to the earliest date of disease progression, second malignancy or death for patients who fail; and the last contact for patients who remain at risk for failure, assessed up to 30 days ]
  Kaplan-Meier estimates of PFS distributions for all eligible patients will be provided. Exact confidence interval estimates will be provided.
• Plasma drug concentrations and pharmacokinetic parameters volume of the central compartment , elimination rate constant, half-life, apparent oral clearance, and area under the plasma concentration time curve (phase I) [ Time Frame: Day 1 of course 1 ]
• Presence or absence of BRAF V600E mutations or BRAF KIAA1549 fusion as assessed by IHC and FISH, respectively (phase II) [ Time Frame: Up to 30 days ]
  Frequency tables summarizing the presence and absence of BRAF aberrations in all patients from whom tissue is available will be provided. The association of presence/absence and type of BRAF aberrations vs. PFS will be explored via Kaplan-Meier-plots. Log-rank tests and/or Cox regression models may also be used to assess statistical associations between BRAF and PFS provided more than 10 events are observed in a given strata to make such assessments meaningful.
• Stratum-specific progression-free survival distribution (PFS) (phase II) [ Time Frame: From the date of initial treatment to the earliest date of disease progression, second malignancy or death for subjects who fail; and to the date of last contact for subjects who remain at risk for failure assessed for up to 30 days ]
  Kaplan-Meier estimates of distributions of PFS for all eligible subjects who received at least one dose of selumetinib will be provided separately for each stratum. It is unlikely that sufficient numbers of subjects will be followed until death to statistically support estimation of the survival distributions but survival estimation will also be considered.

Original Secondary Outcome:

• Objective response
• Progression-free survival
• Inter- and intra-patient variability of AZD6244 pharmacokinetics

Dates:
Date Received: March 17, 2010
Date Started: April 2010
Date Completion:
Last Updated: May 18, 2017
Last Verified: May 2017