Clinical Trial: Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas That Cannot Be Removed by Surgery

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

Official Title: Phase II Trial of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas

Brief Summary: This phase II trial studies how well selumetinib works in treating patients with neurofibromatosis type 1 and plexiform neurofibromas (tumors which arise from the nerves) that cannot be removed by surgery (inoperable). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Summary:

PRIMARY OBJECTIVES:

I. Determine the objective response rate (plexiform neurofibromas [PN] volume decrease >= 20% compared to baseline) to selumetinib in adult patients with neurofibromatosis type 1 (NF1) and inoperable PN.

SECONDARY OBJECTIVES:

I. Correlate 3 dimensional (3D) magnetic resonance imaging (MRI) responses with percent target inhibition (phosphorylated extracellular signal-related kinase [pERK]) in PN biopsies obtained pretreatment and on treatment with selumetinib.

II. Pathology evaluation of tumor changes on treatment with selumetinib. III. Analyze paired biopsies for mechanisms of response and resistance to selumetinib: measurement of phosphorylated v-akt murine thymoma viral oncogene homolog 1 (pAKT), tumor kinome, and tumor transcriptome.

IV. Compare pERK inhibition in dermal neurofibromas and in PN. V. Evaluate immune infiltrate of plexiform neurofibromas, as well as peripheral blood for presence of circulating tumor cells.

VI. Evaluate steady state pharmacokinetics of selumetinib (in blood) and correlate steady state levels with response and pERK inhibition.

VII. Analyze bone marrow derived precursor cells and cytokines from blood samples obtained pretreatment and on treatment with selumetinib.

VIII. Compare volumetric response and target inhibition and pathway activation in PN and nodular lesions.

IX. Establish patient derived xenografts. X. Characterize the effect of selumetinib on pain, quality of life, and physical functioning.

Same as current

Current Secondary Outcome:

• Change in levels of pAKT [ Time Frame: Baseline to up to 30 days ]
  The changes from baseline will be determined and tested for statistical significance using a Wilcoxon signed rank test. The inhibition of AKT will be compared between patients with a tumor response and those without a response using a Wilcoxon rank sum test.
• Change in levels of pERK [ Time Frame: Baseline to up to 30 days ]
  The changes from baseline will be determined and tested for statistical significance using a Wilcoxon signed rank test. The correlation of levels and changes of levels of P-ERK in PNs, dermal tumors, and PBMCs will be determined using Spearman rank correlation. The inhibition of P-ERK will be compared between patients with a tumor response and those without a response using a Wilcoxon rank sum test.
• Change in quality of life [ Time Frame: Baseline to up to 30 days ]
  Changes will be assessed using appropriate paired tests.
• Development of morbidity [ Time Frame: Up to 30 days ]
  The fraction of patients who have improvement, stability or worsening of morbidity will be determined and reported in appropriate categories depending on the initial state of their condition.
• Functional improvement or decrease in pain [ Time Frame: Up to 30 days ]
• Kinome analysis [ Time Frame: Up to 30 days ]
• Tumor transcriptome [ Time Frame: Up to 30 days ]

Original Secondary Outcome:

• Change in levels of pERK [ Time Frame: Baseline to up to 30 days ]
  The changes from baseline will be determined and tested for statistical significance using a Wilcoxon signed rank test. The correlation of levels and changes of levels of P-ERK in PNs, dermal tumors, and PBMCs will be determined using Spearman rank correlation. The inhibition of P-ERK will be compared between patients with a tumor response and those without a response using a Wilcoxon rank sum test.
• Change in levels of pAKT [ Time Frame: Baseline to up to 30 days ]
  The changes from baseline will be determined and tested for statistical significance using a Wilcoxon signed rank test. The inhibition of AKT will be compared between patients with a tumor response and those without a response using a Wilcoxon rank sum test.
• Tumor transcriptome [ Time Frame: Up to 30 days ]
• Kinome analysis [ Time Frame: Up to 30 days ]
• Development of morbidity [ Time Frame: Up to 30 days ]
  The fraction of patients who have improvement, stability or worsening of morbidity will be determined and reported in appropriate categories depending on the initial state of their condition.
• Change in quality of life [ Time Frame: Baseline to up to 30 days ]
  Changes will be assessed using appropriate paired tests.
• Functional improvement or decrease in pain [ Time Frame: Up to 30 days ]

Dates:
Date Received: April 2, 2015
Date Started: December 2015
Date Completion:
Last Updated: December 30, 2016
Last Verified: December 2016