Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas That Cannot Be Removed by Surgery
|Neurofibromatosis Type 1 Plexiform Neurofibroma||Other: Laboratory Biomarker Analysis Other: Pharmacological Study Other: Quality-of-Life Assessment Drug: Selumetinib||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|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|
- Objective response rate (PN volume decrease >= 20% compared to baseline) [ Time Frame: Up to 30 days ]
- 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 ]
|Study Start Date:||December 2015|
|Estimated Primary Completion Date:||June 2019 (Final data collection date for primary outcome measure)|
Experimental: Treatment (selumetinib)
Patients receive selumetinib PO BID (approximately every 12 hours) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studiesOther: Pharmacological Study
Correlative studiesOther: Quality-of-Life Assessment
Other Name: Quality of Life AssessmentDrug: Selumetinib
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.
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.
XI. Determine baseline functional impairments secondary to PN, and the effect of selumetinib on functional outcomes depending on PN location.
XII. Determine the effect of selumetinib on the PN growth rate based on volumetric analysis of MRI studies obtained prior to enrollment (if available and amenable to volumetric analysis).
XIII. Determine time to progression (TTP) and progression free survival (PFS) in progressive PN (>= 20% increase in PN volume within 12-15 months prior to enrollment).
XIV. Evaluate change in dermal neurofibroma burden using digital photography.
Patients receive selumetinib orally (PO) twice daily (BID) (approximately every 12 hours) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02407405
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: Brigitte C. Widemann 301-496-7387 email@example.com|
|Principal Investigator: Brigitte C. Widemann|
|Principal Investigator:||Brigitte Widemann||National Cancer Institute Pediatric Oncology Branch|