MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas

NCT02407405 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: 16004316-C-0043
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Neurofibromatosis type 1 (NF1) is a disorder that can cause plexiform neurofibromas (PNs). These are tumors that grow along nerves. Some PNs cause serious health problems. PNs often can t be operated on because of their large size, location, or number. There are no effective treatments known for people with NF1 and PNs. Researchers want to test if the drug selumetinib (AZD6244 hydrogen sulfate) causes PNs to shrink or slows down their growth. Objectives: To test if selumetinib helps treat PNs. To test how the body handles selumetinib and how it affects peoples symptoms. Eligibility: People ages 18 and older with NF1, with an inoperable PN that causes morbidity or is growing Design: Participants will be screened with: Medical history and physical exam Blood, urine, and heart tests Eye exam MRI: They lie in a machine that takes pictures of the body. PN biopsy: A small piece of the tumor is removed by a large needle. Questionnaires Participants will swallow selumetinib capsules every 12 hours for several 28-day cycles. The capsules are taken with a full glass of water on an empty stomach. Participants may have only water for 2 hours before and 1 hour after each dose. Participants will keep a drug diary. They will continue taking the drug as long as they tolerate it and their disease doesn t progress. Participants will have several visits throughout the study. These will include repeats of the screening tests. Participants will have a final visit after they stop taking selumetinib.

Conditions

Neurofibromatosis 1 (NF1); Plexiform Neurofibromas (PN)

Keywords

Objective Response; pERK inhibition; MEK Inhibition; Biopsy; Volumetric MRI

Outcome Measures

Primary Outcomes (1)

• Determine objective response rate

  Efficacy

  at each response evaluation visit

Secondary Outcomes (8)

• Evaluate immune infiltrate of PN and Peripheral blood for circulating tumor cells

  Prior to cycle 2 or 3, at time of progression and/or prior to cycle 2 or 3 after dose reduction

• evalaute change in dermal neurofibroma by photography.

  Prior to cycle 5, 9, 13, 17, 21, 25 Then after every 12 cycles

• determine time to progression and progression free survival

  at time of progression

• correlate 3D MRI responses with % target inhibition of pERK in PN biopsies

  rior to cycle 5, 9, 13, 17, 21, 25 Then after every 6 cycles

• compare pERK inhibition in dermal neurofibromas and PN

  Prior to cycle 2 or 3, at time of progression and/or prior to cycle 2 or 3 after dose reduction

Study Arms (1)

1

EXPERIMENTAL

Selumetinib 50 mg BID daily

Drug: Selumetinib

Interventions

Selumetinib DRUG

orally 50 mg/dose, every 12 hours every day continuously (1 cycle = 28 days)

1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have positive genetic testing for NF1 in a CLIA certified laboratory or a diagnosis of NF1 based on clinical NIH consensus criteria of at least one other diagnostic criterion in addition to the presence of a PN. NF1 mutation analysis will be performed on germline DNA. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and imaging findings, but should be considered if malignant transformation of a PN is clinically suspected. Additional criteria are as follows:
• Six or more cafe-au-lait macules (\>=0.5cm in prepubertal subjects or \>=1.5 cm in post pubertal subjects)
• Freckling in axilla or groin
• Optic glioma
• Two or more Lisch nodules
• A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
• A first-degree relative with NF1
• Measurable disease: Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable as per criteria above. Measurability and suitability for volumetric MRI analysis of the target PN must be confirmed with the NCI POB prior to enrolling a patient. The target PN will be defined as the clinically most relevant PN, which has to be amenable to volumetric MRI analysis. PN will be classified as typical PN versus nodular PN versus solitary nodular PN prior to enrollment
• The PN must be inoperable, defined as a PN that cannot be surgically completely removed without risk for substantial morbidity due to: encasement of or close proximity to vital structures, invasiveness, or high vascularity of the PN. The PN either causes morbidity or it is growing and has the potential to cause morbidity such as (but not limited to): Head and neck lesions that could compromise the airway or great vessels, paraspinal lesions that can cause myelopathy, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or are significantly disfiguring, and lesions of the extremity that cause limb hypertrophy or loss of function or pain. PN growth will be defined as a \>=20% increase in PN volume within approximately 3 years prior to enrollment on this trial.
• Patients must have a PN amenable to a percutaneous biopsy to participate in the biopsy portion of this study, and must be willing to undergo pre-, and on treatment tumor biopsies. There should be no contraindication for serial biopsies. NOTE: Up to 10 patients who meet all criteria, but have PN which cannot be biopsied safely, will be eligible for the treatment portion of the study.
• Must be able to undergo serial MRI scans for response evaluation
• Age \>=18 years
• ECOG performance status \<=2 (Patients who are wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be considered ambulatory when they are up in their wheelchair. Similarly, patients with limited mobility secondary to need for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be considered ambulatory for the purpose of the study.)
• ECOG Performance Status:\*
• Grade/ECOG

You may not qualify if:

• Patients who are receiving any other investigational agents, or have received an investigational agent within the past 30 days.
• May not have a NF1 related tumor such as optic pathway glioma or malignant peripheral nerve sheath tumor, which requires treatment with chemotherapy or surgery.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements. Patients with HIV who have adequate CD4 counts and who have no requirement for antiviral therapy will be eligible.
• Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic adverse events of an investigational agent. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
• Prior treatment with selumetinib or another specific MEK 1/2 inhibitor.
• Supplementation with vitamin E greater than 100% of the daily recommended dose.
• Inability to swallow capsules, since capsules cannot be crushed or broken.
• Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
• Uncontrolled hypertension (despite medical therapy); blood pressure should be \<140/90 in accordance with American Heart Association definition of hypertension.
• Known Cardiac Disorder, including:
• Known inherited coronary disease
• Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease)
• Current cardiomyopathy
• Severe valvular heart disease

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Gross AM, O'Sullivan Coyne G, Dombi E, Tibery C, Herrick WG, Martin S, Angus SP, Shern JF, Rhodes SD, Foster JC, Rubinstein LV, Baldwin A, Davis C, Dixon SAH, Fagan M, Ong MJ, Wolters PL, Tamula MA, Reid O, Sankaran H, Fang F, Govindharajulu JP, Browne AT, Kaplan RN, Heisey K, On TJ, Xuei X, Zhang X, Johnson BC, Parchment RE, Clapp DW, Srivastava AK, Doroshow JH, Chen AP, Widemann BC. Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial. Nat Med. 2025 Jan;31(1):105-115. doi: 10.1038/s41591-024-03361-4. Epub 2025 Jan 6.

  PMID: 39762421 DERIVED

• Curry BP, Alvarez R, Widemann BC, Johnson M, Agarwal PK, Lehky T, Valera V, Chittiboina P. Robotic Nerve Sheath Tumor Resection With Intraoperative Neuromonitoring: Case Series and Systematic Review. Oper Neurosurg. 2022 Feb 1;22(2):44-50. doi: 10.1227/ONS.0000000000000051.

  PMID: 35007270 DERIVED

• Herrick WG, Kilpatrick CL, Hollingshead MG, Esposito D, O'Sullivan Coyne G, Gross AM, Johnson BC, Chen AP, Widemann BC, Doroshow JH, Parchment RE, Srivastava AK. Isoform- and Phosphorylation-specific Multiplexed Quantitative Pharmacodynamics of Drugs Targeting PI3K and MAPK Signaling in Xenograft Models and Clinical Biopsies. Mol Cancer Ther. 2021 Apr;20(4):749-760. doi: 10.1158/1535-7163.MCT-20-0566. Epub 2021 Feb 3.

  PMID: 33536190 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms

Study Officials

• Brigitte C Widemann, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 2, 2015
• First Posted: April 3, 2015
• Study Start: January 7, 2016
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2030
• Last Updated: March 5, 2026

Record last verified: 2026-03-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. Requests for all collected IPD data from clinical trials, conducted under a binding collaborative agreement between NCI/DCTD and a pharmaceutical/biotechnology company, that are not under DSMB monitoring must be in compliance with the terms of the binding collaborative agreement and must be approved by NCI/DCTD and the Pharmaceutical Collaborator (i.e., the NCI ETCTN Director in conjunction with the NCI/DCTD Regulatory Affairs Branch).

Locations

US (1)