Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma

NCT02839720 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: NCI-2016-010879990P30CA013148
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

Brief Summary

This pilot phase II trial studies how well selumetinib works in treating patients with neurofibromatosis type 1 and cutaneous neurofibromas. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

Cutaneous Neurofibroma; Neurofibromatosis Type 1; Optic Nerve Glioma

Outcome Measures

Primary Outcomes (1)

• Median Best Response of Cutaneous Neurofibromas in Participants With at Least One Restaging Evaluation

  Average percent change in volume of target cutaneous neurofibromas from baseline. Cutaneous neurofibromas measured with calipers and volumes calculated by multiplying length, width and height of each target neurofibroma. At each response evaluation (baseline and then after every 4 cycles), the sum of the on-treatment volumes for the target cutaneous neurofibromas were subtracted from the pre-treatment volumes of the same tumors to arrive at an overall percentage change in target cutaneous neurofibroma size for each participant at each restaging evaluation. The average percent change that was most decreased from baseline (best response) for each participant was collected and the timepoint at which this occurred was noted. The median and range of these average percent change best responses are reported here.

  Up to 24 cycles of treatment (1 cycle = 28 days)

Secondary Outcomes (1)

• Change in the Number of Cutaneous Neurofibromas

  Baseline to up to 1 year

Other Outcomes (3)

• Changes in Skin Related Morbidity

  Baseline to up to 1 year

• Changes in Pathway Biomarkers Assessed by Kinome Analysis

  Baseline to up to 1 year

• Changes in Levels of pERK and pAKT Assessed by Quantitative Enzyme-linked Immunosorbent Assay

  Baseline to up to 1 year

Study Arms (1)

Treatment (selumetinib sulfate)

EXPERIMENTAL

Patients receive selumetinib sulfate PO twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience a volume decrease in the target cutaneous neurofibromas may continue treatment for 12 additional cycles.

Other: Laboratory Biomarker Analysis; Drug: Selumetinib Sulfate

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (selumetinib sulfate)

Selumetinib Sulfate DRUG

Given PO

Also known as: AZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Koselugo, Selumetinib Sulphate

Treatment (selumetinib sulfate)

Eligibility Criteria

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

You may qualify if:

• Patients be \>= 18 years old at the time of enrollment and must have a documented germline neurofibromatosis 1 (NF1) mutation in a Clinical Laboratory Improvement Act (CLIA) certified laboratory or a diagnosis of NF1 based on clinical National Institutes of Health (NIH) consensus criteria; in addition to substantial cutaneous neurofibroma burden, at least one of the criteria below have to be present
• Six or more cafe-au-lait macules (\>= 0.5 cm 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
• Histologic confirmation of tumor is not necessary in the presence of consistent clinical findings
• Patients must have substantial cutaneous neurofibroma burden causing distress to the patient by disfigurement or itching; patients must have \>= 9 measurable cutaneous neurofibromas; for the purpose of this study measurability will be defined for each of the lesions selected as target lesions as a neurofibroma with a longest diameter \>= 4 mm in the longest diameter
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
• Hemoglobin \>= 10 g/dL (not requiring red blood cell \[RBC\] transfusions)
• Absolute neutrophil count \>= 1,500/mcL
• Platelets \>= 100,000/mcL (not requiring platelet transfusions)
• Total bilirubin =\< 1.5 X upper limit of normal (ULN), with the exception of patients with Gilbert syndrome who are required to have =\< 3 X ULN
• Alanine transferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 X ULN

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, radiation, 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 cluster of differentiation (CD)4 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
• No supplementation with vitamin E is permitted
• Inability to swallow capsules, since capsules cannot be crushed or broken
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
• Strong inhibitors or inducers of hepatic microsomal isoenzymes
• Known cardiac disorder, including:
• Uncontrolled hypertension (blood pressure \[BP\] of \>= 150/95 despite medical support/management)
• Acute coronary syndrome within 6 months prior to starting treatment
• Uncontrolled angina - Canadian Cardiovascular Society grade II-IV despite medical support/management
• Heart failure New York Heart Association (NYHA) class II or above
• Prior or current cardiomyopathy including but not limited to the following:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, 35233, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (2)

• Gross AM, Reid OH, Baldwin LA, Cannon A, Choo-Wosoba H, Steinberg SM, Lobbous M, Wolters PL, Pichard DC, Tibery CM, Dombi E, Derdak J, Widemann BC, Korf BR. Treatment of Cutaneous Neurofibromas in Neurofibromatosis Type 1 With MEK Inhibitor Selumetinib: A Nonrandomized Clinical Trial. JAMA Dermatol. 2025 Feb 26;161(5):533-7. doi: 10.1001/jamadermatol.2024.6574. Online ahead of print.

  PMID: 40009403 DERIVED

• Church C, Fay CX, Kriukov E, Liu H, Cannon A, Baldwin LA, Crossman DK, Korf B, Wallace MR, Gross AM, Widemann BC, Kesterson RA, Baranov P, Wallis D. snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response. Acta Neuropathol Commun. 2024 Jun 21;12(1):102. doi: 10.1186/s40478-024-01821-z.

  PMID: 38907342 DERIVED

MeSH Terms

Conditions

Neurofibromatosis 1; Optic Nerve Glioma

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; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Optic Nerve Neoplasms; Cranial Nerve Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Peripheral Nervous System Neoplasms; Cranial Nerve Diseases; Optic Nerve Diseases; Eye Diseases

Limitations and Caveats

Study was terminated early by CTEP due to low accrual but allowed participants who were already on study to continue to receive treatment if they were responding or had stable disease. Low accrual was exacerbated by the COVID-19 pandemic leading to a small number of subjects analyzed and with many subjects having missing data or evaluations due to an inability to travel to the study site. Due to the limited data set, we are only able to provide descriptive analyses of results.

Results Point of Contact

• Title: Bruce R. Korf, MD, PhD
• Organization: UAB Heersink School of Medicine

bkorf@uabmc.edu

205-996-9487

Study Officials

• Bruce R Korf

  University of Alabama at Birmingham Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

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: July 20, 2016
• First Posted: July 21, 2016
• Study Start: August 26, 2017
• Primary Completion: November 5, 2022
• Study Completion: August 31, 2023
• Last Updated: December 6, 2023
• Results First Posted: December 5, 2023

Record last verified: 2023-12

Locations

US (2)