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Cutaneous NeurofibromaPhase 2NCT02839720

Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma

A Phase 2 study testing Laboratory Biomarker Analysis and Selumetinib Sulfate in people with Cutaneous Neurofibroma and Neurofibromatosis Type 1, run by National Cancer Institute (NCI) at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis and Selumetinib Sulfate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
2 sitesUnited States
Study dates
26 Aug 2017to 31 Aug 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Ability of subject or legally authorized representative (LAR) to understand and the willingness to sign a written informed consent document
  • Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated
  • Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products containing these fruits, e.g. grapefruit juice or marmalade) during the study
  • Since there is no standard effective chemotherapy for patients with NF1 and cutaneous neurofibromas, patients may be treated on this trial without having received prior medical therapy directed at their plexiform neurofibromas (PN)
  • Since selumetinib is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimens previously received for NF1 related; or other tumor manifestations
  • Patients who have received previous investigational agents or biologic therapy, such as tipifarnib, pirfenidone, Peg-intron, sorafenib, or other vascular endothelial growth factor (VEGFR) inhibitors are eligible for enrollment
  • Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days and are not permitted while on the study
  • At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy, and the target cutaneous neurofibromas have to be in areas outside of a prior radiation field
  • At least 4 weeks must have elapsed since receiving medical therapy directed at NF1 related tumor manifestations
  • At least 4 weeks must have elapsed since any surgeries, with evidence of completed wound healing
  • Patients who received prior medical therapy for a NF1 related tumor must have recovered from the acute toxic effects of all prior therapy to =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 before entering this study
  • The effects of selumetinib on the developing human fetus at the recommended therapeutic dose are unknown; for this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 weeks after dosing with selumetinib ceases; women of child-bearing potential must have a negative pregnancy test prior to entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform her treating physician immediately; please note that the selumetinib manufacturer recommends that adequate contraception for male patients should be used for 12 weeks post-last dose due to sperm life cycle
  • Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients, which can be accomplished using the study specific informed consent or another consent, such as the National Cancer Institute (NCI), Pediatric Oncology Branch (POB) screening protocol; studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for screening or baseline values even if the studies were done before informed consent was obtained, if the patient agrees

Who cannot join

  • 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
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  • 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
  • While not an exclusion criterion, unless clinically indicated, patients should avoid taking other additional non-study medications that may interfere with the study medications; in particular, patients should avoid medications that are known to strong inhibitor or inducers of hepatic microsomal isoenzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4/5, UGT1A1, UGT1A3 and transporters BCRP and P-gp
  • 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:
  • Known hypertrophic cardiomyopathy
  • Known arrhythmogenic right ventricular cardiomyopathy
  • Baseline left ventricular ejection fraction (LVEF) =< 53%
  • Previous moderate or severe impairment of left ventricular systolic function (LVEF < 40% on echocardiography or equivalent on multi-gated acquisition scan [MUGA]) even if full recovery has occurred
  • Severe valvular heart disease
  • Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on electrocardiography (ECG) at rest
  • Fridericia's correction formula (QTcF) interval > 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) are excluded; the use of medication(s) that can prolong corrected QT (QTc) interval is prohibited while treated on this study
  • Known ophthalmologic conditions, such as:
  • Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR)
  • Current or past history of retinal vein occlusion
  • Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) may be eligible after discussion with the study chair
  • Subjects with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed with the study chair for potential eligibility
  • Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
  • Known severe hypersensitivity to selumetinib or any excipient of selumetinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib
  • Have had recent major surgery within a minimum of 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access
  • Have any unresolved chronic toxicity with CTCAE grade >= 2, from previous anti-NF1 therapy, except for alopecia
  • Clinical judgment by the investigator that the patient should not participate in the study

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

  • University of Alabama at Birmingham Cancer Center

    Birmingham, Alabama, 35233

Other trials in United States

About this study

Official title: Pilot Study of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) for Adults With Neurofibromatosis Type 1 (NF1) and Cutaneous Neurofibromas (CNF)

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. Determine if selumetinib sulfate (selumetinib) can result in shrinkage of cutaneous neurofibromas.

SECONDARY OBJECTIVE:

  1. Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior treatment and on treatment with selumetinib for analysis of percent inhibition of phosphorylated ERK (pERK), and changes in phosphorylated AKT (pAKT).

EXPLORATORY OBJECTIVES:

  1. Assess the effect of selumetinib on the development on new cutaneous neurofibromas while on treatment with selumetinib.

II. Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior treatment and on treatment with selumetinib for analysis of the tumor kinome.

III. Assess the effect of selumetinib skin related morbidity and pain using the Skindex, the Global Impression of Change Scale and Numeric Rating Scale, all of which are patient reported outcome measures.

IV. Quantify the development of new cutaneous neurofibromas on treatment with selumetinib.

  1. Detailed pathologic analysis of cutaneous neurofibromas pretreatment and on treatment with selumetinib for changes in cell composition (including macrophage and mast cell infiltration).

VI. Investigate alterations that correlate with cutaneous neurofibroma (cNF) response to selumetinib treatment with pilot genomic, deoxyribonucleic acid (DNA) methylation, and transcriptomic studies.

OUTLINE:

Patients receive selumetinib sulfate orally (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.

After completion of study treatment, patients are followed up every 4 months for 1 year.

Being tested
Laboratory Biomarker Analysis, Selumetinib Sulfate
Medical subject headings
Neurofibromatosis 1, Optic Nerve Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Selumetinib SulfateDrug

    Also called AZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Koselugo

    Given PO

Study groups in NCT02839720
Study groupRoleWhat they receive
Treatment (selumetinib sulfate)ExperimentalPatients 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.
Receives: Other: Laboratory Biomarker Analysis; Drug: Selumetinib Sulfate

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (1)

  1. Change in the Number of Cutaneous Neurofibromas

    At the time of each response evaluation (baseline and then after every 4 cycles), the number of cutaneous neurofibromas (cNFs) that are greater than 4mm as measured with a caliper were counted in the picture frames. We report here the change in overall number of cutaneous neurofibromas counted after 12 cycles of treatment (Number of cNFs counted after 12 cycles - Number of cNFs counted at baseline).

    Measured: Baseline to up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jul 2016 (estimated)
  2. Study start26 Aug 2017
  3. Primary completion5 Nov 2022
  4. Study completion31 Aug 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02839720
Sponsor's protocol ID
NCI-2016-01087
Other IDs
NCI-2016-01087, 9990, 9990, P30CA013148
Status last verified
Dec 2023
First submitted
20 Jul 2016
Last updated
6 Dec 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 40009403

  • 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.

    PubMed 38907342

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Laboratory Biomarker Analysis and Selumetinib Sulfate in people with Cutaneous Neurofibroma and Neurofibromatosis Type 1, run by National Cancer Institute (NCI) at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Median Best Response of Cutaneous Neurofibromas in Participants With at Least One Restaging Evaluation (time frame: Up to 24 cycles of treatment (1 cycle = 28 days)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02839720, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2023.

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