Cutaneous Neurofibroma, Neurofibromatosis Type 1, Optic Nerve Glioma
Conditions
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.
Detailed description
PRIMARY OBJECTIVE: I. Determine if selumetinib sulfate (selumetinib) can result in shrinkage of cutaneous neurofibromas. SECONDARY OBJECTIVE: I. 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: I. 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. V. 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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 * 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
Exclusion criteria
* 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Best Response of Cutaneous Neurofibromas in Participants With at Least One Restaging Evaluation | Up to 24 cycles of treatment (1 cycle = 28 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Number of Cutaneous Neurofibromas | Baseline to up to 1 year | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Skin Related Morbidity | Baseline to up to 1 year | Assessed by Skindex. Global Impression of Change Scale and Numeric Rating Scale evaluations were not used in this outcome measure due to limited data set. Skindex is a dermatology survey whose scores are normalized to a 0-100 scale with higher scores indicating worse quality of life. We report here the change in overall Skindex score after 12 cycles of treatment (Score at 12 cycles - Score at Baseline). |
| Changes in Pathway Biomarkers Assessed by Kinome Analysis | Baseline to up to 1 year | Will be tested for statistical significance using a Wilcoxon signed rank test. |
| Changes in Levels of pERK and pAKT Assessed by Quantitative Enzyme-linked Immunosorbent Assay | Baseline to up to 1 year | Will be correlated with tumor volume changes using Spearman rank correlation. Exploratory comparisons between patients with a tumor response and those without a response will be done using a Wilcoxon rank sum test. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Selumetinib) Participants receive selumetinib capsules at a dose of 50mg by mouth (PO) twice daily (BID) every 12 hours with option to increase to 75mg PO BID after first cycle if tolerated. Treatment repeats every 28 days (1 cycle = 28 days) for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Participants who experience a volume decrease in the target cutaneous neurofibromas may continue treatment for 12 additional cycles. Volume decrease defined as a greater than or equal to 20 percent decrease in the sum of the volumes of the smaller and/or larger target cutaneous neurofibromas. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Intercurrent Illness | 1 |
| Overall Study | Non-compliance | 2 |
| Overall Study | Non-compliance due to COVID-19 pandemic | 2 |
Baseline characteristics
| Characteristic | Treatment (Selumetinib) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 54 years |
| Average cutaneous neurofibroma (cNF) volume | 159.1 microliters |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 5 / 11 |
Outcome results
Primary
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.
Time frame: Up to 24 cycles of treatment (1 cycle = 28 days)
Population: Includes all participants who had at least one restaging evaluation on treatment with selumetinib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Selumetinib) | Median Best Response of Cutaneous Neurofibromas in Participants With at Least One Restaging Evaluation | -28.5 percent change |
Secondary
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).
Time frame: Baseline to up to 1 year
Population: Includes all participants that completed 12 cycles of selumetinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Selumetinib) | Change in the Number of Cutaneous Neurofibromas | -7 neurofibromas |
Other Pre-specified
Changes in Levels of pERK and pAKT Assessed by Quantitative Enzyme-linked Immunosorbent Assay
Will be correlated with tumor volume changes using Spearman rank correlation. Exploratory comparisons between patients with a tumor response and those without a response will be done using a Wilcoxon rank sum test.
Time frame: Baseline to up to 1 year
Population: Trial was terminated due to low accrual that was exacerbated by the COVID-19 pandemic leading to limited data set for this outcome measure. Not enough samples to justify proceeding with this analysis.
Other Pre-specified
Changes in Pathway Biomarkers Assessed by Kinome Analysis
Will be tested for statistical significance using a Wilcoxon signed rank test.
Time frame: Baseline to up to 1 year
Population: Trial was terminated due to low accrual that was exacerbated by the COVID-19 pandemic leading to limited data set for this outcome measure. Not enough samples to justify proceeding with this analysis.
Other Pre-specified
Changes in Skin Related Morbidity
Assessed by Skindex. Global Impression of Change Scale and Numeric Rating Scale evaluations were not used in this outcome measure due to limited data set. Skindex is a dermatology survey whose scores are normalized to a 0-100 scale with higher scores indicating worse quality of life. We report here the change in overall Skindex score after 12 cycles of treatment (Score at 12 cycles - Score at Baseline).
Time frame: Baseline to up to 1 year
Population: Only included analysis of the 5 participants who had baseline and 1 year on treatment Overall SkinDex scores available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Selumetinib) | Changes in Skin Related Morbidity | -1.72 score on a scale |