Patient case: 70-year-old male with melanoma; genetic feature: NF1 truncation

Clinical trial: Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Dermal Neurofibroma

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

Detailed description: PRIMARY OBJECTIVES:
  I. Determine if selumetinib can result in shrinkage of dermal neurofibromas.
  SECONDARY OBJECTIVES:
  I. Assess the effect of selumetinib on the development on new dermal neurofibromas while on treatment with selumetinib.
  II. Assess the effect of selumetinib on target inhibition in dermal 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) and in the tumor kinome.
  III. Assess the effect of selumetinib on the tumor microenvironment by analyzing peripheral blood bone marrow derived progenitor cells and cytokines obtained pretreatment and on treatment with selumetinib.
  IV. Assess the effect of selumetinib skin related morbidity using the Skindex patient reported outcome measure.
  V. Quantify the development of new dermal neurofibromas on treatment with selumetinib.
  VI. Detailed pathologic analysis of dermal neurofibromas pretreatment and on treatment with selumetinib for changes in cell composition (including macrophage and mast cell infiltration).
  OUTLINE:
  Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Eligibility: Inclusion Criteria:
  -  Patients must have a documented germline neurofibromatosis 1 (NF1) mutation in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory or a diagnosis of NF1 based on clinical National Institutes of Health (NIH) consensus criteria; in addition to substantial dermal neurofibroma burden, at least one of the criteria below have to be present:
  -  Six or more cafe-au-lait macules (>= 0.5cm in prepubertal subjects or >= 1.5cm 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
  -  Patients must have substantial dermal neurofibroma burden causing distress to the patient by disfigurement or itching; patients must have >= 9 measurable dermal 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 >= 3 mm in the longest diameter
  -  Eastern Cooperative Oncology Group (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 positive nasal (PN) requiring tracheostomy or continuous positive airway pressure [CPAP]) will also be considered ambulatory for the purpose of the study)
  -  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
  -  Hematologic parameters for patients undergoing biopsy only: patients should have International Normalized Ratio (INR) < 1.4 and prothrombin time (PT) =< 40 seconds (unless due to lupus anticoagulant); in patients not meeting these parameters, clearance by hematology will be required prior to undergoing a biopsy
  -  Cardiac function: normal ejection fraction (ECHO) >= 53% (if a range is given then the upper value of the range will be used) or cardiac magnetic resonance imaging (MRI); corrected QT using Fridericia's formula (QTcF) =< 450 msec
  -  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 dermal neurofibromas, patients may be treated on this trial without having received prior medical therapy directed at their 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 dermal 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) 4 before entering this study
  -  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
  -  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), prevention of blindness (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; 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
  -  Uncontrolled hypertension (despite medical therapy); blood pressure should be < 140/90 in accordance with American Heart Association definition of hypertension
  -  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 either induce or inhibit the activity of hepatic microsomal isoenzymes CYP1A2, CYP2C19 and CYP3A4
  -  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 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) =< 55%
  -  Previous moderate or severe impairment of left ventricular systolic function (LVEF < 45% 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 bpm on ECG at rest
  -  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

Relevance to patient case: not relevant