- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02839720
Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma
Pilot Study of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) for Adults With Neurofibromatosis Type 1 (NF1) and Cutaneous Neurofibromas (CNF)
Study Overview
Status
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Alabama
-
Birmingham, Alabama, United States, 35233
- University of Alabama at Birmingham Cancer Center
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (selumetinib sulfate)
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.
|
Correlative studies
Given PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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)
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in the Number of Cutaneous Neurofibromas
Time Frame: 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).
|
Baseline to up to 1 year
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Changes in Skin Related Morbidity
Time Frame: 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).
|
Baseline to up to 1 year
|
Changes in Pathway Biomarkers Assessed by Kinome Analysis
Time Frame: Baseline to up to 1 year
|
Will be tested for statistical significance using a Wilcoxon signed rank test.
|
Baseline to up to 1 year
|
Changes in Levels of pERK and pAKT Assessed by Quantitative Enzyme-linked Immunosorbent Assay
Time Frame: 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.
|
Baseline to up to 1 year
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Bruce R Korf, University of Alabama at Birmingham Cancer Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Eye Diseases
- Genetic Diseases, Inborn
- Neuromuscular Diseases
- Neurodegenerative Diseases
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Peripheral Nervous System Diseases
- Nervous System Neoplasms
- Heredodegenerative Disorders, Nervous System
- Neoplastic Syndromes, Hereditary
- Optic Nerve Diseases
- Cranial Nerve Diseases
- Nerve Sheath Neoplasms
- Neurocutaneous Syndromes
- Peripheral Nervous System Neoplasms
- Cranial Nerve Neoplasms
- Optic Nerve Neoplasms
- Neurofibromatoses
- Neurofibromatosis 1
- Neurofibroma
- Optic Nerve Glioma
Other Study ID Numbers
- NCI-2016-01087 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- 9990 (Other Identifier: CTEP)
- P30CA013148 (U.S. NIH Grant/Contract)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Neurofibromatosis Type 1
-
University of UtahUniversity of British Columbia; Children's Hospital Medical Center, Cincinnati and other collaboratorsTerminatedNeurofibromatosis Type 1 (NF1)United States, Canada
-
University of Alabama at BirminghamCompletedNeurofibromatosis Type 1 and Growing or Symptomatic, Inoperable PNUnited States
-
Novartis PharmaceuticalsTerminatedPlexiform Neurofibroma Associated With Neurofibromatosis Type 1Israel
-
SpringWorks Therapeutics, Inc.Active, not recruitingPlexiform Neurofibroma | Neurofibromatosis Type 1 (NF1)United States
-
AstraZenecaCompletedHealthy Participants | Neurofibromatosis Type 1 (NF1)-Related Plexiform Neurofibromas (PNs)United States
-
National Cancer Institute (NCI)CompletedPlexiform Neurofibroma | Neurofibromatosis Type IUnited States
-
SpringWorks Therapeutics, Inc.AvailableNeurofibromatosis Type 1-Associated Plexiform Neurofibromas | Histiocytic Neoplasm | Other MAP-K Pathway Driven Diseases
-
Johns Hopkins UniversityNeurofibromatosis Therapeutic Acceleration ProgramRecruitingNeurofibromatosis 1 | Neurofibromatosis Type 1 | Cutaneous Neurofibroma | Neurofibromatosis (Nonmalignant)United States
-
Ann & Robert H Lurie Children's Hospital of ChicagoNational Institute of Neurological Disorders and Stroke (NINDS); Children's...RecruitingNeurofibromatosis 1 | Neurofibromatosis Type 1 | NF1United States
-
Guy's and St Thomas' NHS Foundation TrustRecruitingNeurofibromatosis Type 1United Kingdom
Clinical Trials on Laboratory Biomarker Analysis
-
ECOG-ACRIN Cancer Research GroupNational Cancer Institute (NCI)CompletedProstate Cancer
-
National Cancer Institute (NCI)Recruiting
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)Not yet recruitingLynch Syndrome | Recurrent Uterine Corpus Carcinoma | Stage I Uterine Corpus Cancer | Stage II Uterine Corpus Cancer | Stage III Uterine Corpus Cancer | Stage IV Uterine Corpus CancerUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)Not yet recruitingRecurrent Uterine Corpus Carcinoma | Stage III Uterine Corpus Cancer | Stage IV Uterine Corpus CancerUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)RecruitingStage IIIA Ovarian Cancer | Stage IIIB Ovarian Cancer | Stage IIIC Ovarian Cancer | Stage IV Ovarian CancerUnited States
-
Ohio State University Comprehensive Cancer CenterActive, not recruitingLung Cancer | Radiation Toxicity | Adult Brain TumorUnited States
-
National Cancer Institute (NCI)Active, not recruitingMalignant NeoplasmUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Askin TumorUnited States, Canada, Puerto Rico, Australia, New Zealand, Switzerland
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)Completed
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized OsteosarcomaUnited States