Pilot Study of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) for Adults With Neurofibromatosis Type 1 (NF1) and Cutaneous Neurofibromas (CNF)
Overview
- Phase
- Phase 2
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Cutaneous Neurofibroma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 11
- Locations
- 2
- Primary Endpoint
- Median Best Response of Cutaneous Neurofibromas in Participants With at Least One Restaging Evaluation
- Status
- Completed
- Last Updated
- 2 years ago
Overview
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
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.
Intervention: Laboratory Biomarker Analysis
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.
Intervention: Selumetinib Sulfate
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- Change in the Number of Cutaneous Neurofibromas(Baseline to up to 1 year)