NFX-179 Topical Gel Treatment in Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF)

Study Overview
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Brief Summary
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This study will enroll and treat subjects with cutaneous neurofibromas with NFX-179, a topical study drug. Eligible subjects will receive treatment for 28 days and be observed by a study doctor for approximately 56 days. Subjects will be randomly assigned to 1 of 4 treatment groups. 3 of the treatment groups will receive a specific dose NFX-179, and 1 group will receive placebo. The subject, study doctor, and NFlection Therapeutics will not know what treatment group each subject is assigned. Study participation requires at least 7 clinic visits, blood, urine, and tissue collection, images of the treated cutaneous neurofibromas, electrocardiograms, and information regarding the subject's medical and disease history.

Official Title
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A Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Phase 2a Study to Determine Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Activity of NFX-179 Gel in Subjects With Cutaneous Neurofibromas

Conditions
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Neurofibromatosis 1, Cutaneous Neurofibroma

Intervention / Treatment
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* Drug: NFX-179 Gel
* Drug: Vehicle Gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is at least 18 years of age Subject must provide written informed consent prior to any study procedures Subject must have a clinical diagnosis of NF1 Subject has 6 Study cNF Tumors (5 Target cNF Tumors [1 on the face; 4 on the anterior trunk or upper extremities] that will be treated with the assigned study medication;1 Untreated cNF Tumor on the anterior trunk or upper extremities) that each meet the following criteria: Has, in the investigator's opinion, a clinically typical appearance Is dome shaped Is not pedunculated Is a discrete tumor Is not irritated Is not in an area subject to repeated trauma (e.g., area that is shaved, on the beltline, under a bra strap, etc.) Does not have an active cutaneous infection Has a diameter that is ≥5mm and ≤10mm Has a height of ≥2mm Is, when centered in the center of the provided template, the only cNF tumor visible Is not within 5mm of the orbital rim. Subject is willing to have the 5 Target cNF Tumors and the 1 Untreated cNF Tumor excised at the end of the treatment period Subject is willing to have hair in the area surrounding the Target cNF Tumors shaved, if necessary, to obtain photographs Subject is willing to minimize exposure of each Target cNF to natural and artificial ultraviolet radiation Subject is willing to forego treatment of the Target cNF Tumors, except protocol specified therapy, during the study Female subjects who are women of childbearing potential must have a negative urine pregnancy test result and be willing to use a protocol approved, contraceptive method for the duration of the study Subject is willing and able to follow all study instructions and to attend all study visits. Exclusion Criteria: Subject has applied any of the following topical products in the previous 30 days on or in proximity to any Study cNF Tumor that, in the investigator's opinion, impairs evaluation of any the tumor or which exposes the subject to an unacceptable risk by study participation: Corticosteroids Retinoids (e.g., tazarotene, tretinoin, adapalene) > 5% of an alpha-hydroxy acid (e.g., glycolic acid, lactic acid) Fluorouracil Imiquimod Any Study cNF Tumor has ever been treated with an MEK inhibitor or a BRAF inhibitor The subject has used any of the following systemic medications in the noted time period: Retinoids (e.g., etretinate, isotretinoin) within the previous 90 days MEK inhibitors within the previous 180 days BRAF inhibitors within the previous 180 days Subject has a history of hypersensitivity to any of the ingredients in the study medications Subject has any known intercurrent illness or physical condition that would, in the investigator's opinion, impair evaluation of a Target cNF Tumor or which exposes the subject to an unacceptable risk by study participation Subject has, in the investigator's opinion, clinically relevant history of liver disease, including viral hepatitis, current alcohol abuse, or cirrhosis Subject has a history of metastatic disease, or active cancer (excluding nonmelanoma skin cancer, Stage I cervical cancer, ductal carcinoma in situ of the breast, or Stage 0 chronic lymphocytic lymphoma) within the previous 5 years Subject has any condition (e.g., other skin conditions or diseases, metabolic dysfunction, physical examination findings, clinical laboratory findings) or situation (e.g., vacation, scheduled surgery) that would, in the investigator's opinion, impair evaluation of a Target cNF Tumor or which exposes the subject to an unacceptable risk by study participation Subject has participated in an investigational drug trial in which administration of an investigational study medication occurred within the previous 30 days

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NFX-179 Gel Low<br>NFX-179 Gel for topical administration, once daily for 28 days | Drug: NFX-179 Gel<br>* gel for topical administration<br>|
| Experimental: NFX-179 Gel Mid<br>NFX-179 Gel for topical administration, once daily for 28 days | Drug: NFX-179 Gel<br>* gel for topical administration<br>|
| Experimental: NFX-179 Gel High<br>NFX-179 Gel for topical administration, once daily for 28 days | Drug: NFX-179 Gel<br>* gel for topical administration<br>|
| Placebo Comparator: Vehicle Arm<br>Vehicle Gel, for topical administration, once daily for 28 days | Drug: Vehicle Gel<br>* vehicle gel for topical administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phospho-erk (p-ERK) Levels of Target cNF Tumors in NFX-179 Gel Group and Vehicle Gel Group After 28 Days of Once-daily (QD) Application | Pharmacodynamic activity (biochemical and physiologic effects of drugs) of NFX-179 Gel as defined by suppression of phospho-ERK (p-ERK) levels in Target cNF Tumors in each NFX-179 Gel group compared with the Vehicle Gel group after 28 days of once-daily (QD) application will be measured at Week 4 | Baseline through Week 4 | 
| Safety and Tolerability of NFX-179 Gel Measured by Local Tolerability Assessment | Safety and tolerability will be measured via a local tolerability assessment. The investigator will assess erythema, edema, scabbing/crusting, vesiculation, and erosion. The subject will assess stinging, burning, and pruritus. All assessments are performed using a 4-point scale (0 none, 1 mild, 2 moderate, 3 severe). | Baseline through Week 4 | 
| Assessment of Adverse Events | Assessment of adverse events (AEs) | Baseline through Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in cNF Tumor Volume (Cubic Millimeters) | Percent change in cNF tumor volume after 28 days of QD applications of NFX-179 gel based on tumor volume derived from ruler measurements. | Baseline through Week 4 | 
| Systemic Exposure of NFX-179 Gel Measured by Plasma Concentration | Systemic exposure of NFX-179 will be measured during the 28 days of QD applications at select investigative sites. Pharmacokinetic samples will be drawn at the baseline visit and week 4 visit. 5 time point samples will be collected at the week 4 visit. | Baseline through Week 4 | 
| Change in Physician Assessment of Tumor Severity Score | Effect of treatment with The Physician Tumor Assessment is the investigator's assessment of the average overall severity of each Target cNF tumor at a particular time point. The Physician Tumor Assessment is a 5-point measuring tumor severity (0 clear/none, 1 almost clear, 2 mild, 3 moderate, 4 severe). The assessment is performed at the Baseline visit and week 4 visit. | Baseline through Week 4 | 
| Change in Subject Self-Assessment of Tumor Severity Score | The Subject Self-Assessment is the subject's assessment of the average overall severity of each Target cNF at a particular time point and is not a comparison with any other time point. The Subject Self-Assessment is a 5-point measuring tumor severity (0 clear/none, 1 almost clear, 2 mild, 3 moderate, 4 severe). The assessment is performed at the Baseline visit and week 4 visit. | Baseline through Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NFX-179