Efficacy and Safety of Selumetinib in Adults With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas

Study Overview
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Brief Summary
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A global study to demonstrate the effectiveness of selumetinib in participants with NF1 who have symptomatic, inoperable plexiform neurofibromas.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, 2 arm multicentre, global Phase III study to assess the efficacy and safety of selumetinib compared with placebo in adult participants with NF1 who have symptomatic, inoperable PN.

Official Title
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A Phase III, Multicentre, International Study With a Parallel, Randomised, Double-blind, Placebo-controlled, 2 Arm Design to Assess the Efficacy and Safety of Selumetinib in Adult Participants With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas (KOMET)

Conditions
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Neurofibromatosis 1, Plexiform Neurofibroma (PN)

Intervention / Treatment
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* Drug: Selumetinib
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adults ≥ 18 years at enrollment with diagnosis of NF1 with symptomatic, inoperable PN At least one inoperable target PN measurable by volumetric MRI analysis Chronic target PN pain score documented for minimum period during screening period Stable chronic PN pain medication use at enrollment Adequate organ and marrow function Key Exclusion Criteria: Confirmed or suspected malignant glioma or MPNST (low grade glioma, including optic glioma not requiring systemic therapy or radiation therapy are exempt from this exclusion) History of malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence Clinically significant cardiovascular disease, including inherited coronary disease, acute coronary syndrome within 6 months prior to enrollment, uncontrolled angina, symptomatic heart failure, cardiomyopathy, severe valvular heart disease, abnormal LVEF and uncontrolled hypertension Ophthalmological findings/conditions including intraocular pressure > 21 mmHg, RPED/CSR or RVO Prior exposure to MEK inhibitors

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: Arm A<br>Selumetinib | Drug: Selumetinib<br>* Selumetinib oral capsules (10 mg and 25 mg)<br>* Other names: AZD6244;|
| Placebo Comparator: Arm B<br>Placebo | Other: Placebo<br>* Placebo oral capsules for Selumetinib masking (10 mg and 25 mg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) for Arm A versus Arm B | ORR will be defined as the proportion of patients who have a confirmed complete response or confirmed partial response as determined by ICR per REiNS criteria | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in chronic target PN pain intensity from baseline for Arm A versus Arm B as assessed using a PRO questionnaire | Difference in mean change from baseline in chronic target PN pain intensity score between Arm A and Arm B, obtained using an NRS-11 scale to assess pain intensity of a target plexiform neurofibroma | Approximately 3 years | 
| Duration of response (DoR) for Arm A | DoR will be defined as the time from the date of first documented response (which is subsequently confirmed) until progression by ICR per REiNS criteria or death due to any cause | Approximately 3 years | 
| Progression Free Survival (PFS) for Arm A | PFS will be defined as the time from first selumetinib dose until date of disease progression by ICR per REiNS criteria or death due to any cause | Approximately 3 years | 
| Time to progression (TTP) for Arm A | TTP is defined as the time from the date of first selumetinib dose until date of disease progression by ICR per REiNS criteria | Approximately 3 years | 
| Time to Response (TTR) for Arm A | TTR is defined as the time from date of first selumetinib dose until the date of objective response by ICR per REiNS criteria | Approximately 3 years | 
| Target PN volume for Arm A vs Arm B | Difference in best percentage change from baseline in target PN volume by ICR per REiNS criteria | Approximately 3 years | 
| Physical functioning assessed using PROMIS physical function items | Difference in change from baseline between Arm A and Arm B | Approximately 3 years | 
| Health Related Quality of Life (HRQoL) outcomes assessed using PlexiQoL | Difference in change from baseline between Arm A and Arm B | Approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PNs, Selumetinib, Neurofibromatosis Type 1, NF1, Plexiform Neurofibroma (PN), MEK inhibitor