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

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)

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

Study Overview

• Status: Active, not recruiting
• Conditions: Neurofibromatosis 1; Plexiform Neurofibroma (PN)
• Intervention / Treatment: Drug: Selumetinib; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 145
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3000
    • Research Site
  • St Leonards, Australia, 2065
    • Research Site
• Brazil
  • Porto Alegre, Brazil, 90035-903
    • Research Site
  • Ribeirão Preto, Brazil, 14051-140
    • Research Site
  • São Paulo, Brazil, 045202-001
    • Research Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Research Site
• China
  • Beijing, China, 100070
    • Research Site
  • Beijing, China, 100730
    • Research Site
  • Guangzhou, China, 510060
    • Research Site
  • Shenyang, China, 110001
    • Research Site
• France
  • Créteil, France, 94000
    • Research Site
  • Lyon, France, 69008
    • Research Site
  • Toulouse, France, 31059
    • Research Site
• Germany
  • Hamburg, Germany, 20246
    • Research Site
  • Tübingen, Germany, 72076
    • Research Site
  • Würzburg, Germany, 97080
    • Research Site
• Italy
  • Milan, Italy, 20133
    • Research Site
  • Naples, Italy, 80131
    • Research Site
  • Roma, Italy, 00165
    • Research Site
• Japan
  • Minatoku, Japan, 105-8471
    • Research Site
  • Nagoya, Japan, 466-8560
    • Research Site
  • Shinjuku-ku, Japan, 160-8582
    • Research Site
• Poland
  • Bydgoszcz, Poland, 85-094
    • Research Site
• Russia
  • Moscow, Russia, 115522
    • Research Site
  • Moscow, Russia, 125412
    • Research Site
• Spain
  • Badalona, Spain, 08916
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Research Site
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Research Site
  • Missouri
    • St Louis, Missouri, United States, 63156
      • Research Site
  • New York
    • Commack, New York, United States, 11725
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Selumetinib	Drug: Selumetinib; Selumetinib oral capsules (10 mg and 25 mg); Other Names: AZD6244
Placebo Comparator: Arm B; Placebo	Other: Placebo; Placebo oral capsules for Selumetinib masking (10 mg and 25 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Partial and Complete Response Rate (ORR) by End of Cycle 16 Using Volumetric MRI Analysis as Determined by ICR (Per REiNS Criteria) in Participants With NF1 Who Have Symptomatic, Inoperable PN.	Objective response rate is defined as the proportion of participants who have a confirmed CR (defined as disappearance of the target PN, confirmed by a consecutive scan within 3 to 6 months after the first response) or confirmed PR (defined as a target PN volume decrease ≥ 20%, compared to baseline, confirmed by a consecutive scan within 3 to 6 months after the first response) by end of Cycle 16 as determined by ICR per REiNS criteria. Increase in the volume of the target PN by 20% or more compared to baseline or the time of best response after documenting a PR is considered as PD.	From first dose up until progression (if it occurs prior to the end of Cycle 16), or the last evaluable assessment up to and including the end of Cycle 16, excluding MRI during prolonged study intervention interruption (defined as interruption >= 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Primary Analysis	The PAINS-pNF (Pain Intensity Scale for Plexiform Neurofibroma) chronic target PN pain intensity measures the participants' experience of chronic PN-related pain intensity with score from 0 (no chronic tumor pain) to 10 (worst chronic tumor pain). Baseline PAINS-pNF chronic target PN pain score is defined as the average of the available daily PAINS-pNF chronic target PN pain scores in the screening perio, while for Cycle 12, it is defined as the average of the available daily scores for the 28-days cycle up to and including the last day assessment of cycle 12. The difference of the means in the change from baseline at Cycle 12 between selumetinib and placebo in participants with a PAINS-pNF chronic target PN pain score of ≥ 3 at baseline is presented.	Baseline and end of cycle 12 of study intervention
(First Key Secondary) The Difference of the Means in the Change From Baseline in PAINS-pNF Chronic Target PN Pain Intensity Score at Cycle 12 Between Selumetinib and Placebo, Supplemental Analysis	The PAINS-pNF (Pain Intensity Scale for Plexiform Neurofibroma) chronic target PN pain intensity measures the participants' experience of chronic PN-related pain intensity with score from 0 (no chronic tumor pain) to 10 (worst chronic tumor pain). Baseline PAINS-pNF chronic target PN pain score is defined as the average of the available daily PAINS-pNF chronic target PN pain scores in the screening perio, while for Cycle 12, it is defined as the average of the available daily scores for the 28-days cycle up to and including the last day assessment of cycle 12. The difference of the means in the change from baseline at Cycle 12 between selumetinib and placebo participants is presented.	Baseline and end of cycle 12 of study intervention
(Second Key Secondary Endpoint) The Difference of the Means in the Change From Baseline in PlexiQoL Total Score at Cycle 12	PlexiQoL (Plexiform Neurofibroma Quality of Life scale) is a patient-derived QoL measure specific to adults with NF1-associated PNs. It assesses the impact of PNs on patients' ability to fulfil their human needs. The measure consists of 18 dichotomous items with 0 =Not True and 1 = True. PlexiQoL total scores were calculated by the sum of all items to a maximum of 18, with lower scores indicating better quality of life. The change from baseline to the end of each cycle in PlexiQoL total score was derived as the PlexiQoL total score at the cycle 12 minus baseline PlexiQoL total score and presented.	Baseline and end of Cycle 12 of study intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of selumetinib as assessed by number and grade of adverse events	Adverse events are defined according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0	Approximately 3 years
Pharmacokinetics (PK) of selumetinib for exposure-response analyses	Selumetinib and N-desmethyl selumetinib plasma concentrations assessment	Approximately 3 years

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Alice P. Chen, MD, National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Chen AP, Coyne GO, Wolters PL, Martin S, Farschtschi S, Blanco I, Chen Z, Darrigo LG Jr, Eoli M, Whittle JR, Nishida Y, Lamarca R, de la Rosa Rodriguez R, Adeyemi A, Herrero I, Llorente N, Diede SJ, Dombi E, Wolkenstein P; KOMET study investigators. Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (KOMET): a multicentre, international, randomised, placebo-controlled, parallel, double-blind, phase 3 study. Lancet. 2025 Jun 21;405(10496):2217-2230. doi: 10.1016/S0140-6736(25)00986-9. Epub 2025 Jun 2.

Helpful Links

• Redacted Protocol
• Redacted Statistical Analysis Plan
• Redacted CSR synopsis

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2021
• Primary Completion (Actual): August 5, 2024
• Study Completion (Estimated): February 15, 2029

Study Registration Dates

• First Submitted: May 14, 2021
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 19, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: MEK inhibitor; Neurofibromatosis Type 1; NF1; Plexiform Neurofibroma (PN); PNs; Selumetinib
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neoplasms by Histologic Type; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Nerve Sheath Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Neurofibroma; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma, Plexiform; AZD 6244
• Other Study ID Numbers: D134BC00001; 2020-005607-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No