PASS of Paediatric Patients Initiating Selumetinib

Study Overview
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Brief Summary
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Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant genetic disorder that is caused by germline mutations in the NF1 tumour suppressor gene, which encodes the tumour suppressor protein neurofibromin 1. Plexiform neurofibromas (PN) are histologically benign nerve sheath tumours, which typically grow along large nerves and plexi. On 5 March 2020, a centralised Marketing Authorisation Application was submitted to the European Medicines Agency (EMA), Marketing Authorisation in EU was granted on 17 Jun 2021. As part of the approval process, a Risk Management Plan (RMP) was developed and submitted to the EMA to summarise the safety concerns emerging from the clinical development program. The RMP included additional pharmacovigilance plans for a noninterventional Post-authorisation Safety Study (PASS) to further characterise the safety of selumetinib in paediatric patients with NF1-related PN in routine clinical practice. The planned non-interventional PASS will address gaps in knowledge identified by the RMP, including the important identified risk and some of the potential risks and missing information on long-term developmental toxicity in children, by characterising the safety profile associated with selumetinib use among paediatric patients (ages > 8 to < 18 years old) with a diagnosis of NF1 with symptomatic, inoperable PN. This study is a specific obligation in the context of a conditional marketing authorisation for selumetinib (ie, Category 2 PASS). Study results will contribute to updating the safety profile of selumetinib in a relatively large population of patients with different personal characteristics across multiple health care systems and patterns of real-world clinical practice in the European Union (EU) and in the UK. The study will enrol 2 cohorts: The Base Cohort includes all enrolled patients aged 3 to < 18 years. The Nested Prospective Cohort will include the subset of Base Cohort patients aged 8 to < 18 years who have not reached Tanner Stage V on the index date.

Detailed Description
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Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant genetic disorder that is caused by germline mutations in the NF1 tumour suppressor gene, which encodes the tumour suppressor protein neurofibromin 1. Plexiform neurofibromas (PN) are histologically benign nerve sheath tumours, which typically grow along large nerves and plexi. On 5 March 2020, a centralized Marketing Authorisation Application was submitted to the European Medicines Agency (EMA), Marketing Authorization in EU was granted on 17 Jun 2021. As part of the approval process, a Risk Management Plan (RMP) was developed and submitted to the EMA to summarise the safety concerns emerging from the clinical development program. The RMP included additional pharmacovigilance plans for a non-interventional Post-authorisation Safety Study (PASS) to further characterise the safety of selumetinib in paediatric patients with NF1-related PN in routine clinical practice. The RMP version 1.0 (succession 4) approved by EMA on 22 April 2021 had 1 important identified risk with selumetinib treatment: -LVEF reduction The RMP also identified 5 important potential risks with selumetinib treatment: Physeal dysplasia Ocular toxicity Myopathy Hepatotoxicity Choking on the capsule Long-term exposure (including long-term safety data on developmental toxicity in children) was identified in the RMP as an area of missing information. The planned non-interventional PASS will address gaps in knowledge identified by the RMP, including the important identified risk and some of the potential risks and missing information on long-term developmental toxicity in children, by characterising the safety profile associated with selumetinib use among paediatric patients (ages > 8 to < 18 years old) with a diagnosis of NF1 with symptomatic, inoperable PN. This study is a specific obligation in the context of a conditional marketing authorisation for selumetinib (ie, Category 2 PASS). Study results will contribute to updating the safety profile of selumetinib in a relatively large population of patients with different personal characteristics across multiple health care systems and patterns of real-world clinical practice in the European Union (EU) and in the UK. The primary objective of this study is: - To characterise the safety of selumetinib, including up to 5 years of long-term safety, in paediatric patients with NF1-related symptomatic, inoperable PN, 8 to < 18 years old who have not reached Tanner Stage V at the start of selumetinib treatment (Nested Prospective Cohort). The secondary objective of this study is: - To describe the demographic and clinical profile of the paediatric population 3 to < 18 years old with NF1-related symptomatic inoperable PN who start selumetinib in routine clinical practice (Base Cohort). This study will be conducted in up to 36 specialist clinics for the treatment of paediatric patients with NF1 across 12 European countries. The study observation period is anticipated to begin in Q1 of 2022, with some variation by country. Patients will be enrolled after commercial launch of selumetinib in each participating country, when patients/physicians have access to medicine as part of standard clinical practice. The target population for this study are patients with NF1 in the EU with symptomatic, inoperable PN who have been prescribed at least 1 dose of selumetinib and who are aged 3 to < 18 years at the start of selumetinib treatment, except for those patients receiving treatment with a mitogen-activated protein kinase inhibitor before the index date. The study will enrol 2 cohorts: The Base Cohort includes all enrolled patients aged 3 to < 18 years. The Nested Prospective Cohort will include the subset of Base Cohort patients aged 8 to < 18 years who have not reached Tanner Stage V on the index date. Patient screening will be conducted throughout the enrolment period and baseline data for all patients will be abstracted from medical records. Those meeting the criteria for enrolment in the Nested Prospective Cohort will be followed up during their routine encounters with the treating clinician (expected to occur every 6 to 12 months) for up to 5 years.

Official Title
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Post-Authorisation Safety Study of Paediatric Patients Initiating Selumetinib: A Multiple-Country Prospective Cohort Study

Conditions
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Neurofibromatosis Type 1

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have been diagnosed with NF1 with symptomatic, inoperable PN Have been newly prescribed at least one dose of selumetinib Are aged 3 years and above, and are < 18 years of age on the index date Parent or legal guardian, as required by country-specific regulation, have provided informed consent (unless a country-specific waiver is obtained) Additional Criteria for Nested Prospective Cohort Are at least 8 years old and Are prior to attainment of Tanner Stage V on the index date Exclusion Criteria: Have received treatment with a mitogen-activated protein kinase inhibitor before the index date Are participating in a randomised controlled trial

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Base Cohort<br>The Base Cohort includes all enrolled patients aged 3 to < 18 years. | |
| Nested Prospective Cohort<br>The Nested Prospective Cohort will include the subset of Base Cohort patients aged 8 to < 18 years who have not reached Tanner Stage V on the index date | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LVEF reduction | LVEF reduction will be detected as present or absent and when present if symptomatic or asymptomatic. All cardiac tests conducted will be collected Measured on routine echocardiogram or a cardiac MRI (CT, angiography, etc.) and then collected into the study from the medical records. | at routine clinical care throughout the follow up, with frequency of 6 to 12 months | 
| Occurrence of Physeal dysplasia after treatment start | Physeal dysplasia will be detected as present or absent based on the physician reading of: MRI: Knee (preferred) or wrist X-ray: Knee (preferred) and/or wrist to assess growth plate Height and weight records | at routine clinical care throughout the follow up, with frequency of 6 to 12 months | 
| Rise of serum creatine phosphokinase levels AND concurrent musculoskeletal symptoms | A clinically meaningful rise in serum creatine phosphokinase (eg, above the normal limit or increase by 1 or more CTCAE grade shift) combined with musculoskeletal symptoms will be detected as present or absent based on the physician's reading, as a marker of potential myopathy | at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 5 years | 
| Rise in transaminase (ALT and AST) and concurrent rise in bilirubin | A clinically meaningful rise in the measured levels (eg, above the normal limit or increase by 1 or more CTCAE grade shift) will be detected as present or absent, and when present if symptomatic or asymptomatic, as a marker of potential hepatotoxicity | at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 5 years | 
| Cumulative incidence of ocular toxicity | An abnormal ocular examination will be detected as present or absent based on the physician's reading, as a marker of potential ocular toxicity | at routine clinical care throughout the follow up, with frequency of 6 to 12 months | 
| Cumulative incidence of Abnormal pubertal development | Tanner staging criteria (Stages I-V). Abnormal pubertal development will require interpretation by the Investigator with respect to Tanner Stage in the context of the patient's age; recorded as normal or abnormal (if abnormal, further specified as delayed puberty or precocious puberty) | at routine clinical care throughout the follow up, with frequency of 6 to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| baseline data - demographics | Demographics: Age | At baseline - most recent assessments made within 365 days before the index date | 
| baseline data - demographics | sex | At baseline - most recent assessments made within 365 days before the index date | 
| baseline data - demographics | height (cm) | At baseline - most recent assessments made within 365 days before the index date | 
| baseline data - demographics | weight (kg) | At baseline - most recent assessments made within 365 days before the index date | 
| baseline data - demographics | Tanner staging level | At baseline - most recent assessments made within 365 days before the index date | 
| baseline data - demographics | Ethnicity (where allowed by GDPR/privacy laws) | At baseline - most recent assessments made within 365 days before the index date | 
| Baseline data - Clinical characteristics | PN(s) (number, location, classification and morbidities) | At baseline - most recent assessments made within 365 days before the index date | 
| Baseline data - Clinical characteristics | prior medication and relevant procedures, concomitant medications | At baseline - most recent assessments made within 365 days before the index date | 
| Baseline data - Clinical characteristics | date of initial NF1 and PN diagnosis, NF1 origin (familial or spontaneous), and any genetic testing results | At baseline - most recent assessments made within 365 days before the index date |