PASS of Paediatric Patients Initiating Selumetinib

Condition(s) studied

Study summary

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 (age d 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 European countries and Israel.

The study will enrol 2 cohorts:

1. The Base Cohort includes all enrolled patients aged 3 to \< 18 years.
2. 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.

Eligibility

Primary outcome measure(s)

• LVEF reduction — at routine clinical care throughout the follow up, with frequency of 6 to 12 months
  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.
• Occurrence of Physeal dysplasia after treatment start — at routine clinical care throughout the follow up, with frequency of 6 to 12 months
  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
• Rise of serum creatine phosphokinase levels AND concurrent musculoskeletal symptoms — at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 years
  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
• Rise in transaminase (ALT and AST) and concurrent rise in bilirubin — at routine clinical care throughout the follow up, with frequency of 6 to 12 months, up to 6 years
  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
• Cumulative incidence of ocular toxicity — at routine clinical care throughout the follow up, with frequency of 6 to 12 months
  An abnormal ocular examination will be detected as present or absent based on the physician's reading, as a marker of potential ocular toxicity
• Cumulative incidence of Abnormal pubertal development — at routine clinical care throughout the follow up, with frequency of 6 to 12 months
  Tanner stage 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)

Trial sites (46)

+ 6 more sites — see the full list on the official registry below.

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