PASS of Paediatric Patients Initiating Selumetinib
- Conditions
- Neurofibromatosis Type 1
- Registration Number
- NCT05388370
- Lead Sponsor
- AstraZeneca
- Brief 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.
- Detailed Description
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 (aged 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 up to 52 specialist clinics for the treatment of pediatric patients with NF1 across up to 12 European countries and in Israel.
The primary objective of this study is:
- To characterise the safety of selumetinib, including up to 6 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).
The study observation period was anticipated to begin in Q2 of 2022, with some variation by country (actual start date was 23 May 2022). Patients will be enrolled after selumetinib access is commercially available and patients are able to receive the medicine as part of local 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:
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.
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 standard of care visits with the treating clinician (expected to occur every 6 to 12 months) for up to 6 years.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 125
- Have been diagnosed with NF1 with symptomatic, inoperable PN
- Have initial treatment with selumetinib up to 6 months (i.e.182 days)prior to enrolment into the study (i.e. signature of the ICF)
- 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
- Have received treatment with a mitogen-activated protein kinase inhibitor before the index date
- Are participating in an interventional study at index date
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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)
- Secondary Outcome Measures
Name Time Method baseline data - demographics At baseline - most recent assessments made within 365 days before the index date Ethnicity (where allowed by GDPR/privacy laws)
Baseline data - Clinical characteristics At baseline - most recent assessments made within 365 days before the index date date of initial NF1 and PN diagnosis, NF1 origin (familial or spontaneous), and any genetic testing results
Trial Locations
- Locations (1)
Research Site
🇬🇧Newcastle, United Kingdom