PASS of Paediatric Patients Initiating Selumetinib

Neurofibromatosis Type 1 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05388370
• Other study ID #: D1346R00004
• Status: Recruiting
• Start date: May 23, 2022
• Est. completion date: May 23, 2028

Study information

• Verified date: June 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 125
• Est. completion date: May 23, 2028
• Est. primary completion date: May 23, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 17 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• Have received treatment with a mitogen-activated protein kinase inhibitor before the index date

• Are participating in an interventional study at index date

Related Conditions & MeSH terms

• Neurofibroma
• Neurofibromatoses
• Neurofibromatosis 1
• Neurofibromatosis Type 1

Locations

Country	Name	City	State
Austria	Research Site	Wien
France	Research Site	Amiens
France	Research Site	Angers
France	Research Site	Bordeaux
France	Research Site	Lille
France	Research Site	Lyon
France	Research Site	Marseille
France	Research Site	Paris
France	Research Site	Strasbourg
France	Research Site	Toulouse
France	Research Site	Tours
France	Research Site	Villejuif Cedex
Germany	Research Site	Duisburg
Germany	Research Site	Hamburg
Germany	Research Site	München
Germany	Research Site	Tubingen
Israel	Research Site	Petach Tikva
Israel	Research Site	Ramat Gan
Italy	Research Site	Firenze
Italy	Research Site	Genova
Italy	Research Site	Milano
Italy	Research Site	Padova
Italy	Research Site	Pavia
Italy	Research Site	Roma
Italy	Research Site	Torino
Italy	Research Site	Trieste
Portugal	Research Site	Lisboa
Portugal	Research Site	Porto
Spain	Research Site	Barcelona
Spain	Research Site	Esplugues de Llobregat
Spain	Research Site	Madrid
Spain	Research Site	Santiago de Compostela
Spain	Research Site	Sevilla
Switzerland	Research Site	Basel
Switzerland	Research Site	Bern
Switzerland	Research Site	Lausanne
Switzerland	Research Site	St. Gallen
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

Austria,  France,  Germany,  Israel,  Italy,  Portugal,  Spain,  Switzerland,  United Kingdom, 

References & Publications (5)

EMA2017b EMA. Guideline on good pharmacovigilance practices (GVP). Module VIII - Post-authorisation safety studies (EMA/813938/2011 Rev 3). European Medicines Agency; 09 October 2017b. Available at: https://www.ema.europa.eu/documents/scientificguideline/ guideline-good-pharmacovigilance-practices-gvp-

ISPE. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf. 2008 Feb;17(2):200-8. doi: 10.1002/pds.1471. No abstract available. — View Citation

KOSELUGO (selumetinib) KOSELUGO (selumetinib) capsules, for oral use, initial US Approval: 2020. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. USPI revised April 2020, Reference ID 4590044.

von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007 Oct 20;370(9596):1453-7. doi: 10.1016/S0140-6736(07)61602-X. — View Citation

Zhou Q. [Recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals]. Zhonghua Gan Zang Bing Za Zhi. 2014 Oct;22(10):781-91. No abstract available. Chinese. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Other Variables and Covariates	Height (cm)	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	Weight (kg)	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	Body surface area	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	Tanner staging (level from I to V)	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	Concomitant medications, including any medications used to treat AEs	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	Comorbidities	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	NF1-related clinical manifestation and complications	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	PN-related variables (including for any clinically important target PNs)	at baseline and throughout follow-up, up to 6 years
Other	Other Variables and Covariates	PN-related symptoms/morbidities	at baseline and throughout follow-up, up to 6 years
Primary	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
Primary	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
Primary	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 6 years
Primary	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 6 years
Primary	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
Primary	Cumulative incidence of Abnormal pubertal development	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)	at routine clinical care throughout the follow up, with frequency of 6 to 12 months
Secondary	baseline data - demographics	Demographics: Age	At baseline - most recent assessments made within 365 days before the index date
Secondary	baseline data - demographics	sex	At baseline - most recent assessments made within 365 days before the index date
Secondary	baseline data - demographics	height (cm)	At baseline - most recent assessments made within 365 days before the index date
Secondary	baseline data - demographics	weight (kg)	At baseline - most recent assessments made within 365 days before the index date
Secondary	baseline data - demographics	Tanner staging level	At baseline - most recent assessments made within 365 days before the index date
Secondary	baseline data - demographics	Ethnicity (where allowed by GDPR/privacy laws)	At baseline - most recent assessments made within 365 days before the index date
Secondary	Baseline data - Clinical characteristics	PN(s) (number, location, classification and morbidities)	At baseline - most recent assessments made within 365 days before the index date
Secondary	Baseline data - Clinical characteristics	prior medication and relevant procedures, concomitant medications	At baseline - most recent assessments made within 365 days before the index date
Secondary	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