A Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)

Neurofibromatosis 1 Clinical Trial

Official title:

A Phase 1 Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Selumetinib, a Selective Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor, in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04590235
• Other study ID #: D1346C00011
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 16, 2020
• Est. completion date: August 31, 2026

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A Phase 1 Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of Selumetinib, a Selective Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor, in Chinese Paediatric and Adult Subjects with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN).

Description:

Paediatric and adult patients with Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN) will be evaluated in the screening visit to confirm eligibility. Approximately 16 paediatric and 16 adult qualified patients will receive oral selumetinib 25 mg/m^2 twice a day (approximately every 12 hours) continuously until disease progression or unacceptable drug-related toxicity, whichever occurs first. Once a patient has discontinued the study treatment then the patient will be followed for specified period for safety assessment

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 32
• Est. completion date: August 31, 2026
• Est. primary completion date: August 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 99 Years

Eligibility

Inclusion Criteria:

• Paediatric cohort: Chinese subjects =3 years and <18 years of age
• Adult cohort: Chinese subjects =18 years of age at the time of study enrollment
• Subjects must be diagnosed with (i) NF1 as per NIH Consensus Development Conference Statement and(ii) PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. (iii) inoperable PN
• Subjects must have at least one measurable typical or nodular PN
• Absolute neutrophil count =1.5×10^9/L, haemoglobin =9g/dL, and platelet count =100×10^9/L. Subject must be without growth factor support and platelet transfusion support 7 days before the screening assessment.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2×upper limit of normal (ULN), total bilirubin =1.5×ULN except in the case of subjects with documented Gilbert's disease (=2.5×ULN).

Exclusion Criteria:

• Evidence of malignant peripheral nerve sheath tumour.
• Clinically significant cardiovascular disease
• Prior malignancy (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject had been disease free for =2 years or which would not have limited survival to <2 years) or other cancer requiring treatment with chemotherapy or radiation therapy.
• Subjects with the following ophthalmological findings/conditions:

Current or past history of retinal pigment epithelial detachment/central serous retinopathy or retinal vein occlusion; Intraocular pressure >21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP); Subjects with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study physician; Any other significant abnormality on ophthalmic examination that would make the subject unsuitable for enrolment into the study, as assessed by the investigator.

Related Conditions & MeSH terms

• Neurofibroma
• Neurofibroma Plexiform
• Neurofibroma, Plexiform
• Neurofibromatoses
• Neurofibromatosis 1

Intervention

Drug:
• Selumetinib
All eligible subjects will first receive a single oral dose of selumetinib 25 mg/m^2. After a washout period of 2 days, oral selumetinib 25 mg/m^2 twice daily will be administered continuously. Subjects will continue to receive selumetinib until disease progression or unacceptable drug-related toxicity, whichever occurs first. 10 mg and 25 mg capsules strengths available.

Locations

Country	Name	City	State
China	Research Site	Shanghai
China	Research Site	Shanghai

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events	Occurrence/frequency.; Relationship to IP as assessed by investigator.; Common Terminology Criteria for Adverse Events (CTCAE) grade.; Seriousness.; Death.; Adverse events leading to discontinuation of IP.; Adverse events of special interest.	For paediatric cohort: from signing the informed consent form until up to 3 years after last subject dosed; For adult cohort: from signing the informed consent form until up to 2 years+30 days after last subject dosed.
Primary	Area under the concentration-time curve from zero to the last measurable concentration (AUC0-t) of selumetinib and its metabolite (N-desmethyl selumetinib) in Chinese paediatric and adult subjects with NF 1 and inoperable Plexiform Neurofibromas	AUC0-t after single dose and multiple doses administration	From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
Primary	Maximum plasma concentration (Cmax) of selumetinib and its metabolite (N-desmethyl selumetinib) in Chinese paediatric and adult subjects with NF 1 and inoperable Plexiform Neurofibromas	Cmax after single dose and multiple doses administration	From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
Primary	Terminal half-life (t1/2) of selumetinib and its metabolite (N-desmethyl selumetinib) in Chinese paediatric and adult subjects with NF 1 and inoperable Plexiform Neurofibromas	t1/2 after single dose and multiple doses administration	From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
Secondary	objective response rate (ORR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas	measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN	First patient first dose until up to 2 years after last subject dosed
Secondary	duration of response (DoR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas	measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN	First patient first dose until up to 2 years after last subject dosed
Secondary	progression-free survival (PFS) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas	measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN	First patient first dose until up to 2 years after last subject dosed
Secondary	time to progression (TTP) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas	measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN	First patient first dose until up to 2 years after last subject dosed
Secondary	time to response (TTR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas	measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN	First patient first dose until up to 2 years after last subject dosed
Secondary	Measures of Physical function via Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures health-related quality of life (HRQoL) via PedsQL (paediatric cohort, self-and parent-reported)		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures of pain via FLACC scale		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures health-related quality of life (HRQoL) via EORTC QLQ-C30 (adult cohort)		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures health-related quality of life (HRQoL) via PlexiQoL (adult cohort)		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures of pain via Faces Pain Scale (revised)		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures of pain via NRS-11		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures of pain via PII		First patient first dose until up to 2 years after last subject dosed
Secondary	Measures of pain via Pain Medication Survey		First patient first dose until up to 2 years after last subject dosed

External Links

•   Clinical Study Protocol Redacted
•   CSR Synopsis Redacted
•   SAP Redacted