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

Study Overview
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Brief Summary
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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).

Detailed Description
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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

Official Title
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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)

Conditions
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Neurofibromatosis 1, Neurofibroma Plexiform

Intervention / Treatment
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* Drug: Selumetinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 99 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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selumetinib<br>All eligible subjects will first receive a single oral dose of selumetinib 25 mg/m^2. Then, selumetinib 25 mg/m^2 oral twice daily will be administered continuously until disease progression or unacceptable drug-related toxicity, whichever occurs first. | Drug: Selumetinib<br>* 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.<br>* Other names: Koselugo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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. | 
| 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. | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Measures of pain via FLACC scale |  | First patient first dose until up to 2 years after last subject dosed | 
| 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 | 
| Measures health-related quality of life (HRQoL) via PlexiQoL (adult cohort) |  | First patient first dose until up to 2 years after last subject dosed | 
| Measures of pain via Faces Pain Scale (revised) |  | First patient first dose until up to 2 years after last subject dosed | 
| Measures of pain via NRS-11 |  | First patient first dose until up to 2 years after last subject dosed | 
| Measures of pain via PII |  | First patient first dose until up to 2 years after last subject dosed | 
| Measures of pain via Pain Medication Survey |  | First patient first dose until up to 2 years after last subject dosed | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurofibromatosis Type 1, Plexiform Neurofibromas, Phase 1, Selumetinib, Chinese, Paediatric, Adult