Back to resultsA Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
Primary Purpose
Neurofibromatosis 1, Neurofibroma Plexiform
Status
Active
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Selumetinib
Sponsored by
About this trial
This is an interventional treatment trial for Neurofibromatosis 1 focused on measuring Neurofibromatosis Type 1, Plexiform Neurofibromas, Phase 1, Selumetinib, Chinese, Paediatric, Adult
Eligibility Criteria
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.
Sites / Locations
- Research Site
- Research Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Selumetinib
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
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
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
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
Secondary Outcome Measures
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
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
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
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
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
Measures of Physical function via Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire
Measures health-related quality of life (HRQoL) via PedsQL (paediatric cohort, self-and parent-reported)
Measures of pain via FLACC scale
Measures health-related quality of life (HRQoL) via EORTC QLQ-C30 (adult cohort)
Measures health-related quality of life (HRQoL) via PlexiQoL (adult cohort)
Measures of pain via Faces Pain Scale (revised)
Measures of pain via NRS-11
Measures of pain via PII
Measures of pain via Pain Medication Survey
Full Information
NCT ID
NCT04590235
First Posted
July 28, 2020
Last Updated
August 9, 2023
Sponsor
AstraZeneca
Collaborators
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT04590235
Brief Title
A Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
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)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 16, 2020 (Actual)
Primary Completion Date
August 16, 2022 (Actual)
Study Completion Date
October 31, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AstraZeneca
Collaborators
Merck Sharp & Dohme LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No
5. Study Description
Brief 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).
Detailed 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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neurofibromatosis 1, Neurofibroma Plexiform
Keywords
Neurofibromatosis Type 1, Plexiform Neurofibromas, Phase 1, Selumetinib, Chinese, Paediatric, Adult
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
32 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Selumetinib
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Selumetinib
Other Intervention Name(s)
Koselugo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Adverse events
Description
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.
Time Frame
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.
Title
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
Description
AUC0-t after single dose and multiple doses administration
Time Frame
From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
Title
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
Description
Cmax after single dose and multiple doses administration
Time Frame
From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
Title
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
Description
t1/2 after single dose and multiple doses administration
Time Frame
From the first consent patient first dose to last patient steady state PK collection. Expected duration is approximately 1 year.
Secondary Outcome Measure Information:
Title
objective response rate (ORR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas
Description
measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
duration of response (DoR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas
Description
measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
progression-free survival (PFS) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas
Description
measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
time to progression (TTP) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas
Description
measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
time to response (TTR) of selumetinib in Chinese paediatric and adult subjects with Neurofibromatosis Type 1 and inoperable Plexiform Neurofibromas
Description
measured by 3D volumetric magnetic resonance imaging (MRI) of the target and nontarget PN
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures of Physical function via Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures health-related quality of life (HRQoL) via PedsQL (paediatric cohort, self-and parent-reported)
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures of pain via FLACC scale
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures health-related quality of life (HRQoL) via EORTC QLQ-C30 (adult cohort)
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures health-related quality of life (HRQoL) via PlexiQoL (adult cohort)
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures of pain via Faces Pain Scale (revised)
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures of pain via NRS-11
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures of pain via PII
Time Frame
First patient first dose until up to 2 years after last subject dosed
Title
Measures of pain via Pain Medication Survey
Time Frame
First patient first dose until up to 2 years after last subject dosed
10. Eligibility
Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Qingfeng Li
Organizational Affiliation
Shanghai Ninth People's Hospital affiliated to Shanghai JiaoTong University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Research Site
City
Shanghai
ZIP/Postal Code
200011
Country
China
Facility Name
Research Site
City
Shanghai
ZIP/Postal Code
CN-200092
Country
China
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
IPD Sharing Time Frame
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
IPD Sharing Access Criteria
When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
IPD Sharing URL
https://astrazenecagroup-dt.pharmacm.com/DT/Home
Learn more about this trial
A Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
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