Selumetinib Paediatric NF1 Japan study

Study identifier:D1346C00013

ClinicalTrials.gov identifier:NCT04495127

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

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

Medical condition

Neurofibromatosis Type 1

Phase

Phase 1

Healthy volunteers

Study drug

Selumetinib

Sex

All

Actual Enrollment

Study type

Interventional

Age

3 Years - 18 Years

Date

Study Start Date: 31 Aug 2020

Primary Completion Date: 16 Jun 2021

Study Completion Date: 24 Mar 2023

Study design

Allocation: N/A
Endpoint Classification: -
Intervention Model: Single Group Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Sept 2024 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

- Three years of age or older, and less than or equal to 18 years of age at the time of obtaining informed consent. BSA greater than or equal to 0.55 m2, and able to swallow the whole study drug (capsules) without entire contents unpacked from the capsules.
- NF1 and inoperable and symptomatic PN who have PN-related morbidities (symptom and/or complications), as judged by the investigator.
- Inoperable PN is defined as PN that cannot be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN.
- A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve.
- In addition to PN, subjects must have at least 1 other diagnostic criterion for NF1 as follows:
1. Six or more café-au-lait macules >5 mm in greatest diameter in pre-pubertal individuals and >15 mm in greatest diameter in post-pubertal individuals.
2. Freckling in the axillary or inguinal regions.
3. Optic glioma.
4. Two or more Lisch nodules (iris hamartomas).
5. A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis.
6. A first-degree relative with NF1.
- At least one measurable typical or nodular PN in principle, defined as a lesion of at least 3 cm measured in one dimension.
- Adequate organ/haematological function

Exclusion Criteria

- Evidence of malignant peripheral nerve sheath tumour.
- Prior malignancy (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low grade optic pathway gliomas associated with NF1 which does not require systemic treatment 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.
- Clinically significant cardiovascular disease
- Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or any uncontrolled active systemic infection
- Subjects with clinically significant ophthalmological findings/conditions
- Inability to undergo MRI and/or contraindication for MRI (i.e. prosthesis or orthopaedic or dental braces that would interfere with volumetric analysis of target PN on MRI).
- Have refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would adversely affect the absorption/bioavailability of the orally administered study medication.
- Receiving supplementation with vitamin E greater than 100% of the daily recommended dose.
- Receiving herbal supplements or medications known to be strong inhibitors or inducers of the cytochrome P450 (CYP) 3A4 enzymes unless such products can be safely discontinued at least 14 days before the first dose of study medication.

Location

Research Site

Setagaya-ku, Japan, 157-8535

Location

Research Site

Minato-ku, Japan, 105-8471

Location

Research Site

Nagoya-shi, Japan, 466-8560

Arms	Assigned Interventions
Experimental: Selumetinib	-

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This is a Phase 1 open label study to assess the safety, tolerability, pharmacokinetics and efficacy of selumetinib, a selective mitogen activated protein kinase kinase (MEK) 1 inhibitor, in Japanese paediatric subjects with neurofibromatosis Type 1 (NF1) and inoperable and symptomatic plexiform neurofibromas (PN). The first subject was enrolled on 31 August 2020. The final data cut-off date was 23 December 2023.

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

This is a Phase 1 open label study to assess the safety, tolerability, pharmacokinetics and efficacy of selumetinib, a selective mitogen activated protein kinase kinase (MEK) 1 inhibitor, in Japanese paediatric subjects with neurofibromatosis Type 1 (NF1) and inoperable and symptomatic plexiform neurofibromas (PN). The first subject was enrolled on 31 August 2020. The final data cut-off date was 23 December 2023.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study had a screening period (up to 28 days), treatment period, and follow-up period (30 days). A total of 12 subjects were enrolled in the study.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Participant Flow: Overall Study

	Selumetinib 25 mg/m2 twice daily (BID).
STARTED	12
COMPLETED	0
NOT COMPLETED	12
Ongoing study	12

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Baseline Measures

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants [units: Participants]	12
Sex: Female, Male [units: ]
Female	9
Male	3
Race/Ethnicity, Customized [units: ] Ethnic group : Asian	12
Age Continuous [units: Years] Median ( Full Range ) Years	13.25 (7.5 to 18.2)
Race/Ethnicity, Customized [units: ] Ethnic population Japanese	12

Outcome Measures

1. Primary Outcome Measure: Safety and tolerability in terms of adverse events [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately 2 years. ]

Measure Type	Primary
Measure Name	Safety and tolerability in terms of adverse events
Measure Description	Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms, safety laboratory parameters, echocardiogram and ophthalmologic assessment.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately 2 years.
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Safety and tolerability in terms of adverse events [units: Participants]
Any AE	12
Any AE possibly related to treatment	11
Any AE of CTCAE Grade 3 or higher	2
Any AE of CTCAE Grade 3 or higher, possibly related to treatment	2
Any AE with outcome = death	0
Any AE with outcome = death, possibly related to treatment	0
Any SAE (including events with outcome = death)	1
Any SAE (including events with outcome = death), possibly related to treatment	1
Any AE leading to discontinuation of selumetinib	0
Any AE leading to dose reduction of selumetinib	4
Any AE leading to dose interruption of selumetinib	4
Any AEs of special interest	5

No statistical analysis provided for Safety and tolerability in terms of adverse events

2. Secondary Outcome Measure: Maximum plasma concentration (Cmax) of selumetinib [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Maximum plasma concentration (Cmax) of selumetinib
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Maximum plasma concentration (Cmax) of selumetinib [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Cycle 1 Day 1	783.1 (52.70%)
Cycle 2 Day 1	869.4 (53.53%)

No statistical analysis provided for Maximum plasma concentration (Cmax) of selumetinib

3. Secondary Outcome Measure: Time to maximum plasma concentration (tmax) of selumetinib [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Time to maximum plasma concentration (tmax) of selumetinib
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Time to maximum plasma concentration (tmax) of selumetinib [units: hour] Median (Full Range)
Cycle 1 Day 1	1.49 (0.50 to 3.05)
Cycle 2 Day 1	1.47 (0.42 to 2.87)

No statistical analysis provided for Time to maximum plasma concentration (tmax) of selumetinib

4. Secondary Outcome Measure: Area under the concentration-time curve from zero to the last measurable concentration (AUC0-t) of selumetinib [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Area under the concentration-time curve from zero to the last measurable concentration (AUC0-t) of selumetinib
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Area under the concentration-time curve from zero to the last measurable concentration (AUC0-t) of selumetinib [units: hour*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Cycle 1 Day 1	2224 (37.61%)
Cycle 2 Day 1	2395 (40.32%)

No statistical analysis provided for Area under the concentration-time curve from zero to the last measurable concentration (AUC0-t) of selumetinib

5. Secondary Outcome Measure: Area under the concentration-time curve from zero to 6 hours (AUC0-6) of selumetinib [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Area under the concentration-time curve from zero to 6 hours (AUC0-6) of selumetinib
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Area under the concentration-time curve from zero to 6 hours (AUC0-6) of selumetinib [units: hour*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Cycle 1 Day 1	1926 (41.64%)
Cycle 2 Day 1	2396 (40.32%)

No statistical analysis provided for Area under the concentration-time curve from zero to 6 hours (AUC0-6) of selumetinib

6. Secondary Outcome Measure: Area under the concentration-time curve from zero to 12 hours (AUC0-12) of selumetinib [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Area under the concentration-time curve from zero to 12 hours (AUC0-12) of selumetinib
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	8
Area under the concentration-time curve from zero to 12 hours (AUC0-12) of selumetinib [units: hour*ng/mL] Geometric Mean (Geometric Coefficient of Variation)	2523 (24.23%)

No statistical analysis provided for Area under the concentration-time curve from zero to 12 hours (AUC0-12) of selumetinib

7. Secondary Outcome Measure: Trough plasma concentration (Ctrough) of selumetinib [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Trough plasma concentration (Ctrough) of selumetinib
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	11
Trough plasma concentration (Ctrough) of selumetinib [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	92.66 (63.21%)

No statistical analysis provided for Trough plasma concentration (Ctrough) of selumetinib

8. Secondary Outcome Measure: Accumulation ratio based on Cmax (RAC[Cmax]) of selumetinib [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Accumulation ratio based on Cmax (RAC[Cmax]) of selumetinib
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	11
Accumulation ratio based on Cmax (RAC[Cmax]) of selumetinib [units: -fold] Geometric Mean (Geometric Coefficient of Variation)	1.101 (34.30%)

No statistical analysis provided for Accumulation ratio based on Cmax (RAC[Cmax]) of selumetinib

9. Secondary Outcome Measure: Accumulation ratio based on AUC (RAC[AUC]) [ Time Frame: From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years. ]

Measure Type	Secondary
Measure Name	Accumulation ratio based on AUC (RAC[AUC])
Measure Description	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.
Time Frame	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least 1 dose of selumetinib and had at least 1 post-dose evaluable concentration-time data point.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	11
Accumulation ratio based on AUC (RAC[AUC]) [units: -fold] Geometric Mean (Geometric Coefficient of Variation)	1.271 (17.32%)

No statistical analysis provided for Accumulation ratio based on AUC (RAC[AUC])

10. Secondary Outcome Measure: Overall response rate [ Time Frame: Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days. ]

Measure Type	Secondary
Measure Name	Overall response rate
Measure Description	Defined as the proportion of subjects who achieve a response by independent central review per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria.
Time Frame	Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Overall response rate [units: % of participants] Number (95% Confidence Interval)	50 (21.1 to 78.9)

No statistical analysis provided for Overall response rate

11. Secondary Outcome Measure: Duration of response [ Time Frame: Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days. ]

Measure Type	Secondary
Measure Name	Duration of response
Measure Description	Defined as the time from the date of the first documented response (which is subsequently confirmed) until the date of documented progression or death in the absence of disease progression, as determined by independent central review per REiNS criteria.
Time Frame	Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	6
Duration of response [units: Participants]	1

No statistical analysis provided for Duration of response

12. Secondary Outcome Measure: Clinical Global Impression of Change (CGIC) [ Time Frame: Assessed at every 2 cycles for the first year and every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days. ]

Measure Type	Secondary
Measure Name	Clinical Global Impression of Change (CGIC)
Measure Description	Comprehensive evaluation will be performed by investigator on the changes of PN related morbidities (symptoms and/or complications), and relevant findings including imaging studies and physical exams from baseline.
Time Frame	Assessed at every 2 cycles for the first year and every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Clinical Global Impression of Change (CGIC) [units: Participants]
Cycle 5 Day 1
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse
Cycle 9 Day 1
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse
Cycle 13 Day 1
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse
Cycle 17 Day 1
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse
Cycle 21 Day 1
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse
Cycle 25 Day 1
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse
Much better	3
Moderately better	2
A little better	6
About the same	1
A little worse	0
Moderately worse	0
Much worse	0

No statistical analysis provided for Clinical Global Impression of Change (CGIC)

13. Secondary Outcome Measure: Total scale score of Paediatric Quality of Life Inventory (PedsQL; self-reported) [ Time Frame: Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days. ]

Measure Type	Secondary
Measure Name	Total scale score of Paediatric Quality of Life Inventory (PedsQL; self-reported)
Measure Description	Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). A Total Scale Score will also be derived as the sum of all the items divided by the number of items answered on all the scales.
Time Frame	Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Total scale score of Paediatric Quality of Life Inventory (PedsQL; self-reported) [units: Change from baseline] Mean (Standard Deviation)
Cycle 03 Day 01	5.34 (6.835)
Cycle 05 Day 01	5.71 (8.997)
Cycle 07 Day 01	6.43 (7.408)
Cycle 09 Day 01	6.07 (6.740)
Cycle 11 Day 01	6.16 (6.478)
Cycle 13 Day 01	6.43 (6.069)
Cycle 17 Day 01	6.79 (6.306)
Cycle 21 Day 01	10.05 (8.548)
Cycle 25 Day 01	8.97 (9.084)

No statistical analysis provided for Total scale score of Paediatric Quality of Life Inventory (PedsQL; self-reported)

14. Secondary Outcome Measure: Total scale score of Paediatric Quality of Life Inventory (PedsQL; parent-reported) [ Time Frame: Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days. ]

Measure Type	Secondary
Measure Name	Total scale score of Paediatric Quality of Life Inventory (PedsQL; parent-reported)
Measure Description	Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). A Total Scale Score will also be derived as the sum of all the items divided by the number of items answered on all the scales.
Time Frame	Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Measured Values

	Selumetinib 25 mg/m2 twice daily (BID).
Number of Participants Analyzed [units:participants]	12
Total scale score of Paediatric Quality of Life Inventory (PedsQL; parent-reported) [units: Change from baseline] Mean (Standard Deviation)
Cycle 03 Day 01	2.81 (7.187)
Cycle 05 Day 01	0.45 (11.329)
Cycle 07 Day 01	0.36 (7.377)
Cycle 09 Day 01	1.45 (11.829)
Cycle 11 Day 01	2.81 (9.837)
Cycle 13 Day 01	1.27 (11.687)
Cycle 17 Day 01	3.62 (7.952)
Cycle 21 Day 01	6.61 (10.982)
Cycle 25 Day 01	3.62 (13.468)

No statistical analysis provided for Total scale score of Paediatric Quality of Life Inventory (PedsQL; parent-reported)

Serious Adverse Events

Time Frame	AEs are reported from first administration of study treatment up to 30 days after the last dose of study treatment.
Additional Description	The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Serious Adverse Events

Selumetinib 25 mg/m2 twice daily (BID).

Total, serious adverse events

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Paronychia¹,^†

# participants affected / at risk

1/12 (8.33%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 25.1

Other Adverse Events

Time Frame	AEs are reported from first administration of study treatment up to 30 days after the last dose of study treatment.
Additional Description	The safety analysis set included all subjects who received at least 1 dose of selumetinib.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Selumetinib 25 mg/m2 twice daily (BID).	Subjects will receive oral dose of selumetinib 25 mg/m2 twice daily (BID) continuously for 28-day cycles.

Other Adverse Events

Selumetinib 25 mg/m2 twice daily (BID).

Total, other (not including serious) adverse events

# participants affected / at risk

12/12 (100.00%)

Infections and infestations

COVID-19¹,^†

# participants affected / at risk

4/12 (33.33%)

Infections and infestations

Cellulitis¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Gastrointestinal infection¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Hordeolum¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Impetigo¹,^†

# participants affected / at risk

3/12 (25.00%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Otitis externa¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Otitis media¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Paronychia¹,^†

# participants affected / at risk

6/12 (50.00%)

Infections and infestations

Sinusitis¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Skin infection¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Tinea cruris¹,^†

# participants affected / at risk

1/12 (8.33%)

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

2/12 (16.67%)

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

1/12 (8.33%)

Metabolism and nutrition disorders

Hypozincaemia¹,^†

# participants affected / at risk

1/12 (8.33%)

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

1/12 (8.33%)

Nervous system disorders

Dysaesthesia¹,^†

# participants affected / at risk

1/12 (8.33%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

4/12 (33.33%)

Eye disorders

Conjunctivitis allergic¹,^†

# participants affected / at risk

2/12 (16.67%)

Eye disorders

Periorbital oedema¹,^†

# participants affected / at risk

2/12 (16.67%)

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

1/12 (8.33%)

Respiratory, thoracic and mediastinal disorders

Epistaxis¹,^†

# participants affected / at risk

2/12 (16.67%)

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

3/12 (25.00%)

Gastrointestinal disorders

Cheilitis¹,^†

# participants affected / at risk

3/12 (25.00%)

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

1/12 (8.33%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

5/12 (41.67%)

Gastrointestinal disorders

Gastritis¹,^†

# participants affected / at risk

1/12 (8.33%)

Gastrointestinal disorders

Gastrointestinal disorder¹,^†

# participants affected / at risk

1/12 (8.33%)

Gastrointestinal disorders

Malocclusion¹,^†

# participants affected / at risk

1/12 (8.33%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

3/12 (25.00%)

Gastrointestinal disorders

Stomatitis¹,^†

# participants affected / at risk

4/12 (33.33%)

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

4/12 (33.33%)

Skin and subcutaneous tissue disorders

Acne¹,^†

# participants affected / at risk

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Alopecia¹,^†

# participants affected / at risk

3/12 (25.00%)

Skin and subcutaneous tissue disorders

Dermatitis acneiform¹,^†

# participants affected / at risk

6/12 (50.00%)

Skin and subcutaneous tissue disorders

Dermatitis atopic¹,^†

# participants affected / at risk

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Dermatitis contact¹,^†

# participants affected / at risk

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Dry skin¹,^†

# participants affected / at risk

3/12 (25.00%)

Skin and subcutaneous tissue disorders

Pruritus¹,^†

# participants affected / at risk

3/12 (25.00%)

Skin and subcutaneous tissue disorders

Rash macular¹,^†

# participants affected / at risk

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Seborrhoeic dermatitis¹,^†

# participants affected / at risk

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Skin fissures¹,^†

# participants affected / at risk

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Urticaria¹,^†

# participants affected / at risk

1/12 (8.33%)

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

1/12 (8.33%)

Musculoskeletal and connective tissue disorders

Pain in extremity¹,^†

# participants affected / at risk

1/12 (8.33%)

Musculoskeletal and connective tissue disorders

Scoliosis¹,^†

# participants affected / at risk

1/12 (8.33%)

Renal and urinary disorders

Pollakiuria¹,^†

# participants affected / at risk

1/12 (8.33%)

Reproductive system and breast disorders

Menstruation irregular¹,^†

# participants affected / at risk

2/12 (16.67%)

General disorders

Face oedema¹,^†

# participants affected / at risk

1/12 (8.33%)

General disorders

Feeling abnormal¹,^†

# participants affected / at risk

1/12 (8.33%)

General disorders

Injection site reaction¹,^†

# participants affected / at risk

2/12 (16.67%)

General disorders

Malaise¹,^†

# participants affected / at risk

2/12 (16.67%)

General disorders

Nodule¹,^†

# participants affected / at risk

1/12 (8.33%)

General disorders

Oedema peripheral¹,^†

# participants affected / at risk

1/12 (8.33%)

General disorders

Pyrexia¹,^†

# participants affected / at risk

5/12 (41.67%)

Investigations

Alanine aminotransferase increased¹,^†

# participants affected / at risk

2/12 (16.67%)

Investigations

Aspartate aminotransferase increased¹,^†

# participants affected / at risk

3/12 (25.00%)

Investigations

Blood creatine phosphokinase increased¹,^†

# participants affected / at risk

1/12 (8.33%)

Investigations

Ejection fraction decreased¹,^†

# participants affected / at risk

2/12 (16.67%)

Injury, poisoning and procedural complications

Arthropod bite¹,^†

# participants affected / at risk

1/12 (8.33%)

Injury, poisoning and procedural complications

Bone contusion¹,^†

# participants affected / at risk

1/12 (8.33%)

Injury, poisoning and procedural complications

Forearm fracture¹,^†

# participants affected / at risk

1/12 (8.33%)

Injury, poisoning and procedural complications

Ligament sprain¹

# participants affected / at risk

1/12 (8.33%)

Injury, poisoning and procedural complications

Skin abrasion¹,^†

# participants affected / at risk

1/12 (8.33%)

Injury, poisoning and procedural complications

Skin laceration¹,^†

# participants affected / at risk

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Eczema¹,^†

# participants affected / at risk

7/12 (58.33%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 25.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

CSR Synopsis

Trial Results Summaries