A Study to Evaluate Bioavailability and Food Effect of Selumetinib (AZD6244) in Healthy Male participants

Study identifier:D1532C00089

ClinicalTrials.gov identifier:NCT03649165

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase I, Open-label, Single-center Relative Bioavailability and Food Effect Randomized Crossover Study of New Granule and Capsule Formulations of Selumetinib (AZD6244) in Healthy Male Subjects

Medical condition

Neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PNs), Healthy Participants

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Treatment A, Treatment B, Treatment C, Treatment D, Acetaminophen

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 45 Years

Date

Study Start Date: 05 Sept 2018

Primary Completion Date: 21 Oct 2018

Study Completion Date: 21 Oct 2018

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Crossover Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Oct 2019 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

1. Provision of signed and dated, written informed consent before any study-specific procedures.
2. Healthy male participants aged 18 to 45 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
3. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg.
4. Participants is able to consume a low-fat meal within a 30-minute period.
5. Participants has a creatinine clearance (CRCL) greater than 50 mL/min using Cockcroft-Gault formula.
6. Participants is willing to comply with contraception requirements as described below:
− Male participants with sexual partners who can become pregnant (i.e., women of childbearing potential) must use 2 highly-effective methods of contraception, one of which must be a barrier method (condom with spermicide) from the time of the first administration of the IMP until 12 weeks after the last administration of the IMP to avoid pregnancy and/or potential adverse effects on the developing embryo.
− Participants with sexual partners who are pregnant must use an effective method of contraception (barrier method) from the time of the first administration of the IMP until 12 weeks after the last administration of the IMP.
− Participants must avoid sperm donation during the study and for 12 weeks after the last administration of the IMP.
− Reliable methods of contraception must be used consistently and correctly.
- Reliable methods of contraception for participants include: Use of barrier methods (condom and spermicide) for the duration of the study until 12 weeks after the last administration of the IMP.
− Acceptable methods for participants partners include:
1) Use of implants, injectables and combined oral contraceptives (must be used in combination with a barrier method of contraception)
2) Use of intrauterine devices (must be used in combination with a barrier method of contraception)

Exclusion Criteria

:
1. Participants of Japanese, non-Japanese Asian or Indian ethnicity.
2. Participants has any one parent or grandparent (maternal or paternal) that was Japanese or non-Japanese Asian (e.g., China, Taiwan, Korea, Philippines, Thailand, Vietnam and Malaysia) or Indian.
3. History or presence of central serous retinopathy or retinal vein thrombosis, IOP greater than 21 mmHg or uncontrolled glaucoma.
4. History of any clinically significant disease or disorder which, in the opinion of the PI, may put the participant at risk because of participation in the study, influence the result of the study or influence the participants ability to participate in the study.
5. Participant has ophthalmologic conditions as follows:
− Current or past history of central serous retinopathy/retinal pigment epithelial detachment or retinal vein occlusion.
− Intra-ocular pressure > 21 mmHg or uncontrolled glaucoma (irrespective of IOP).
6. Participant has any cardiac conditions as follows:
− Uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy).
− Acute coronary syndrome within 6 months before starting treatment.
− Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical therapy.
− Symptomatic heart failure New York Heart Association (NYHA) Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease.
− Prior or current cardiomyopathy including but not limited to the following: 1) Known hypertrophic cardiomyopathy.
2) Known arrhythmogenic right ventricular cardiomyopathy.
3) Previous moderate or severe impairment of LVEF < 45% on echocardiography even if full recovery has occurred.
− Left ventricular ejection fraction below the lower limit of normal (LLN) or < 55% measured by ECHO at the Screening Visit.
− Severe valvular heart disease.
− Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on ECG at rest.
− QTcF > 450 ms or other factors that increase the risk of QT prolongation.
7. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
8. Any clinically relevant abnormal findings in physical examination, hematology, clinical chemistry, urinalysis, vital signs or ECG at the Screening Visit, which in the opinion of the PI, may put the participant at risk because of his participation in the study. Test may be repeated twice at the discretion of the Investigator if abnormal.
9. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
10. A suspected/manifested infection according to the International Air Transport Association (IATA) Categories A and B infectious substances.
11. History of, or current alcohol or drug abuse, as judged by the principal investigator (PI).
12. Participation in another clinical study (investigational product administered within 30 days before the Screening Visit, or participation in a method development study [no drug] 30 days before the Screening Visit). Participation is defined as the completion of a treatment related visit.
13. Planned in-patient surgery, dental procedure or hospitalization during the study.
14. Plasma donation within 30 days of the Screening Visit or any blood donation/loss more than 500 mL during the 90 days before the Screening Visit.
15. A definite or suspected personal history of intolerance or hypersensitivity to drugs and/or their excipients, judged to be clinically relevant by the PI.
16. Known severe hypersensitivity to selumetinib or acetaminophen or any excipient of these medicinal products or history of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib.
17. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 90 days before the Screening Visit.
18. Positive screen for drugs of abuse, alcohol or cotinine at the Screening Visit or on each admission to the Clinical Unit or positive screen for alcohol on each admission to the Clinical Unit.
19. Use of drugs with enzyme-inducing properties such as St John’s Wort within 4 weeks before the first administration of IMP.
20. Use of any prescribed medicine and over-the-counter (OTC) drugs (including herbal remedies, vitamins and minerals) within 2 weeks or 5 times the half-life, whichever is the longer, of the respective drug before Day -1 or Treatment Period 1. No medications known to prolong the QT/QTc interval are allowed.
21. Excessive intake of caffeine-containing drinks or food e.g., coffee, tea, chocolate, Red Bull or cola (more than 6 units of caffeine per day). One caffeine unit is contained in the following items: 1 (6 oz) cup of coffee, 2 (12 oz) cans of cola, 1 (12 oz) cup of tea, ½ (4 oz) cup of energy drink (e.g., Red Bull) or 3 oz of chocolate.
22. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI.
23. Involvement of any AstraZeneca, PAREXEL or Clinical Unit employee or their close relatives.
24. Participants who have previously been randomized to treatment in the current study.
25. Judgment by the PI that the participant should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
26. Vulnerable participants , e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

This study will be a 2-part, open-label, single-center relative bioavailability and food effect randomized crossover study of new granule and capsule formulations of selumetinib. A total of 24 healthy male participants aged between 18 to 45 years (inclusive), will be included to ensure at least 20 evaluable participants. The study is divided in 2 study parts; the same participants will participate in both parts of the study. Part 1 of the study is designed to investigate the PK of the selumetinib granule compared to the PK of selumetinib capsule, when administered with water under the fasted conditions. Part 2 of the study is designed to investigate the PK of selumetinib granule and capsule under fed conditions. Participants will consume a low-fat, low-calorie meal. Thirty minutes after the start of the meal, selumetinib will be administered to the participants. In all treatment periods, participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration where it will act as a marker for gastric emptying. The study will also assess the palatability of the selumetinib granule in both parts of the study. Each participant will receive the following treatments: • Treatment A: 25 mg granule, fasted state • Treatment B: 50 mg capsule, fasted state • Treatment C: 25 mg granule, fed state • Treatment D: 50 mg capsule, fed state Participant will be randomly assigned to 1 of 4 treatment sequences. In all cases the treatments in Part 1 will be administered before the treatments in Part 2. The study will comprise of a screening period of maximum 28 days. Four treatment periods during which participants will be resident from the day before dosing (Day -1) until at least 48 hours after dosing; discharged on the morning of Day 3. A follow-up visit, will be within 7 to 10 days after the last dose of investigational medicinal product (IMP). There will be a minimum washout period of at least 5 days between each IMP administration. Each participant will be involved in the study for approximately 8 to 9 weeks.

Location

Research Site

Baltimore, MD, United States, 21225

Arms	Assigned Interventions
Experimental: Treatment Sequence 1 Participants will receive Treatment A (selumetinib 25 mg granule, fasted state) in Part 1, Period 1, Treatment B (selumetinib 50 mg capsule, fasted state) in Part 1, Period 2, Treatment C (selumetinib 25 mg granule, fed state) in Part 2, Period 3, and Treatment D (selumetinib 50 mg capsule, fed state) in Part 2, Period 4. Participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration where it will act as a marker for gastric emptying.	Drug: Treatment A During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment B During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment C During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Treatment D During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Acetaminophen Participants will receive a single 500mg dose of acetaminophen at the same time.
Experimental: Treatment Sequence 2 Participants will receive Treatment B (selumetinib 50 mg capsule, fasted state) in Part 1, Period 1, Treatment A (selumetinib 25 mg granule, fasted state) in Part 1, Period 2, Treatment C (selumetinib 25 mg granule, fed state) in Part 2, Period 3 and Treatment D (selumetinib 50 mg capsule, fed state) in Part 2, Period 4. Participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration where it will act as a marker for gastric emptying.	Drug: Treatment A During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment B During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment C During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Treatment D During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Acetaminophen Participants will receive a single 500mg dose of acetaminophen at the same time.
Experimental: Treatment Sequence 3 Participants will receive Treatment A (selumetinib 25 mg granule, fasted state) in Part 1, Period 1, Treatment B (selumetinib 50 mg capsule, fasted state) in Part 1, Period 2, Treatment D (selumetinib 50 mg capsule, fed state) in Part 2, Period 3 and Treatment C (selumetinib 25 mg granule, fed state) in Part 2, Period 4. Participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration where it will act as a marker for gastric emptying.	Drug: Treatment A During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment B During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment C During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Treatment D During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Acetaminophen Participants will receive a single 500mg dose of acetaminophen at the same time.
Experimental: Treatment Sequence 4 Participants will receive Treatment B (selumetinib 50 mg capsule, fasted state) in Part 1, Period 1, Treatment A (selumetinib 25 mg granule, fasted state) in Part 1, Period 2, Treatment D (selumetinib 50 mg capsule, fed state) in Part 2, Period 3 and Treatment C (selumetinib 25 mg granule, fed state) in Part 2, Period 4. Participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration where it will act as a marker for gastric emptying.	Drug: Treatment A During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment B During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose. Drug: Treatment C During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Treatment D During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Drug: Acetaminophen Participants will receive a single 500mg dose of acetaminophen at the same time.

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 study was conducted on healthy male participants at a single study center: PAREXEL International, Baltimore.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study consisted of a Screening Period of maximum 28 days. Assessments were done as per the schedule of assessment.

Reporting Groups

	Description
All Participants	Each participant received the following treatments of Selumetinib: Treatment A: 25 mg granule, fasted state; Treatment B: 50 mg capsule, fasted state; Treatment C: 25 mg granule, fed state; and Treatment D: 50 mg capsule, fed state. In all treatment periods the participants also received a single 500 mg dose of acetaminophen at the same time as selumetinib administration.

Participant Flow: Overall Study

	All Participants
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

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

Reporting Groups

	Description
All Participants	Each participant received the following treatments of Selumetinib: Treatment A: 25 mg granule, fasted state; Treatment B: 50 mg capsule, fasted state; Treatment C: 25 mg granule, fed state; and Treatment D: 50 mg capsule, fed state. In all treatment periods the participants also received a single 500 mg dose of acetaminophen at the same time as selumetinib administration.

Baseline Measures

	All Participants
Number of Participants [units: Participants]	24
Age Continuous [units: years] Mean ± Standard Deviation	33.2 ± 5.76
Sex: Female, Male [units: ]
Female	0
Male	24
Race (NIH/OMB) [units: ]
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	20
White	3
More than one race	0
Unknown or Not Reported	1
Ethnicity (NIH/OMB) [units: ]
Hispanic or Latino	4
Not Hispanic or Latino	20
Unknown or Not Reported	0

Outcome Measures

1. Primary Outcome Measure: Selumetinib plasma Pharmacokinetic (PK) parameter: Dose normalized area under plasma concentration-time curve from time zero to infinity (AUC/D) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Primary
Measure Name	Selumetinib plasma Pharmacokinetic (PK) parameter: Dose normalized area under plasma concentration-time curve from time zero to infinity (AUC/D)
Measure Description	To compare the AUC/D of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma Pharmacokinetic (PK) parameter: Dose normalized area under plasma concentration-time curve from time zero to infinity (AUC/D) [units: h*ng/mL/mg] Geometric Mean (Geometric Coefficient of Variation)	51.97 (26.03%)	60.09 (25.29%)	50.14 (23.70%)	37.43 (38.66%)

Statistical Analysis 1 for Selumetinib plasma Pharmacokinetic (PK) parameter: Dose normalized area under plasma concentration-time curve from time zero to infinity (AUC/D)

Groups^[1]	Treatment A; Granule 25 mg, Treatment B; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.865
90% Confidence Interval	( 0.811 to 0.922 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
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[3]	Other relevant information, such as adjustments or degrees of freedom:
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[5]	Other relevant estimation information:
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Statistical Analysis 2 for Selumetinib plasma Pharmacokinetic (PK) parameter: Dose normalized area under plasma concentration-time curve from time zero to infinity (AUC/D)

Groups^[1]	Treatment C; Granule 25 mg, Treatment D; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	1.340
90% Confidence Interval	( 1.171 to 1.532 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
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[5]	Other relevant estimation information:
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2. Primary Outcome Measure: Selumetinib plasma PK parameter: Dose normalized area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast/D) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Primary
Measure Name	Selumetinib plasma PK parameter: Dose normalized area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast/D)
Measure Description	To compare the AUClast/D of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Dose normalized area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast/D) [units: h*ng/mL/mg] Geometric Mean (Geometric Coefficient of Variation)	50.05 (27.19%)	58.65 (25.95%)	47.19 (24.68%)	35.68 (39.76%)

Statistical Analysis 1 for Selumetinib plasma PK parameter: Dose normalized area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast/D)

Groups^[1]	Treatment A; Granule 25 mg, Treatment B; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.853
90% Confidence Interval	( 0.799 to 0.912 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Selumetinib plasma PK parameter: Dose normalized area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast/D)

Groups^[1]	Treatment C; Granule 25 mg, Treatment D; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	1.323
90% Confidence Interval	( 1.151 to 1.520 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Selumetinib plasma PK parameter: Dose normalized maximum observed plasma concentration (Cmax/D) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Primary
Measure Name	Selumetinib plasma PK parameter: Dose normalized maximum observed plasma concentration (Cmax/D)
Measure Description	To compare the Cmax/D of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Dose normalized maximum observed plasma concentration (Cmax/D) [units: ng/mL/mg] Geometric Mean (Geometric Coefficient of Variation)	13.19 (39.95%)	20.17 (41.48%)	7.99 (32.32%)	8.08 (52.14%)

Statistical Analysis 1 for Selumetinib plasma PK parameter: Dose normalized maximum observed plasma concentration (Cmax/D)

Groups^[1]	Treatment A; Granule 25 mg, Treatment B; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.654
90% Confidence Interval	( 0.581 to 0.736 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Selumetinib plasma PK parameter: Dose normalized maximum observed plasma concentration (Cmax/D)

Groups^[1]	Treatment C; Granule 25 mg, Treatment D; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.988
90% Confidence Interval	( 0.819 to 1.191 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Primary Outcome Measure: Selumetinib plasma PK parameter: Fraction of administered selumetinib granule dose systemically available relative to the capsule reference (Frel) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Primary
Measure Name	Selumetinib plasma PK parameter: Fraction of administered selumetinib granule dose systemically available relative to the capsule reference (Frel)
Measure Description	To compare the Frel of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment Ratio; A versus B	Treatment A: During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. Treatment B: During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. For both Treatment A and Treatment B, dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment Ratio; C versus D	Treatment C: During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Treatment D: During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions.For both Treatment C and Treatment D, following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Description

Treatment Ratio; A versus B

Treatment A: During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. Treatment B: During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. For both Treatment A and Treatment B, dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose

Treatment Ratio; C versus D

Treatment C: During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Treatment D: During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions.For both Treatment C and Treatment D, following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment Ratio; A versus B	Treatment Ratio; C versus D
Number of Participants Analyzed [units:participants]	24	24
Selumetinib plasma PK parameter: Fraction of administered selumetinib granule dose systemically available relative to the capsule reference (Frel) [units: ratio] Geometric Mean (Geometric Coefficient of Variation)	86.50 (17.95%)	134 (38.95%)

No statistical analysis provided for Selumetinib plasma PK parameter: Fraction of administered selumetinib granule dose systemically available relative to the capsule reference (Frel)

5. Secondary Outcome Measure: Selumetinib plasma PK parameter: Area under plasma concentration time curve from time zero to infinity (AUC) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Area under plasma concentration time curve from time zero to infinity (AUC)
Measure Description	To compare AUC of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Area under plasma concentration time curve from time zero to infinity (AUC) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)	1299 (26.03%)	3004 (25.29%)	1253 (23.70%)	1871 (38.66%)

Statistical Analysis 1 for Selumetinib plasma PK parameter: Area under plasma concentration time curve from time zero to infinity (AUC)

Groups^[1]	Treatment A; Granule 25 mg, Treatment C; Granule 25 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.965
90% Confidence Interval	( 0.913 to 1.019 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Selumetinib plasma PK parameter: Area under plasma concentration time curve from time zero to infinity (AUC)

Groups^[1]	Treatment B; Capsule 50 mg, Treatment D; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.623
90% Confidence Interval	( 0.554 to 0.701 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Selumetinib plasma PK parameter: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast)
Measure Description	AUClast of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)	1251 (27.19%)	2933 (25.95%)	1180 (24.68%)	1784 (39.76%)

Statistical Analysis 1 for Selumetinib plasma PK parameter: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast)

Groups^[1]	Treatment A; Granule 25 mg, Treatment C; Granule 25 mg
Method^[3]	Other [Liner mixed effect model]
Other^[5]	0.943
90% Confidence Interval	( 0.890 to 0.999 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Selumetinib plasma PK parameter: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast)

Groups^[1]	Treatment B; Capsule 50 mg, Treatment D; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.608
90% Confidence Interval	( 0.539 to 0.686 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Selumetinib plasma PK parameter: Area under the plasma concentration-time curve from zero to 12 hours post-dose [AUC(0-12)] [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Area under the plasma concentration-time curve from zero to 12 hours post-dose [AUC(0-12)]
Measure Description	To compare AUC (0-12) of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Area under the plasma concentration-time curve from zero to 12 hours post-dose [AUC(0-12)] [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)	959.4 (27.41%)	2301 (29.20%)	803.5 (23.20%)	1287 (44.05%)

No statistical analysis provided for Selumetinib plasma PK parameter: Area under the plasma concentration-time curve from zero to 12 hours post-dose [AUC(0-12)]

8. Secondary Outcome Measure: Selumetinib plasma PK parameter: Maximum observed plasma concentration (Cmax) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Maximum observed plasma concentration (Cmax)
Measure Description	To compare Cmax of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Maximum observed plasma concentration (Cmax) [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	329.7 (39.95%)	1009 (41.48%)	199.6 (32.32%)	404.2 (52.14%)

Statistical Analysis 1 for Selumetinib plasma PK parameter: Maximum observed plasma concentration (Cmax)

Groups^[1]	Treatment A; Granule 25 mg, Treatment C; Granule 25 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.605
90% Confidence Interval	( 0.512 to 0.716 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Selumetinib plasma PK parameter: Maximum observed plasma concentration (Cmax)

Groups^[1]	Treatment B; Capsule 50 mg, Treatment D; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	0.401
90% Confidence Interval	( 0.334 to 0.481 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: Selumetinib plasma PK parameter: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
Measure Description	To compare t½λz of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) [units: h] Mean (Standard Deviation)	8.76 (2.35)	9.73 (2.81)	11.79 (3.85)	11.91 (2.65)

No statistical analysis provided for Selumetinib plasma PK parameter: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)

10. Secondary Outcome Measure: Selumetinib plasma PK parameter: Time to reach maximum observed plasma concentration (tmax) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Time to reach maximum observed plasma concentration (tmax)
Measure Description	To compare tmax of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameter: Time to reach maximum observed plasma concentration (tmax) [units: h] Median (Full Range)	1.73 (1.20 to 5.00)	1.14 (0.75 to 2.25)	3.03 (1.73 to 5.00)	2.00 (0.98 to 3.53)

Statistical Analysis 1 for Selumetinib plasma PK parameter: Time to reach maximum observed plasma concentration (tmax)

Groups^[1]	Treatment A; Granule 25 mg, Treatment C; Granule 25 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	1.750
90% Confidence Interval	( 1.515 to 2.022 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Selumetinib plasma PK parameter: Time to reach maximum observed plasma concentration (tmax)

Groups^[1]	Treatment B; Capsule 50 mg, Treatment D; Capsule 50 mg
Method^[3]	Other [Linear mixed effect model]
Other^[5]	1.766
90% Confidence Interval	( 1.501 to 2.709 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

11. Secondary Outcome Measure: 10.Selumetinib plasma PK parameters: Apparent total body clearance of drug from plasma after extravascular administration (parent drug only) (CL/F) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	10.Selumetinib plasma PK parameters: Apparent total body clearance of drug from plasma after extravascular administration (parent drug only) (CL/F)
Measure Description	To compare CL/F of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
10.Selumetinib plasma PK parameters: Apparent total body clearance of drug from plasma after extravascular administration (parent drug only) (CL/F) [units: L/h] Mean (Standard Deviation)	19.86 (5.20)	17.15 (4.38)	20.47 (4.75)	28.50 (10.19)

No statistical analysis provided for 10.Selumetinib plasma PK parameters: Apparent total body clearance of drug from plasma after extravascular administration (parent drug only) (CL/F)

12. Secondary Outcome Measure: Selumetinib plasma PK parameters: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameters: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
Measure Description	To compare CL/F of selumetinib capsule fasted versus capsule low-fat fed state and selumetinib granule fasted versus granule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Selumetinib plasma PK parameters: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) [units: L] Mean (Standard Deviation)	245.7 (80.52)	243.6 (99.53)	348.5 (159)	493.2 (215.8)

No statistical analysis provided for Selumetinib plasma PK parameters: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)

13. Secondary Outcome Measure: Selumetinib plasma PK parameter: Ratio of AUC in fed state to AUC in the fasted state (FRAUC) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Ratio of AUC in fed state to AUC in the fasted state (FRAUC)
Measure Description	To compare FRAUC of selumetinib capsule fasted versus capsule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

Description

Treatment ratio; C versus A

Treatment C: During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Treatment A: During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose

Traetment ratio; D versus B

Treatment D: During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided. Treatment B: During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose

Measured Values

	Treatment ratio; C versus A	Traetment ratio; D versus B
Number of Participants Analyzed [units:participants]	24	24
Selumetinib plasma PK parameter: Ratio of AUC in fed state to AUC in the fasted state (FRAUC) [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)	0.96 (15.89%)	0.62 (34.53%)

No statistical analysis provided for Selumetinib plasma PK parameter: Ratio of AUC in fed state to AUC in the fasted state (FRAUC)

14. Secondary Outcome Measure: Selumetinib plasma PK parameter: Ratio of Cmax in fed state to Cmax in the fasted state (FRCmax) [ Time Frame: At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3) ]

Measure Type	Secondary
Measure Name	Selumetinib plasma PK parameter: Ratio of Cmax in fed state to Cmax in the fasted state (FRCmax)
Measure Description	To compare FRCmax of selumetinib capsule fasted versus capsule low-fat fed state.
Time Frame	At pre-dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 hours post-dose (Days -1 to 3)
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 primary PK analysis set consisted of all participants in the safety analysis set for whom at least 1 of the primary PK parameters selumetinib could be calculated for at least 2 treatment periods, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

Description

Treatment Ratio; C versus A

Treatment Ratio; D versus B

Measured Values

	Treatment Ratio; C versus A	Treatment Ratio; D versus B
Number of Participants Analyzed [units:participants]	24	24
Selumetinib plasma PK parameter: Ratio of Cmax in fed state to Cmax in the fasted state (FRCmax) [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)	0.61 (50.65%)	0.40 (56.19%)

No statistical analysis provided for Selumetinib plasma PK parameter: Ratio of Cmax in fed state to Cmax in the fasted state (FRCmax)

15. Secondary Outcome Measure: Number of participants with adverse events (AEs) [ Time Frame: From the time of informed consent, throughout the treatment periods up to and including the Follow-up Visit (7 to 10 days after last dose) ]

Measure Type	Secondary
Measure Name	Number of participants with adverse events (AEs)
Measure Description	To assess the safety and tolerability of single doses of selumetinib in healthy participants.
Time Frame	From the time of informed consent, throughout the treatment periods up to and including the Follow-up Visit (7 to 10 days after last dose)
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 participants who received at least 1 dose of selumetinib and for whom any safety post-dose data were available.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Measured Values

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Number of Participants Analyzed [units:participants]	24	24	24	24
Number of participants with adverse events (AEs) [units: Participants]
All AEs	6	6	3	3
AEs considered related to the IMP	2	0	0	0
Mild AEs	6	6	3	3
Moderate AEs	0	0	0	0
Severe AEs	0	0	0	0
Deaths	0	0	0	0
Serious adverse events	0	0	0	0
AEs leading to discontinuation of IMP	0	0	0	0

No statistical analysis provided for Number of participants with adverse events (AEs)

Serious Adverse Events

Time Frame	From the time of informed consent, throughout the treatment periods up to and including the Follow-up Visit (7 to 10 days after last dose).
Additional Description	No text entered.

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Serious Adverse Events

	Treatment A; Granule 25 mg	Treatment B; Capsule 50 mg	Treatment C; Granule 25 mg	Treatment D; Capsule 50 mg
Total, serious adverse events
# participants affected / at risk	0/24 (0.00%)	0/24 (0.00%)	0/24 (0.00%)	0/24 (0.00%)

Other Adverse Events

Time Frame	From the time of informed consent, throughout the treatment periods up to and including the Follow-up Visit (7 to 10 days after last dose).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Treatment A; Granule 25 mg	During Part 1 of the study, participants will receive single doses of selumetinib 25 mg granule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The Investigational medicinal product (IMP) will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment B; Capsule 50 mg	During Part 1 of the study, participants will receive single doses of selumetinib 50 mg capsule under fasted conditions. The dose will be administered after an overnight fast of at least 10 hours. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose
Treatment C; Granule 25 mg	During Part 2 of the study, participants will receive single doses of selumetinib 25 mg granule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided
Treatment D; Capsule 50 mg	During Part 2 of the study, participants will receive single doses of selumetinib 50 mg capsule under fed conditions. Following an overnight fast of at least 10 hours, participants will start consumption of the recommended meal within 30 minutes before administration of the IMP. Participants will be required to consume the entire meal in 30 minutes or less; however, the IMP should be administered 30 minutes after start of the meal. The IMP will be administered with approximately 240 mL of water. No food will be allowed for at least 4 hours post-dose, where after a meal may be provided

Other Adverse Events

Treatment A; Granule 25 mg

Treatment B; Capsule 50 mg

Treatment C; Granule 25 mg

Treatment D; Capsule 50 mg

Total, other (not including serious) adverse events