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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03649165
• Date of registration: 24/08/2018
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca
• Public title: A Study to Evaluate Bioavailability and Food Effect of Selumetinib (AZD6244) in Healthy Male Participants
• Scientific 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
• Date of first enrolment: September 5, 2018
• Target sample size: 24
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03649165
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Crossover Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

United States

Contacts

• Name: Ronald Goldwater, MD
• Affiliation: PAREXEL Early Phase Clinical Unit Baltimore

Key inclusion & 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


Age minimum: 18 Years
Age maximum: 45 Years
Gender: Male

Health Condition(s) or Problem(s) studied

Healthy Participants

Neurofibromatosis Type 1 (NF1)-Related Plexiform Neurofibromas (PNs)

Intervention(s)

Drug: Treatment B

Drug: Treatment A

Drug: Acetaminophen

Drug: Treatment C

Drug: Treatment D

Primary Outcome(s)

Selumetinib and N-desmethyl 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)]

Selumetinib and N-desmethyl 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)]

Selumetinib and N-desmethyl selumetinib plasma 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)]

Selumetinib and N-desmethyl 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)]

Secondary Outcome(s)

Laboratory assessments: hematology - erythrocyte count [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

12-lead electrocardiogram (ECG) [Time Frame: From baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: hematology - Hemoglobin (Hb) [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: hematology: leucocyte cell count [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: Serum clinical chemistry - Liver enzymes [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: Serum clinical chemistry - electrolytes [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: Serum clinical chemistry: Total bilirubin [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: Serum clinical chemistry: Troponin (isoform as per institutional norm) [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments:hematology - differential count [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: 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)]

Laboratory assessments: Clinical urinalysis - glucose [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Ophthalmic examinations [Time Frame: At screening Visit or on Day -1 of Treatment Period 1]

Selumetinib and N-desmethyl 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)]

Laboratory assessments: Clinical Urinalysis - protein [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: Serum clinical chemistry - urea nitrogen [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: Clinical Urinalysis - blood [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: 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)]

Laboratory assessments: Serum clinical chemistry: Total Calcium [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: 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)]

Selumetinib and N-desmethyl 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)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: 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)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: t½?z [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)]

Taste questionnaire [Time Frame: At Days -1 to 3 (within 10 minutes following intake of selumetinib granule)]

Selumetinib and N-desmethyl 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)]

Vital signs (diastolic BP) [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: 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)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: ?z [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)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: 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)]

Selumetinib and N-desmethyl 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)]

Selumetinib and N-desmethyl 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)]

Laboratory assessments: hematology: leucocyte differential count (absolute count) [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: hematology: Platelet count [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Laboratory assessments: Serum clinical chemistry - creatinine [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Selumetinib and N-desmethyl 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)]

Laboratory assessments: Serum clinical chemistry: albumin [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: Terminal elimination rate constant (?z) [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)]

Laboratory assessments: Serum clinical chemistry: Creatine phosphokinase (CPK) [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Vital signs (systolic blood pressure [BP]) [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Pulse rate [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: Half-life associated with terminal slope (?z) of a semi-logarithmic concentration-time curve (t½?z) [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)]

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)]

Laboratory assessments: Serum clinical chemistry: Total protein [Time Frame: Change from baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

Number of participants with abnormal findings in physical examination [Time Frame: From baseline up to follow-up/early termination visit (7 to 10 days after last dose)]

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)]

Selumetinib and N-desmethyl 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)]

Selumetinib and N-desmethyl selumetinib plasma PK parameter: 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)]

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)]

Selumetinib plasma PK parameters: 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)]

Selumetinib plasma PK parameters: 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)]

Secondary ID(s)

D1532C00089

Source(s) of Monetary Support

Please refer to primary and secondary sponsors