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

NCT03649165 | Completed Phase 1 FDA Drug

• 1 other identifier: D1532C00089
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate bioavailability and food effect of selumetinib (AZD6244) in healthy male participants. A total of 24 healthy male participants 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 to investigate the pharmacokinetics (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 to investigate the PK of selumetinib granule and capsule under fed conditions. Participants will also receive a single 500 mg dose of acetaminophen at the same time as selumetinib administration.

Conditions

Neurofibromatosis Type 1 (NF1)-Related Plexiform Neurofibromas (PNs); Healthy Participants

Keywords

MEK Inhibitor; Selumetinib capsule; Selumetinib granule; PK; Bioavailibilty; Crossover study; Open-label; Food effect

Outcome Measures

Primary Outcomes (4)

• Selumetinib and N-desmethyl selumetinib plasma PK parameter: Dose normalized area under plasma concentration-time curve from time zero to infinity (AUC/D)

  To compare the AUC/D of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.

  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)

  To compare the AUClast/D of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.

  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)

  To compare the Cmax/D of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.

  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: Fraction of administered selumetinib granule dose systemically available relative to the capsule reference (Frel)

  To compare the Frel. of the new selumetinib granule formulation with selumetinib capsule formulation in fasted state.

  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 Outcomes (49)

• Selumetinib and N-desmethyl selumetinib plasma PK parameter: Area under plasma concentration time curve from time zero to infinity (AUC)

  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: Area under the plasma concentration time curve from time zero to time of last quantifiable concentration (AUClast)

  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: Area under the plasma concentration-time curve from zero to 12 hours post-dose [AUC(0-12)]

  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)

  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)

  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)

Study Arms (4)

Treatment Sequence 1

EXPERIMENTAL

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; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D; Drug: Acetaminophen

Treatment Sequence 2

EXPERIMENTAL

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; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D; Drug: Acetaminophen

Treatment Sequence 3

EXPERIMENTAL

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; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D; Drug: Acetaminophen

Treatment Sequence 4

EXPERIMENTAL

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; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D; Drug: Acetaminophen

Interventions

Treatment A DRUG

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.

Treatment Sequence 1; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4

Treatment B DRUG

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 Sequence 1; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4

Treatment C DRUG

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 Sequence 1; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4

Treatment D DRUG

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 Sequence 1; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4

Acetaminophen DRUG

Participants will receive a single 500mg dose of acetaminophen at the same time.

Treatment Sequence 1; Treatment Sequence 2; Treatment Sequence 3; Treatment Sequence 4

Eligibility Criteria

• Age: 18 Years - 45 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent before any study-specific procedures.
• Healthy male participants aged 18 to 45 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
• Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg.
• Participants is able to consume a low-fat meal within a 30-minute period.
• Participants has a creatinine clearance (CRCL) greater than 50 mL/min using Cockcroft-Gault formula.
• 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:
• Use of implants, injectables and combined oral contraceptives (must be used in combination with a barrier method of contraception)
• Use of intrauterine devices (must be used in combination with a barrier method of contraception)

You may not qualify if:

• Participants of Japanese, non-Japanese Asian or Indian ethnicity.
• 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.
• History or presence of central serous retinopathy or retinal vein thrombosis, IOP greater than 21 mmHg or uncontrolled glaucoma.
• 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.
• 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).
• 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.
• \) 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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Baltimore, Maryland, 21225, United States

Location

Related Publications (2)

• Cohen-Rabbie S, Mattinson A, So K, Wang N, Goldwater R. A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. Clin Ther. 2022 Apr;44(4):565-576. doi: 10.1016/j.clinthera.2022.02.009. Epub 2022 Apr 9.

  PMID: 35410754 DERIVED

• Cohen-Rabbie S, Mattinson A, So K, Wang N, Goldwater R. Effect of food on capsule and granule formulations of selumetinib. Clin Transl Sci. 2022 Apr;15(4):878-888. doi: 10.1111/cts.13209. Epub 2022 Feb 15.

  PMID: 35170228 DERIVED

MeSH Terms

Conditions

Neurofibromatosis 1

Interventions

Acetaminophen

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Ronald Goldwater, MD

  PAREXEL Early Phase Clinical Unit Baltimore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 24, 2018
• First Posted: August 28, 2018
• Study Start: September 5, 2018
• Primary Completion: October 21, 2018
• Study Completion: October 21, 2018
• Last Updated: November 8, 2018

Record last verified: 2018-11

Locations

US (1)