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This study will be an open-label, randomized, 3-way, 6-sequence crossover study in healthy participants for determining the relative bioavailability of the tablet formulation to the capsule formulation and the effect of food on the relative bioavailability of the tablet formulation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment A first, then Treatment B, followed by Treatment C | Experimental | Treatment A: One 20-mg tablet of cobimetinib will be administered orally with 240 milliliter (mL) room temperature water after at least an 8-hour fast, in first intervention period. Treatment B: Four 5-mg capsules of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment C: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water within 30 minutes of eating a standard Food and Drug Administration (FDA) high-fat meal, in third intervention period. The washout period between each period will be a minimum of 10 days. |
|
| Treatment A first, then Treatment C, followed by Treatment B | Experimental | Treatment A: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in first intervention period. Treatment C: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in second intervention period. Treatment B: Four 5-mg capsules of cobimetinib administered will be orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
|
| Treatment B first, then Treatment A, followed by Treatment C | Experimental | Treatment B: Four 5-mg capsules of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in first intervention period. Treatment A: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment C: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in third intervention period. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cobimetinib | Drug | Cobimetinib 20 mg will be given orally as tablet formulation in fasted or fed state, or as capsule formulation in fasted state. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) | AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose |
| Maximum Observed Plasma Concentration (Cmax) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose | |
| Minimum Observed Plasma Concentration (Cmin) | Day 1 at 0 hour (predose) | |
| Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose |
| Apparent Volume of Distribution (V/F) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose |
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Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Isabelle Rooney, M.D., PhD | Genentech, Inc. | Study Director |
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment A First, Then Treatment B, Followed by Treatment C | Treatment A: One 20-milligram (mg) tablet of cobimetinib administered orally with 240 milliliter (mL) room temperature water after at least an 8-hour fast, in first intervention period. Treatment B: Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment C: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard Food and Drug Administration (FDA) high-fat meal, in third intervention period. The washout period between each period was a minimum of 10 days. |
| FG001 | Treatment A First, Then Treatment C, Followed by Treatment B | Treatment A: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in first intervention period. Treatment C: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in second intervention period. Treatment B: Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
| FG002 | Treatment B First, Then Treatment A, Followed by Treatment C | Treatment B first, then Treatment A, followed by Treatment C Treatment B: Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in first intervention period. Treatment A: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment C: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in third intervention period. |
| FG003 | Treatment B First, Then Treatment C, Followed by Treatment A | Treatment B first, then Treatment C, followed by Treatment A Treatment B: Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in first intervention period. Treatment C: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in second intervention period. Treatment A: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
| FG004 | Treatment C First, Then Treatment A, Followed by Treatment B | Treatment C: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in first intervention period. Treatment A: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment B: Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
| FG005 | Treatment C First, Then Treatment B, Followed by Treatment A | Treatment C: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in first intervention period. Treatment B: Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment A: One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
| |||||||||||||
| Washout Period of 10 Days |
| |||||||||||||
| Second Intervention |
| |||||||||||||
| Washout Period of 10 Days |
| |||||||||||||
| Third Intervention |
|
All enrolled participants
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | All participants randomized to any treatment. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) | AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). | Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanograms*hours/milliliter (ng*hr/mL) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose |
|
Adverse events were recorded from start of study treatment in first period to end of last period (up to 30 days)
One participant discontinued study in first period and did not receive Cobimetinib One 20 mg Tablet [Fasted] in second period and Cobimetinib Four 5 mg Capsules [Fasted] in third period. Therefore, only 19 participants were evaluable for adverse events in these treatment arms.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cobimetinib One 20 mg Tablet [Fasted] | One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Hoffmann-La Roche | 800-821-8590 | genentech@druginfo.com |
| ID | Term |
|---|---|
| C574276 | cobimetinib |
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|
| Treatment B first, then Treatment C, followed by Treatment A | Experimental | Treatment B: Four 5-mg capsules of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in first intervention period. Treatment C: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in second intervention period. Treatment A: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
|
| Treatment C first, then Treatment A, followed by Treatment B | Experimental | Treatment C: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in first intervention period. Treatment A: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment B: Four 5-mg capsules of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
|
| Treatment C first, then Treatment B, followed by Treatment A | Experimental | Treatment C: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal, in first intervention period. Treatment B: Four 5-mg capsules of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in second intervention period. Treatment A: One 20-mg tablet of cobimetinib will be administered orally with 240 mL room temperature water after at least an 8-hour fast, in third intervention period. |
|
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 |
| Cobimetinib Four 5 mg Capsules [Fasted] |
Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. |
| OG002 | Cobimetinib One 20 mg Tablet [Fed] | One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal. |
|
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) | Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanograms per milliliter (ng/mL) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose |
|
|
|
|
| Primary | Minimum Observed Plasma Concentration (Cmin) | Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Day 1 at 0 hour (predose) |
|
|
|
| Primary | Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters per hour (L/hr) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose |
|
|
|
| Primary | Apparent Volume of Distribution (V/F) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters (L) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose |
|
|
|
| 0 |
| 19 |
| 6 |
| 19 |
| EG001 | Cobimetinib Four 5 mg Capsules [Fasted] | Four 5-mg capsules of cobimetinib administered orally with 240 mL room temperature water after at least an 8-hour fast. | 0 | 19 | 9 | 19 |
| EG002 | Cobimetinib One 20 mg Tablet [Fed] | One 20-mg tablet of cobimetinib administered orally with 240 mL room temperature water within 30 minutes of eating a standard FDA high-fat meal. | 0 | 20 | 8 | 20 |
| Abdominal discomfort | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Faecal incontinence | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Rectal haemorrhage | Gastrointestinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Conjunctivitis | Eye disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Ocular hyperaemia | Eye disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Photophobia | Eye disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Visual impairment | Eye disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Vitreous detachment | Eye disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Chills | General disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Vessel puncture site haematoma | General disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Chest pain | General disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Feeling hot | General disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Vessel puncture site pain | General disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Vessel puncture site reaction | General disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Lymphadenitis | Blood and lymphatic system disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA 13.1 | Non-systematic Assessment |
|
| Viral infection | Infections and infestations | MedDRA 13.1 | Non-systematic Assessment |
|
| Viral upper respiratory tract infection | Infections and infestations | MedDRA 13.1 | Non-systematic Assessment |
|
| Excoriation | Injury, poisoning and procedural complications | MedDRA 13.1 | Non-systematic Assessment |
|
| Scratch | Injury, poisoning and procedural complications | MedDRA 13.1 | Non-systematic Assessment |
|
| Skin laceration | Injury, poisoning and procedural complications | MedDRA 13.1 | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 13.1 | Non-systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA 13.1 | Non-systematic Assessment |
|
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
| Ratio of LS Means (in %) |
| 107 |
| 2-Sided |
| 90 |
| 93.8 |
| 123 |
LS mean was calculated from ANOVA. Data for dose-normalized Cmax were natural log-transformed prior to analysis. Ratio of Cmax LS means for log-transformed parameter (expressed as a percent). |
| Superiority or Other |