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This study is an open-label, multi-center, single-dose, parallel group study to determine the pharmacokinetics, safety, and tolerability of cobimetinib administered at 10 mg to fasted male and female adult subjects with varying degrees of hepatic function. The study will be conducted based on the Child-Pugh classification of hepatic impairment. The anticipated duration of the study is 7.5 weeks. The target sample sizes are: 18 volunteers with varying degrees of hepatic function and up to 12 healthy control volunteers.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1: Normal function | Experimental |
| |
| Cohort 2: Mild Hepatic Impairment | Experimental |
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| Cohort 3: Moderate Hepatic Impairment | Experimental |
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| Cohort 4: Severe Hepatic Impairment | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| cobimetinib | Drug | single oral 10-mg dose of cobimetinib |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | Pre-dose (0 hours [hrs]), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] | AUC (0-t) was defined as area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞) was defined as AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t- ∞). | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
| Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | AUC% extrapolated was defined as the percentage of AUC [0-∞] obtained by forward extrapolation. It is calculated as [AUC (0-∞) minus AUC(0-t]*100/ AUC (0-∞), where AUC [0-∞] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUC(0-t) is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
| Apparent Terminal Elimination Rate Constant (λZ) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Trials | Hoffmann-La Roche | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Anaheim | California | 92801 | United States | |||
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1: Normal Hepatic Function | Participants with normal hepatic function received single oral dose of 10 milligrams (mg) cobimetinib (two 5 mg capsules) on Day 1 of study. |
| FG001 | Cohort 2: Mild Hepatic Impairment | Participants with mild hepatic impairment (Child-Pugh Class A, score of 5 to 6, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
| FG002 | Cohort 3: Moderate Hepatic Impairment | Participants with moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
| FG003 | Cohort 4: Severe Hepatic Impairment | Participants with severe hepatic impairment (Child-Pugh Class C, score of 10 to 15, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety population included all participants who received at least one dose of cobimetinib and had at least one post-dose safety assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1: Normal Hepatic Function | Participants with normal hepatic function received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
| BG001 | Cohort 2: Mild Hepatic Impairment |
| Units | Counts |
|---|---|
| Participants |
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| 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 | Maximum Observed Plasma Concentration (Cmax) | Pharmacokinetic (PK) population included all participants who received at least one dose of cobimetinib and had evaluable PK data. | Posted | Mean | Standard Deviation | nanograms per milliliter (ng/mL) | Pre-dose (0 hours [hrs]), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
Up to 30 days after the last dose of study drug (up to approximately 2 months)
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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 | Cohort 1: Normal Hepatic Function | Participants with normal hepatic function received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Haematochezia | Gastrointestinal disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Genentech | 800-821-8590 | genentech@druginfo.com |
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| ID | Term |
|---|---|
| C574276 | cobimetinib |
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λZ was defined as the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase.
| Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration of cobimetinib to decrease by one half. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
| 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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
| Apparent Volume of Distribution (Vz/F) | Volume of distribution was 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. Vz/F after the oral dose is influenced by the fraction absorbed. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
| Miami |
| Florida |
| 330014 |
| United States |
| Orlando | Florida | 32809 | United States |
Participants with mild hepatic impairment (Child-Pugh Class A, score of 5 to 6, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study.
| BG002 | Cohort 3: Moderate Hepatic Impairment | Participants with moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
| BG003 | Cohort 4: Severe Hepatic Impairment | Participants with severe hepatic impairment (Child-Pugh Class c, score of 10 to 15, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
| BG004 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG002 | Cohort 3: Moderate Hepatic Impairment | Participants with moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
| OG003 | Cohort 4: Severe Hepatic Impairment | Participants with severe hepatic impairment (Child-Pugh Class C, score of 10 to 15, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. |
|
|
|
| Primary | Time to Reach Maximum Observed Plasma Concentration (Tmax) | PK population. | Posted | Median | Full Range | hrs | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
|
|
| Primary | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] | AUC (0-t) was defined as area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). | PK Population. | Posted | Mean | Standard Deviation | ng*hr/mL | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
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|
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| Primary | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞) was defined as AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t- ∞). | PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ng*hr/mL | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
|
|
|
| Primary | Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | AUC% extrapolated was defined as the percentage of AUC [0-∞] obtained by forward extrapolation. It is calculated as [AUC (0-∞) minus AUC(0-t]*100/ AUC (0-∞), where AUC [0-∞] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUC(0-t) is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. | PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | % extrapolated | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
|
|
| Primary | Apparent Terminal Elimination Rate Constant (λZ) | λZ was defined as the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase. | PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | 1 per hr (1/hr) | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
|
|
| Primary | Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration of cobimetinib to decrease by one half. | PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | hr | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
|
|
| 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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | Liter per hr (L/hr) | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
|
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| Primary | Apparent Volume of Distribution (Vz/F) | Volume of distribution was 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. Vz/F after the oral dose is influenced by the fraction absorbed. | PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | Liter | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |
|
|
|
| 0 |
| 10 |
| 3 |
| 10 |
| EG001 | Cohort 2: Mild Hepatic Impairment | Participants with mild hepatic impairment (Child-Pugh Class A, score of 5 to 6, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. | 0 | 6 | 3 | 6 |
| EG002 | Cohort 3: Moderate Hepatic Impairment | Participants with moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. | 0 | 6 | 2 | 6 |
| EG003 | Cohort 4: Severe Hepatic Impairment | Participants with severe hepatic impairment (Child-Pugh Class A, score of 10 to 15, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. | 0 | 6 | 1 | 6 |
| Dyspepsia | Gastrointestinal disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Vessel puncture site haematoma | General disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Muscle strain | Injury, poisoning and procedural complications | MedDRA (17.0) | Non-systematic Assessment |
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| Gout | Metabolism and nutrition disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (17.0) | Non-systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (17.0) | 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.
| AUC (0-t) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and moderate hepatic impairment (test) where, hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate). | LS means ratio | 102.2 | 2-Sided | 90 | 54.0 | 193.2 | The 90% CI for differences in LS means between the test and reference treatments obtained from the mixed model were also back-transformed to give 90% CIs for the ratio of the test treatment relative to the reference treatment. | No | Superiority or Other |
| AUC (0-t) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and severe hepatic impairment (test) where, hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate). | LS means ratio | 42.5 | 2-Sided | 90 | 22.5 | 80.5 | The 90% CI for differences in LS means between the test and reference treatments obtained from the mixed model were also back-transformed to give 90% CIs for the ratio of the test treatment relative to the reference treatment. | No | Superiority or Other |
| AUC (0 - ∞) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and moderate hepatic impairment (test) where hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate). | LS means ratio | 103.0 | 2-Sided | 90 | 62.6 | 169.6 | The 90% CI for differences in LS means between the test and reference treatments obtained from the mixed model were also back-transformed to give 90% CIs for the ratio of the test treatment relative to the reference treatment. | No | Superiority or Other |
| AUC (0 - ∞) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and severe hepatic impairment (test) where hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate). | LS means ratio | 68.5 | 2-Sided | 90 | 40.4 | 116.2 | The 90% CI for differences in LS means between the test and reference treatments obtained from the mixed model were also back-transformed to give 90% CIs for the ratio of the test treatment relative to the reference treatment. | No | Superiority or Other |