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This open-label, 2-period, fixed sequence, drug interaction study will investigate the effect of co-administration of itraconazole on the pharmacokinetics of cobimetinib in healthy participants. Participants will receive multiple repeating doses of cobimetinib and itraconazole.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cobimetinib + Itraconazole | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cobimetinib | Drug | 10 milligram (mg) (2* 5 mg capsules) will be administered orally on Day 1 of Period 1 and Day 4 of Period 2 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole | Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach. | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole | AUC (0 - inf) = 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) of cobimetinib with and without itraconazole, assessed using a model independent approach. | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole | Time to reach maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach. | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Trials | Genentech, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dallas | Texas | 75247 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cobimetinib + Itraconazole | Cobimetinib 10 milligram (mg) (two 5 mg capsules) administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
| |||||||||||||
| Period 2 |
|
Safety population consisted of all participants who received at least 1 dose of cobimetinib and had at least 1 postdose safety assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Cobimetinib + Itraconazole | Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2. |
| 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 | Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole | Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach. | Pharmacokinetic (PK) population consisted of all participants who received at least 1 dose of cobimetinib and had evaluable PK data. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram per milliliter (ng/mL) | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
|
approximately 2 months
Safety population
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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 + Itraconazole | Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA (15.1) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Hoffmann-La Roche | 800-821-8590 | genentech@druginfo.com |
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| ID | Term |
|---|---|
| C574276 | cobimetinib |
| D017964 | Itraconazole |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Itraconazole | Drug | 200 mg oral solution will be administered once daily from Day 1 to Day 14 of Period 2 |
|
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole | AUC (0-t) = Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (0-t) of cobimetinib with and without itraconazole was assessed. It was calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations using a model independent approach. | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole | Plasma half-life is the time measured for the plasma concentration to decrease by one half. | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole | 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 using a model independent approach. | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole | 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 of drug absorbed. | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Cmax of Itraconazole and Hydroxy-Itraconazole | Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. | Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Tmax of Itraconazole and Hydroxy-Itraconazole | Time to reach maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. | Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
| Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole | AUC (0-24) = Area under the plasma concentration versus time curve from time zero (predose) to 24 hours postdose (0-24) of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. | Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4 |
|
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
|
|
|
| Primary | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole | AUC (0 - inf) = 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) of cobimetinib with and without itraconazole, assessed using a model independent approach. | PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
|
|
|
|
| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole | Time to reach maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach. | PK population | Posted | Median | Full Range | hours | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
|
|
|
| Secondary | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole | AUC (0-t) = Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (0-t) of cobimetinib with and without itraconazole was assessed. It was calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations using a model independent approach. | PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram*hour per milliliter (ng*hr/mL) | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
|
|
|
|
| Secondary | Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole | Plasma half-life is the time measured for the plasma concentration to decrease by one half. | PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category. | Posted | Median | Full Range | hours | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
|
|
|
| Secondary | Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole | 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 using a model independent approach. | PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter per hour (L/hr) | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
|
|
|
| Secondary | Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole | 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 of drug absorbed. | PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | liter (L) | Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
|
|
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| Secondary | Cmax of Itraconazole and Hydroxy-Itraconazole | Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. | PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
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| Secondary | Tmax of Itraconazole and Hydroxy-Itraconazole | Time to reach maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. | PK population | Posted | Median | Full Range | hours | Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 |
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|
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| Secondary | Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole | AUC (0-24) = Area under the plasma concentration versus time curve from time zero (predose) to 24 hours postdose (0-24) of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. | PK population | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4 |
|
|
|
| 0 |
| 16 |
| 6 |
| 16 |
| Diarrhoea | Gastrointestinal disorders | MedDRA (15.1) | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (15.1) | Non-systematic Assessment |
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| Erythema | Skin and subcutaneous tissue disorders | MedDRA (15.1) | Non-systematic Assessment |
|
| Rash macular | Skin and subcutaneous tissue disorders | MedDRA (15.1) | Non-systematic Assessment |
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| Alanine aminotransferase increased | Investigations | MedDRA (15.1) | Non-systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA (15.1) | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (15.1) | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (15.1) | Non-systematic Assessment |
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| Rhinitis | Infections and infestations | MedDRA (15.1) | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (15.1) | 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.
| D010879 |
| Piperazines |