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| ID | Type | Description | Link |
|---|---|---|---|
| GO01329 | Other Identifier | Hoffmann-La Roche | |
| XL518-001 | Other Identifier | Exelixis |
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This non-randomized, open-label, study will determine the highest safe dose of cobimetinib, how often it should be taken, how well participants with cancer tolerate cobimetinib and will assess the pharmacokinetic effect of midazolam and dextromethorphan on the study drug.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Stage 1: Cobimetinib Dose Escalation (21/7 Schedule) | Experimental | Participants will receive cobimetinib (GDC-0973/XL518) at the starting dose of 0.05 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment [21/7 schedule]). Treatment will continue until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
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| Stage 1A: Cobimetinib Dose Escalation (14/14 Schedule) | Experimental | Participants will receive cobimetinib at the starting dose of 60 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment [14/14 schedule]). Treatment will continue until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
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| Stage 2: Cobimetinib Expansion (21/7 Schedule) | Experimental | Participants will receive cobimetinib at the maximum tolerated dose (MTD) established in Stage 1, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment [21/7 schedule]). Treatment will continue until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
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| Stage 2 A: Cobimetinib Expansion (14/14 Schedule) | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| cobimetinib | Drug | Repeating oral dose |
|
| Measure | Description | Time Frame |
|---|---|---|
| Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | Adverse events (AE) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0. DLT was defined as either of the following occurring during the Study Treatment Period. The occurrence of a drug-related AE that, in the opinion of the cohort review committee (CRC), was of potential clinical significance such that further dose escalation would expose participants in higher dose cohorts to risk of irreversible medical harm or require medical treatment to avoid irreversible medical harm or non-hematologic toxicity
| Stage 1 and 1A: Days 1 to 28 of Cycle 1 |
| Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule | AEs were graded according to the NCI-CTCAE v3.0. A DLT was determined from clinical findings during the Study Treatment Period (Cycle 1, Days 1). MTD was defined as the dose at which no DLTs were observed. DLT was defined as either of the following occurring during the Study Treatment Period. The occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants in higher dose cohorts to risk of irreversible medical harm or require medical treatment to avoid irreversible medical harm or non-hematologic toxicity
| Stage 1: Days 1 to 28 of Cycle 1 |
| Stage 1A: MTD of Cobimetinib in 14/14 Schedule | AEs were graded according to NCI-CTCAE v3.0. A DLT was the basis for determining MTD in Stage 1A participants. The participants of Stage 1A are dose-escalation cohorts, starting at the MTD of the 21/7 schedule, were treated on a 14/14 schedule to determine the MTD. A DLT was defined as either of the following occurring during the Study Treatment Period: Occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants to risk of irreversible medical harm; Nonhematologic toxicity: Grade 3 or 4 events, including Grade 3 nausea and/or vomiting and/or Grade 3 diarrhea, despite prophylaxis and/or treatment; Hematologic toxicity: Grade 4 thrombocytopenia. Grade 4 neutropenia of more than 4 days' duration; Grade 4 neutropenia of any duration with fever or documented infection. AEs (Grade 3 or higher) for which a clinical cause unrelated to cobimetinib was evident was not considered DLTs. |
| Measure | Description | Time Frame |
|---|---|---|
| Stage 1: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 1 in steady state. Steady state was reached when overall intake of cobimetinib was in dynamic equilibrium with its elimination. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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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 |
|---|---|---|---|---|---|---|
| Los Angeles | California | 90095 | United States | |||
Study included following stages: Stage 1, Stage 1A, Stage 2, Stage 2A, and Stage 3. Different participants were recruited in each stage.
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| ID | Title | Description |
|---|---|---|
| FG000 | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Participants received cobimetinib (GDC-0973/XL518) 0.05 milligrams per kilograms (mg/kg) via solution or capsule, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment [21/7 schedule]). Treatment was continued until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG001 | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Participants received cobimetinib 0.10 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG002 | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Participants received cobimetinib 0.20 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG003 | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Participants received cobimetinib 10 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG004 | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Participants received cobimetinib 20 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG005 | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Participants received cobimetinib 40 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG006 | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG007 | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG008 | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG009 | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment [14/14 schedule]). Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG010 | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG011 | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG012 | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Participants received cobimetinib 125 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG013 | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| FG014 | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | Participants received a single dose of midazolam (2 mg of midazolam syrup) and dextromethorphan (30 mg tablet) on Cycle 1 Day 1, in the absence of cobimetinib. After a 2-day washout period, participants received 21 consecutive daily doses of cobimetinib (60-mg) followed by a 7-day washout period.Participants received another single dose of midazolam and dextromethorphan on Cycle 1 Day 15, in the presence of steady-state cobimetinib concentrations. In Cycle 2 and beyond received cobimetinib alone, administered as a 60-mg daily dose for 21 consecutive days in 28-day cycles. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
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| Stage 1 |
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| Stage 1A |
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| Stage 2 |
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| Stage 3 |
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Safety population consisted of all participants who received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Participants received cobimetinib 0.05 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG001 |
| Units | Counts |
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| 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 | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | Adverse events (AE) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0. DLT was defined as either of the following occurring during the Study Treatment Period. The occurrence of a drug-related AE that, in the opinion of the cohort review committee (CRC), was of potential clinical significance such that further dose escalation would expose participants in higher dose cohorts to risk of irreversible medical harm or require medical treatment to avoid irreversible medical harm or non-hematologic toxicity
| Safety population; Stages 1 and 1A participants only. | Posted | Number | participants | Stage 1 and 1A: Days 1 to 28 of Cycle 1 |
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AEs were recorded from the Day 1 of treatment period until the 30 plus or minus 4 days after the last treatment (up to approximately 6 years) .
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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 | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Participants received cobimetinib 0.05 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Hoffmann-LaRoche | 1-800-821-8590 | genentech@druginfo.com |
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| ID | Term |
|---|---|
| C574276 | cobimetinib |
| D003915 | Dextromethorphan |
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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Participants will receive cobimetinib at the MTD established in Stage 1A, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment [14/14 schedule]). Treatment will continue until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor.
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| Stage 3: Cobimetinib+Midazolam+Dextromethorphan | Experimental | Participants will receive a single dose of midazolam (2 mg of midazolam syrup) and dextromethorphan (30 mg tablet) on Cycle 1 Day 1, in the absence of cobimetinib. After a 2-day washout period, participants will receive 21 consecutive daily doses of cobimetinib (60-mg) followed by a 7-day washout period. Participants will receive another single dose of midazolam and dextromethorphan on Cycle 1 Day 15, in the presence of steady-state cobimetinib concentrations. In Cycle 2 and beyond participants will receive cobimetinib alone, administered as a 60-mg daily dose for 21 consecutive days in 28-day cycles (21/7 schedule). |
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| dextromethorphan | Drug | In Stage III only: single dose of dextromethorphan |
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| midazolam | Drug | In Stage III only: single dose of midazolam |
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| Stage 1A: Days 1 to 28 of Cycle 1 |
| Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on Day 1, Cycle 1 in Stage 1 and was measured as nanograms per milliliter (ng/mL). | Stage 1: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1 and pre-dose on Cycle 1 Day 2 |
| Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samples. AUC is measured as hours times nanograms per milliliter (h*ng/mL). | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
| Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1 and pre-dose on Cycle 1 Day 2 |
| Stage 1: AUC 0-24 of Cobimetinib at Steady State | The area under the AUC0-24 for steady state in stage 1 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
| Stage 1: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
| Stage 1: Accumulation Ratio of Cobimetinib at Steady State | Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1, Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
| Stage 1: Apparent Clearance of Cobimetinib at Steady State | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
| Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1 in steady state. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
| Stage 1: Cmax of Cobimetinib at Steady State | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1 and was measured at steady state in ng/mL. | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
| Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1 | Tmax is defined as the time to reach Cmax during stage 1A at Day 1. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
| Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1 | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on on Day 1 in Stage 1A and was measured as ng/mL. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
| Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | AUC0-24 for stage 1A was calculated on Day 1 with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
| Stage 1A: t1/2 of Cobimetinib at Steady State | t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1A in steady state. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
| Stage 1A: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 1A in steady state. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
| Stage 1A: Apparent Clearance of Cobimetinib at Steady State | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
| Stage 1A: Accumulation Ratio of Cobimetinib at Steady State | Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
| Stage 1A: AUC 0-24 of Cobimetinib at Steady State | The area under the AUC0-24 for steady state in stage 1A was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
| Stage 1A: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
| Stage 1A: Cmax of Cobimetinib at Steady State | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1A and was measured in steady state as ng/mL. | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
| Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1 | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 2 and was measured in ng/mL. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
| Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | The area under the AUC0-24 on Day 1 in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
| Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1 | Tmax is defined as the time to reach Cmax during stage 2 on Day 1. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
| Stage 2: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 2 in steady state. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
| Stage 2: AUC 0-24 of Cobimetinib at Steady State | The area under the AUC0-24 for steady state in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
| Stage 2: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
| Stage 2: Accumulation Ratio of Cobimetinib at Steady State | Accumulation ratio is AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
| Stage 2: Apparent Clearance of Cobimetinib at Steady State | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
| Stage 2:Half-Life of Cobimetinib at Steady State | T1/2 half-life of cobimetinib measured over the terminal phase by noncompartmental analysis. | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
| Stage 2A: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
| Stage 2A: Accumulation Ratio of Cobimetinib at Steady State | Accumulation Ratio AUC0-24 is ratio of AUC on Day 20: Day 1. | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
| Stage 2A: Apparent Clearance of Cobimetinib at Steady State | Apparent clearance is the plasma clearance of absorbed drug. | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
| Stage 2A: Half-Life of Cobimetinib at Steady State | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
| Stage 2A: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 2A in steady state. | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
| Stage 2A: Cmax of Cobimetinib at Steady State | Cmax is the maximum plasma concentration achieved following the Day 20 dose in Stage 2A. | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
| Stage III: Cmax of Dextromethorphan | Cmax is defined as maximum observed plasma concentration and was determined both in the presence (Cycle 1 Day 15) and absence of cobimetinib (Cycle 1 Day 1). | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
| Stage III: AUC 0-24 of Dextromethorphan | AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was determined both in presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
| Stage III: AUC 0-inf of Dextromethorphan | AUC0-inf is AUC from time 0 to infinity and was calculated both in presence Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
| Stage III: Cmax of Midazolam | Cmax is the maximum observed plasma concentration and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
| Stage III: AUC0-24 of Midazolam | AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was calculated both in the presence (Cycle 1 Day 15) and absence (CXycle 1 Day 1) of cobimetinib. | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
| Stage III: AUC0-inf of Midazolam | AUC0-inf is the AUC from time 0 to infinity and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
| Stanford |
| California |
| 94305-5821 |
| United States |
| Detroit | Michigan | 48201 | United States |
| Buffalo | New York | 14263 | United States |
| Disease Progression |
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| Unspecified Reason |
|
| Physician Decision |
|
| Withdrawal by Subject |
|
| COMPLETED |
|
| NOT COMPLETED |
|
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| COMPLETED |
|
| NOT COMPLETED |
|
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| COMPLETED |
|
| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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|
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) |
Participants received cobimetinib 0.10 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG002 | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Participants received cobimetinib 0.20 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG003 | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Participants received cobimetinib 10 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG004 | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Participants received cobimetinib 20 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG005 | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Participants received cobimetinib 40 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG006 | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG007 | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG008 | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG009 | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment [14/14 schedule]). Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG010 | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG011 | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG012 | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Participants received cobimetinib 125 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG013 | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| BG014 | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | Participants received a single dose of midazolam (2 mg of midazolam syrup) and dextromethorphan (30 mg tablet) on Cycle 1 Day 1, in the absence of cobimetinib. After a 2-day washout period, participants received 21 consecutive daily doses of cobimetinib (60-mg) followed by a 7-day washout period.Participants received another single dose of midazolam and dextromethorphan on Cycle 1 Day 15, in the presence of steady-state cobimetinib concentrations. In Cycle 2 and beyond received cobimetinib alone, administered as a 60-mg daily dose for 21 consecutive days in 28-day cycles. |
| BG015 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
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| OG000 | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Participants received cobimetinib (GDC-0973/XL518) 0.05 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment [21/7 schedule]). Treatment was continued until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG001 | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Participants received cobimetinib 0.10 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG002 | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Participants received cobimetinib 0.20 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG003 | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Participants received cobimetinib 10 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG004 | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Participants received cobimetinib 20 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG005 | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Participants received cobimetinib 40 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG006 | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG007 | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG008 | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment [14/14 schedule]). Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG009 | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG010 | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
| OG011 | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Participants received cobimetinib 125 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. |
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| Primary | Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule | AEs were graded according to the NCI-CTCAE v3.0. A DLT was determined from clinical findings during the Study Treatment Period (Cycle 1, Days 1). MTD was defined as the dose at which no DLTs were observed. DLT was defined as either of the following occurring during the Study Treatment Period. The occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants in higher dose cohorts to risk of irreversible medical harm or require medical treatment to avoid irreversible medical harm or non-hematologic toxicity
| Safety population; Stage 1 participants only. | Posted | Number | milligrams (mg) | Stage 1: Days 1 to 28 of Cycle 1 |
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| Primary | Stage 1A: MTD of Cobimetinib in 14/14 Schedule | AEs were graded according to NCI-CTCAE v3.0. A DLT was the basis for determining MTD in Stage 1A participants. The participants of Stage 1A are dose-escalation cohorts, starting at the MTD of the 21/7 schedule, were treated on a 14/14 schedule to determine the MTD. A DLT was defined as either of the following occurring during the Study Treatment Period: Occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants to risk of irreversible medical harm; Nonhematologic toxicity: Grade 3 or 4 events, including Grade 3 nausea and/or vomiting and/or Grade 3 diarrhea, despite prophylaxis and/or treatment; Hematologic toxicity: Grade 4 thrombocytopenia. Grade 4 neutropenia of more than 4 days' duration; Grade 4 neutropenia of any duration with fever or documented infection. AEs (Grade 3 or higher) for which a clinical cause unrelated to cobimetinib was evident was not considered DLTs. | Safety population; Stage 1A participants only. | Posted | Number | mg | Stage 1A: Days 1 to 28 of Cycle 1 |
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| Primary | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on Day 1, Cycle 1 in Stage 1 and was measured as nanograms per milliliter (ng/mL). | Safety population; Stage 1 participants only. | Posted | Geometric Mean | Standard Deviation | ng/mL | Stage 1: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1 and pre-dose on Cycle 1 Day 2 |
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| Primary | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samples. AUC is measured as hours times nanograms per milliliter (h*ng/mL). | Safety population; Stage 1 participants only. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
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| Primary | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1. | Safety population; Stage 1 participants only. | Posted | Median | Full Range | hours | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1 and pre-dose on Cycle 1 Day 2 |
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| Secondary | Stage 1: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 1 in steady state. Steady state was reached when overall intake of cobimetinib was in dynamic equilibrium with its elimination. | Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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| Secondary | Stage 1: AUC 0-24 of Cobimetinib at Steady State | The area under the AUC0-24 for steady state in stage 1 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | h*ng/mL | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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| Secondary | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Safety Population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ng*hr/mL/mg | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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| Secondary | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state. | Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ratio | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1, Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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| Secondary | Stage 1: Apparent Clearance of Cobimetinib at Steady State | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state. | Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | Liters per hour (L/hr) | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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| Secondary | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1 in steady state. | Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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| Secondary | Stage 1: Cmax of Cobimetinib at Steady State | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1 and was measured at steady state in ng/mL. | Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ng/mL | Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively) |
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| Secondary | Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1 | Tmax is defined as the time to reach Cmax during stage 1A at Day 1. | Safety population; Stage 1A participants only. | Posted | Median | Full Range | hours | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
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| Secondary | Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1 | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on on Day 1 in Stage 1A and was measured as ng/mL. | Safety population; Stage 1A participants only. | Posted | Mean | Standard Deviation | ng/mL | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
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| Secondary | Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | AUC0-24 for stage 1A was calculated on Day 1 with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Safety population; Stage 1A participants only. | Posted | Mean | Standard Deviation | h*ng/mL | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
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| Secondary | Stage 1A: t1/2 of Cobimetinib at Steady State | t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1A in steady state. | Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
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| Secondary | Stage 1A: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 1A in steady state. | Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
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| Secondary | Stage 1A: Apparent Clearance of Cobimetinib at Steady State | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state. | Safety population; Stage 1A participants only. Number pf participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | L/hr | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
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| Secondary | Stage 1A: Accumulation Ratio of Cobimetinib at Steady State | Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state. | Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ratio | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
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| Secondary | Stage 1A: AUC 0-24 of Cobimetinib at Steady State | The area under the AUC0-24 for steady state in stage 1A was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | h*ng/mL | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
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| Secondary | Stage 1A: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ng*hr/mL/mg | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
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| Secondary | Stage 1A: Cmax of Cobimetinib at Steady State | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1A and was measured in steady state as ng/mL. | Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ng/mL | Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively) |
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| Secondary | Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1 | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 2 and was measured in ng/mL. | Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | ng/mL | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
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| Secondary | Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | The area under the AUC0-24 on Day 1 in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
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| Secondary | Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1 | Tmax is defined as the time to reach Cmax during stage 2 on Day 1. | Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2 |
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| Secondary | Stage 2: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 2 in steady state. | Safety population; Stage 2 participants only; Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
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| Secondary | Stage 2: AUC 0-24 of Cobimetinib at Steady State | The area under the AUC0-24 for steady state in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings. | Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
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| Secondary | Stage 2: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
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|
| Secondary | Stage 2: Accumulation Ratio of Cobimetinib at Steady State | Accumulation ratio is AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state. | Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | ratio | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
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|
| Secondary | Stage 2: Apparent Clearance of Cobimetinib at Steady State | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state. | Safety population | Posted | Mean | Standard Deviation | L/hr | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
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|
| Secondary | Stage 2:Half-Life of Cobimetinib at Steady State | T1/2 half-life of cobimetinib measured over the terminal phase by noncompartmental analysis. | Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28 |
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|
| Secondary | Stage 2A: AUC 0-24/D of Cobimetinib at Steady State | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. | Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | h*ng/mL | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
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| Secondary | Stage 2A: Accumulation Ratio of Cobimetinib at Steady State | Accumulation Ratio AUC0-24 is ratio of AUC on Day 20: Day 1. | Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | ratio | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
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|
| Secondary | Stage 2A: Apparent Clearance of Cobimetinib at Steady State | Apparent clearance is the plasma clearance of absorbed drug. | Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Mean | Standard Deviation | L/hr | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
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|
|
| Secondary | Stage 2A: Half-Life of Cobimetinib at Steady State | Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
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|
| Secondary | Stage 2A: Tmax of Cobimetinib at Steady State | Tmax is defined as the time to reach Cmax during stage 2A in steady state. | Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Median | Full Range | hours | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
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| Secondary | Stage 2A: Cmax of Cobimetinib at Steady State | Cmax is the maximum plasma concentration achieved following the Day 20 dose in Stage 2A. | Analysis population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | ng/mL | Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28 |
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| Secondary | Stage III: Cmax of Dextromethorphan | Cmax is defined as maximum observed plasma concentration and was determined both in the presence (Cycle 1 Day 15) and absence of cobimetinib (Cycle 1 Day 1). | Safety population; Stage 3 participants only. n=number of participants analyzed for specified category. | Posted | Geometric Mean | Standard Deviation | ng/mL | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
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| Secondary | Stage III: AUC 0-24 of Dextromethorphan | AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was determined both in presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Safety population; Stage 3 participants only. n = number of participants analyzed for specified category. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
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| Secondary | Stage III: AUC 0-inf of Dextromethorphan | AUC0-inf is AUC from time 0 to infinity and was calculated both in presence Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Safety population; Stage 3 participants only. n = number of participants analyzed for specified category. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
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| Secondary | Stage III: Cmax of Midazolam | Cmax is the maximum observed plasma concentration and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Safety population; Stage 3 participants only. n = number of participants analyzed for specified category. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | ng/mL | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
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| Secondary | Stage III: AUC0-24 of Midazolam | AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was calculated both in the presence (Cycle 1 Day 15) and absence (CXycle 1 Day 1) of cobimetinib. | Safety population; Stage 3 participants only. n = number of participants analyzed for specified category. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
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| Secondary | Stage III: AUC0-inf of Midazolam | AUC0-inf is the AUC from time 0 to infinity and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib. | Safety population; Stage 3 participants only. n = number of participants analyzed for specified category. Number of participants analyzed = participants who were evaluable for this outcome. | Posted | Geometric Mean | Standard Deviation | h*ng/mL | Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1 |
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| 2 |
| 4 |
| 4 |
| 4 |
| EG001 | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Participants received cobimetinib 0.10 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 0 | 3 | 3 | 3 |
| EG002 | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Participants received cobimetinib 0.20 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 1 | 3 | 3 | 3 |
| EG003 | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Participants received cobimetinib 10 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 0 | 3 | 3 | 3 |
| EG004 | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Participants received cobimetinib 20 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 1 | 3 | 3 | 3 |
| EG005 | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Participants received cobimetinib 40 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 | 6 | 6 | 6 |
| EG006 | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 | 7 | 7 | 7 |
| EG007 | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 5 | 7 | 7 | 7 |
| EG008 | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 7 | 21 | 20 | 21 |
| EG009 | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment [14/14 schedule]). Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 0 | 3 | 3 | 3 |
| EG010 | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 1 | 3 | 3 | 3 |
| EG011 | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 4 | 8 | 8 | 8 |
| EG012 | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Participants received cobimetinib 125 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 | 6 | 6 | 6 |
| EG013 | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 11 | 22 | 21 | 22 |
| EG014 | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | Participants received a single dose of midazolam (2 mg of midazolam syrup) and dextromethorphan (30 mg tablet) on Cycle 1 Day 1, in the absence of cobimetinib. After a 2-day washout period, participants received 21 consecutive daily doses of cobimetinib (60-mg) followed by a 7-day washout period. Participants received another single dose of midazolam and dextromethorphan on Cycle 1 Day 15, in the presence of steady-state cobimetinib concentrations. in Cycle 2 and beyond received cobimetinib alone, administered as a 60-mg daily dose for 21 consecutive days in 28-day cycles. | 8 | 20 | 18 | 20 |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Cardio-respiratory arrest | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Cardiac arrest | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Supraventricular tachycardia | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Ileus | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Intestinal obstruction | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Faecal incontinence | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastrointestinal obstruction | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastrointestinal perforation | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Impaired gastric emptying | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Small intestinal obstruction | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Chest pain | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Generalised oedema | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Bile duct obstruction | Hepatobiliary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hepatic failure | Hepatobiliary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Cellulitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Tonsillitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Feeding tube complication | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastrointestinal stoma complication | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Troponin increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.0) | Non-systematic Assessment |
|
| Colon cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.0) | Non-systematic Assessment |
|
| Lung neoplasm malignant | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.0) | Non-systematic Assessment |
|
| Metastases to central nervous system | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.0) | Non-systematic Assessment |
|
| Ovarian cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.0) | Non-systematic Assessment |
|
| Pancreatic carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.0) | Non-systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hepatic encephalopathy | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Respiratory arrest | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pulmonary oedema | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pleurodesis | Surgical and medical procedures | MedDRA (16.0) | Non-systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Peripheral artery thrombosis | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Haematochezia | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Rectal haemorrhage | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Retching | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Abdominal pain lower | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Oral pain | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Anorectal discomfort | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Aphthous stomatitis | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Faecal incontinence | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastrointestinal sounds abnormal | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Impaired gastric emptying | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Tongue disorder | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Upper gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Skin fissures | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Swelling face | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pain of skin | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Photosensitivity reaction | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pruritus generalised | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Skin exfoliation | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Drug eruption | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Facial wasting | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyperkeratosis | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Nail discolouration | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Papule | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Rash generalised | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Rash macular | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Skin disorder | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Skin hyperpigmentation | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Skin reaction | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Yellow skin | Skin and subcutaneous tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Oedema | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Asthenia | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Chills | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Face oedema | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Chest pain | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Malaise | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Feeling hot | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Generalised oedema | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pain | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Early satiety | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Gait disturbance | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypothermia | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Injection site pain | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Irritability | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Localised oedema | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Tenderness | General disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypermagnesaemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Cachexia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Electrolyte imbalance | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Iron deficiency | Metabolism and nutrition disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Neuropathy peripheral | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Convulsion | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Tremor | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Ataxia | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Cerebral haemorrhage | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Drug withdrawal headache | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hemiparesis | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyperreflexia | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Loss of proprioception | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Speech disorder | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vocal cord paralysis | Nervous system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Musculoskeletal stiffness | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Critical illness myopathy | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Groin pain | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Intervertebral disc protrusion | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Muscle fatigue | Musculoskeletal and connective tissue disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Weight decreased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Weight increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Activated partial thromboplastin time prolonged | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Ammonia increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood potassium decreased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood pressure increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Blood urine present | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Carbon dioxide decreased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Electrocardiogram QRS complex abnormal | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Haemoglobin | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Haemoglobin decreased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Oxygen saturation decreased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Platelet count increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Protein total decreased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Waist circumference increased | Investigations | MedDRA (16.0) | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Paranasal sinus hypersecretion | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pleuritic pain | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Sinus congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Upper-airway cough syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Visual impairment | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Periorbital oedema | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Macular degeneration | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vitreous floaters | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Abnormal sensation in eye | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Cataract | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Ocular icterus | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Uveitis | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Diplopia | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Eye pain | Eye disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Hordeolum | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Gastroenteritis viral | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Bacteraemia | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Clostridium difficile colitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Escherichia infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Groin infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Herpes virus infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Nail bed infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Peritonitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Rash pustular | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Respiratory tract infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Syphilis | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Viral upper respiratory tract infection | Infections and infestations | MedDRA (16.0) | Non-systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Lymphadenopathy | Blood and lymphatic system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hallucination, visual | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Disorientation | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Mental status changes | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Mood swings | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Restlessness | Psychiatric disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Procedural site reaction | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Laceration | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Animal bite | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Hand fracture | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Incision site pain | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Joint injury | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Meniscus injury | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Muscle strain | Injury, poisoning and procedural complications | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Bloody discharge | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Thrombosis | Vascular disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Urinary retention | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Costovertebral angle tenderness | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hydronephrosis | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Nocturia | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Renal artery stenosis | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Renal failure acute | Renal and urinary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Pelvic pain | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Scrotal oedema | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vaginal discharge | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Breast pain | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Genital rash | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Menstruation irregular | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Oedema genital | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vulvovaginal erythema | Reproductive system and breast disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Jaundice | Hepatobiliary disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Bradycardia | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Hypersensitivity | Immune system disorders | MedDRA (16.0) | Non-systematic Assessment |
|
| Melanocytic naevus | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (16.0) | Non-systematic Assessment |
|
| Wisdom teeth removal | Surgical and medical procedures | MedDRA (16.0) | 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.
| D006572 |
| Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |