Study of Cobimetinib in Participants With Solid Tumors
Sponsor
Genentech, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00467779
Collaborator
(none)
119
4
5
83
29.8
0.4
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
119 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of GDC-0973/XL518 Administered Orally Daily to Subjects With Solid Tumors
Study Start Date
:
May 1, 2007
Actual Primary Completion Date
:
Apr 1, 2014
Actual Study Completion Date
:
Apr 1, 2014
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Stage 1: Cobimetinib Dose Escalation (21/7 Schedule) 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. |
Drug: cobimetinib
Repeating oral dose
Other Names:
|
| Experimental: Stage 1A: Cobimetinib Dose Escalation (14/14 Schedule) 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. |
Drug: cobimetinib
Repeating oral dose
Other Names:
|
| Experimental: Stage 2: Cobimetinib Expansion (21/7 Schedule) 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. |
Drug: cobimetinib
Repeating oral dose
Other Names:
|
| Experimental: Stage 2 A: Cobimetinib Expansion (14/14 Schedule) 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. |
Drug: cobimetinib
Repeating oral dose
Other Names:
|
| Experimental: Stage 3: Cobimetinib+Midazolam+Dextromethorphan 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). |
Drug: cobimetinib
Repeating oral dose
Other Names:
Drug: dextromethorphan
In Stage III only: single dose of dextromethorphan
Drug: midazolam
In Stage III only: single dose of midazolam
|
Outcome Measures
Primary Outcome Measures
- Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) [Stage 1 and 1A: Days 1 to 28 of Cycle 1]
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 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 greater than or equal to (≥) 4 days' duration Grade 4 neutropenia of any duration with fever or documented infection
- Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule [Stage 1: Days 1 to 28 of Cycle 1]
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 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 greater than or equal to (≥) 4 days' duration Grade 4 neutropenia of any duration with fever or documented infection
- Stage 1A: MTD of Cobimetinib in 14/14 Schedule [Stage 1A: Days 1 to 28 of Cycle 1]
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.
- Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 [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]
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: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) 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, pre-dose on Cycle 1 Day 2]
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: Time to Maximum Concentration (Tmax) of Cobimetinib 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]
Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1.
Secondary Outcome Measures
- Stage 1: Tmax of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)]
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: AUC 0-24 of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)]
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: AUC 0-24/D of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)]
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
- Stage 1: Accumulation Ratio of Cobimetinib 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)]
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: Apparent Clearance of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)]
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: Half-Life (t1/2) of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)]
t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1 in steady state.
- Stage 1: Cmax of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)]
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 1A: Tmax of Cobimetinib at Cycle 1 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]
Tmax is defined as the time to reach Cmax during stage 1A at Day 1.
- Stage 1A: Cmax of Cobimetinib at Cycle 1 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]
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: AUC 0-24 of Cobimetinib at Cycle 1 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]
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: t1/2 of Cobimetinib at 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)]
t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1A in steady state.
- Stage 1A: Tmax of Cobimetinib at 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)]
Tmax is defined as the time to reach Cmax during stage 1A in steady state.
- Stage 1A: Apparent Clearance of Cobimetinib at 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)]
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: Accumulation Ratio of Cobimetinib 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)]
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: AUC 0-24 of Cobimetinib at 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)]
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: AUC 0-24/D of Cobimetinib at 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)]
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
- Stage 1A: Cmax of Cobimetinib at 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)]
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 2: Cmax of Cobimetinib at Cycle 1 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]
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 2 and was measured in ng/mL.
- Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 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]
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: Tmax of Cobimetinib at Cycle 1 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]
Tmax is defined as the time to reach Cmax during stage 2 on Day 1.
- Stage 2: Tmax of Cobimetinib 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]
Tmax is defined as the time to reach Cmax during stage 2 in steady state.
- Stage 2: AUC 0-24 of Cobimetinib 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]
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: AUC 0-24/D of Cobimetinib 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]
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
- Stage 2: Accumulation Ratio of Cobimetinib 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]
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: Apparent Clearance of Cobimetinib 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]
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:Half-Life of Cobimetinib 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]
T1/2 half-life of cobimetinib measured over the terminal phase by noncompartmental analysis.
- Stage 2A: AUC 0-24/D 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]
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
- Stage 2A: Accumulation Ratio 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]
Accumulation Ratio AUC0-24 is ratio of AUC on Day 20: Day 1.
- Stage 2A: Apparent Clearance 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]
Apparent clearance is the plasma clearance of absorbed drug.
- 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 [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]
Tmax is defined as the time to reach Cmax during stage 2A in steady state.
- Stage 2A: Cmax 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]
Cmax is the maximum plasma concentration achieved following the Day 20 dose in Stage 2A.
- Stage III: Cmax of Dextromethorphan [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]
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: AUC 0-24 of Dextromethorphan [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]
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: AUC 0-inf of Dextromethorphan [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]
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: Cmax of Midazolam [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]
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: AUC0-24 of Midazolam [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]
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: AUC0-inf of Midazolam [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]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Histologically confirmed solid tumor that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective, and there are no known therapies to prolong survival
-
Disease that is measurable according to Response Evaluation Criteria in Solid Tumors (RECIST)
-
Adequate organ and marrow function
-
Sexually active participants must use medically acceptable methods of contraception during the course of the study and at least 11 days after the last dose of study treatment
-
Female participants of childbearing potential must have a negative serum pregnancy test at screening
-
No other history of/or ongoing malignancy that would potentially interfere with the interpretation of the pharmacodynamic or efficacy assays
Exclusion Criteria:
-
Anticancer treatment (e.g., chemotherapy, radiotherapy, cytokines, or hormones) within 28 days (6 weeks for nitrosoureas or mitomycin C, or 14 days for hormonal therapy or kinase inhibitors) before the first dose of study drug
-
The participant has not recovered to Grade </=1 from adverse events (AEs) or to within 10% of baseline values due to investigational or other agents administered more than 28 days prior to study enrollment
-
The participant has received another investigational agent within 28 days of the first dose of study drug
-
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, diabetes, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
-
The participant is pregnant or breastfeeding
-
The participant is known to be positive for the human immunodeficiency virus (HIV)
-
Allergy or hypersensitivity to components of the cobimetinib formulation
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Los Angeles | California | United States | 90095 | |
| 2 | Stanford | California | United States | 94305-5821 | |
| 3 | Detroit | Michigan | United States | 48201 | |
| 4 | Buffalo | New York | United States | 14263 |
Sponsors and Collaborators
- Genentech, Inc.
Investigators
- Study Director: Clinical Trials, Genentech, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00467779
Other Study ID Numbers:
- MEK4592g
- GO01329
- XL518-001
First Posted:
May 1, 2007
Last Update Posted:
Aug 26, 2016
Last Verified:
Jul 1, 2016
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Study included following stages: Stage 1, Stage 1A, Stage 2, Stage 2A, and Stage 3. Different participants were recruited in each stage. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Period Title: Stage 1 | |||||||||||||||
| STARTED | 4 | 3 | 3 | 3 | 3 | 6 | 7 | 7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 4 | 3 | 3 | 3 | 3 | 5 | 7 | 7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Stage 1 | |||||||||||||||
| STARTED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 8 | 6 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 8 | 6 | 0 | 0 |
| Period Title: Stage 1 | |||||||||||||||
| STARTED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 21 | 0 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 21 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Stage 1 | |||||||||||||||
| STARTED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 22 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 21 | 0 |
| Period Title: Stage 1 | |||||||||||||||
| STARTED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 20 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 17 |
Baseline Characteristics
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Total of all reporting groups |
| Overall Participants | 4 | 3 | 3 | 3 | 3 | 6 | 7 | 7 | 21 | 3 | 3 | 8 | 6 | 22 | 20 | 119 |
| Age (years) [Mean (Standard Deviation) ] | ||||||||||||||||
| Mean (Standard Deviation) [years] |
66.0
(11.52)
|
60.7
(19.73)
|
51.3
(6.35)
|
66.0
(10.82)
|
60.7
(9.61)
|
62.0
(12.38)
|
63.9
(5.87)
|
54.4
(8.40)
|
59.7
(13.08)
|
52.7
(13.20)
|
49.7
(21.08)
|
55.1
(13.46)
|
61.5
(13.61)
|
61.1
(11.45)
|
57.1
(15.60)
|
59.1
(12.8)
|
| Sex: Female, Male (Count of Participants) | ||||||||||||||||
| Female |
3
75%
|
0
0%
|
2
66.7%
|
3
100%
|
1
33.3%
|
3
50%
|
2
28.6%
|
3
42.9%
|
11
52.4%
|
1
33.3%
|
3
100%
|
4
50%
|
4
66.7%
|
10
45.5%
|
9
45%
|
59
49.6%
|
| Male |
1
25%
|
3
100%
|
1
33.3%
|
0
0%
|
2
66.7%
|
3
50%
|
5
71.4%
|
4
57.1%
|
10
47.6%
|
2
66.7%
|
0
0%
|
4
50%
|
2
33.3%
|
12
54.5%
|
11
55%
|
60
50.4%
|
Outcome Measures
| Title | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) |
|---|---|
| Description | 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 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 greater than or equal to (≥) 4 days' duration Grade 4 neutropenia of any duration with fever or documented infection |
| Time Frame | Stage 1 and 1A: Days 1 to 28 of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stages 1 and 1A participants only. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 4 | 3 | 3 | 3 | 3 | 6 | 7 | 7 | 3 | 3 | 8 | 6 |
| Number [participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
1
14.3%
|
2
28.6%
|
0
0%
|
0
0%
|
0
0%
|
2
25%
|
| Title | Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule |
|---|---|
| Description | 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 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 greater than or equal to (≥) 4 days' duration Grade 4 neutropenia of any duration with fever or documented infection |
| Time Frame | Stage 1: Days 1 to 28 of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. |
| Arm/Group Title | Stage 1 All Cohorts (21/7) |
|---|---|
| Arm/Group Description | Participants received cobimetinib via solution or capsule, once daily for Days 1-21 of each 28-day cycle and were on 21-days-on and 7-days-off 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. |
| Measure Participants | 36 |
| Number [milligrams (mg)] |
60
|
| Title | Stage 1A: MTD of Cobimetinib in 14/14 Schedule |
|---|---|
| Description | 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. |
| Time Frame | Stage 1A: Days 1 to 28 of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. |
| Arm/Group Title | Stage 1A - All Cohorts (14/14) |
|---|---|
| Arm/Group Description | Participants received cobimetinib via solution or capsule, once daily for Days 1-14 of each 28-day cycle and were on a 14-days-on and 14-days-off 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. |
| Measure Participants | 20 |
| Number [mg] |
100
|
| Title | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 |
|---|---|
| Description | 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). |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 4 | 3 | 3 | 3 | 3 | 6 | 7 | 7 |
| Geometric Mean (Standard Deviation) [ng/mL] |
4.51
(5.8)
|
6.92
(3.8)
|
18.3
(13.0)
|
18.8
(5.1)
|
30.8
(69.0)
|
71.7
(57.0)
|
163.0
(79.0)
|
261.0
(110.0)
|
| Title | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 |
|---|---|
| Description | 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). |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 4 | 3 | 3 | 3 | 3 | 6 | 7 | 7 |
| Geometric Mean (Standard Deviation) [h*ng/mL] |
56.2
(65.0)
|
68.0
(47.0)
|
203.0
(130.0)
|
242.0
(64.0)
|
440.0
(870.0)
|
785.0
(560.0)
|
1620.0
(830.0)
|
3060.0
(950.0)
|
| Title | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 |
|---|---|
| Description | Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 4 | 3 | 3 | 3 | 3 | 6 | 7 | 7 |
| Median (Full Range) [hours] |
2.0
|
1.0
|
1.5
|
3.0
|
4.0
|
2.5
|
2.0
|
2.0
|
| Title | Stage 1: Tmax of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 3 | 3 | 3 | 6 | 7 | 7 |
| Median (Full Range) [hours] |
4.0
|
1.0
|
2.25
|
4.0
|
3.0
|
2.0
|
3.0
|
2.5
|
| Title | Stage 1: AUC 0-24 of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 2 | 3 | 1 | 5 | 4 | 6 |
| Mean (Standard Deviation) [h*ng/mL] |
202.0
(158.0)
|
288.0
(200.0)
|
411.0
(199.0)
|
763.0
(168.0)
|
886.0
|
5370.0
(4600.0)
|
6250.0
(3540.0)
|
10500.0
(10500.0)
|
| Title | Stage 1: AUC 0-24/D of Cobimetinib at Steady State |
|---|---|
| Description | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 2 | 3 | 1 | 5 | 4 | 6 |
| Mean (Standard Deviation) [ng*hr/mL/mg] |
62.4
(36.3)
|
34
(16.9)
|
28.2
(8.43)
|
76.3
(16.8)
|
44.3
|
134
(115)
|
104
(59.1)
|
132
(131)
|
| Title | Stage 1: Accumulation Ratio of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 2 | 3 | 1 | 4 | 4 | 5 |
| Mean (Standard Deviation) [ratio] |
3.56
(1.76)
|
3.66
(0.901)
|
2.65
(0.886)
|
3.23
(1.03)
|
2.96
|
3.61
(2.27)
|
2.87
(0.787)
|
3.26
(2.1)
|
| Title | Stage 1: Apparent Clearance of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 2 | 3 | 1 | 5 | 4 | 6 |
| Mean (Standard Deviation) [Liters per hour (L/hr)] |
22.4
(17.2)
|
34.0
(14.2)
|
37.1
(11.1)
|
13.5
(2.71)
|
22.6
|
14.0
(10.1)
|
11.8
(5.71)
|
11.6
(5.42)
|
| Title | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State |
|---|---|
| Description | t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1 in steady state. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 1 | 3 | 2 | 3 | 1 | 5 | 4 | 5 |
| Median (Full Range) [hours] |
80.0
|
64.0
|
47.8
|
66.0
|
50.5
|
41.3
|
51.3
|
60.0
|
| Title | Stage 1: Cmax of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 2 | 3 | 1 | 5 | 4 | 6 |
| Mean (Standard Deviation) [ng/mL] |
13.5
(9.53)
|
19.8
(15.2)
|
28.7
(8.63)
|
53.0
(5.4)
|
54.7
|
341.0
(244.0)
|
401.0
(214.0)
|
641.0
(514.0)
|
| Title | Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1 |
|---|---|
| Description | Tmax is defined as the time to reach Cmax during stage 1A at Day 1. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 8 | 6 |
| Median (Full Range) [hours] |
3.0
|
4.0
|
3.5
|
2.5
|
| Title | Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1 |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 8 | 6 |
| Mean (Standard Deviation) [ng/mL] |
78.4
(88.0)
|
167.0
(63.0)
|
258.0
(140.0)
|
533.0
(347.0)
|
| Title | Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1 |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 8 | 6 |
| Mean (Standard Deviation) [h*ng/mL] |
1140
(1150)
|
2130
(70.1)
|
4020
(2000)
|
7190
(3640)
|
| Title | Stage 1A: t1/2 of Cobimetinib at Steady State |
|---|---|
| Description | t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1A in steady state. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 1 | 1 | 3 | 1 |
| Median (Full Range) [hours] |
59.4
|
44.1
|
51.6
|
47.7
|
| Title | Stage 1A: Tmax of Cobimetinib at Steady State |
|---|---|
| Description | Tmax is defined as the time to reach Cmax during stage 1A in steady state. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 5 | 3 |
| Median (Full Range) [hours] |
2.0
|
2.0
|
3
|
6
|
| Title | Stage 1A: Apparent Clearance of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. Number pf participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 5 | 3 |
| Mean (Standard Deviation) [L/hr] |
25.1
(13.5)
|
14.9
(8.33)
|
21.9
(20.3)
|
6.9
(3.22)
|
| Title | Stage 1A: Accumulation Ratio of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 5 | 3 |
| Mean (Standard Deviation) [ratio] |
2.32
(0.448)
|
3.14
(1.77)
|
2.6
(2.32)
|
5.15
(2.08)
|
| Title | Stage 1A: AUC 0-24 of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 5 | 3 |
| Mean (Standard Deviation) [h*ng/mL] |
2990.0
(1750.0)
|
6740.0
(3830.0)
|
11500.0
(10500.0)
|
21500.0
(11300.0)
|
| Title | Stage 1A: AUC 0-24/D of Cobimetinib at Steady State |
|---|---|
| Description | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 5 | 3 |
| Mean (Standard Deviation) [ng*hr/mL/mg] |
49.8
(29.2)
|
84.2
(47.8)
|
115.0
(105.0)
|
172.0
(90.4)
|
| Title | Stage 1A: Cmax of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) |
|---|---|---|---|---|
| Arm/Group Description | 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. | 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. | 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. | 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. |
| Measure Participants | 3 | 3 | 5 | 3 |
| Mean (Standard Deviation) [ng/mL] |
180.0
(101.0)
|
494.0
(175.0)
|
640.0
(511.0)
|
1160.0
(540.0)
|
| Title | Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1 |
|---|---|
| Description | Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 2 and was measured in ng/mL. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 19 |
| Geometric Mean (Standard Deviation) [ng/mL] |
184.0
(160.0)
|
| Title | Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1 |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 19 |
| Geometric Mean (Standard Deviation) [h*ng/mL] |
3060.0
(2110.0)
|
| Title | Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1 |
|---|---|
| Description | Tmax is defined as the time to reach Cmax during stage 2 on Day 1. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 19 |
| Median (Full Range) [hours] |
3.0
|
| Title | Stage 2: Tmax of Cobimetinib at Steady State |
|---|---|
| Description | Tmax is defined as the time to reach Cmax during stage 2 in steady state. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only; Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 13 |
| Median (Full Range) [hours] |
4.0
|
| Title | Stage 2: AUC 0-24 of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 13 |
| Geometric Mean (Standard Deviation) [h*ng/mL] |
10200.0
(5630.0)
|
| Title | Stage 2: AUC 0-24/D of Cobimetinib at Steady State |
|---|---|
| Description | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 13 |
| Geometric Mean (Standard Deviation) [h*ng/mL] |
102.0
(56.3)
|
| Title | Stage 2: Accumulation Ratio of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 13 |
| Geometric Mean (Standard Deviation) [ratio] |
2.5
(0.9)
|
| Title | Stage 2: Apparent Clearance of Cobimetinib at Steady State |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 13 |
| Mean (Standard Deviation) [L/hr] |
9.8
(9.9)
|
| Title | Stage 2:Half-Life of Cobimetinib at Steady State |
|---|---|
| Description | T1/2 half-life of cobimetinib measured over the terminal phase by noncompartmental analysis. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 13 |
| Median (Full Range) [hours] |
53.4
|
| Title | Stage 2A: AUC 0-24/D of Cobimetinib at Steady State |
|---|---|
| Description | AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 15 |
| Mean (Standard Deviation) [h*ng/mL] |
84.8
(52.0)
|
| Title | Stage 2A: Accumulation Ratio of Cobimetinib at Steady State |
|---|---|
| Description | Accumulation Ratio AUC0-24 is ratio of AUC on Day 20: Day 1. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 15 |
| Mean (Standard Deviation) [ratio] |
2.3
(1.2)
|
| Title | Stage 2A: Apparent Clearance of Cobimetinib at Steady State |
|---|---|
| Description | Apparent clearance is the plasma clearance of absorbed drug. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 15 |
| Mean (Standard Deviation) [L/hr] |
11.8
(5.2)
|
| Title | Stage 2A: Half-Life of Cobimetinib at Steady State |
|---|---|
| Description | |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 15 |
| Median (Full Range) [hours] |
42.7
|
| Title | Stage 2A: Tmax of Cobimetinib at Steady State |
|---|---|
| Description | Tmax is defined as the time to reach Cmax during stage 2A in steady state. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 15 |
| Median (Full Range) [hours] |
3.0
|
| Title | Stage 2A: Cmax of Cobimetinib at Steady State |
|---|---|
| Description | Cmax is the maximum plasma concentration achieved following the Day 20 dose in Stage 2A. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 15 |
| Geometric Mean (Standard Deviation) [ng/mL] |
315.0
(220.0)
|
| Title | Stage III: Cmax of Dextromethorphan |
|---|---|
| Description | 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). |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population; Stage 3 participants only. n=number of participants analyzed for specified category. |
| Arm/Group Title | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 20 |
| With cobimetinib - Cycle 1 Day 15(n=17) |
3.44
(150.0)
|
| Without cobimetinib - Cycle 1 Day 1 (n=20) |
3.16
(273.0)
|
| Title | Stage III: AUC 0-24 of Dextromethorphan |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 19 |
| With cobimetinib - Cycle 1 Day 1 (n=17) |
24.8
(180.0)
|
| Without cobimetinib - Cycle 1 Day1 (n=19) |
25.8
(240)
|
| Title | Stage III: AUC 0-inf of Dextromethorphan |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 19 |
| With cobimetinib - Cycle 1 Day 15 (n=13) |
29.1
(250.0)
|
| Without cobimetinib - Cycle 1 Day1 (n=19) |
18.9
(124.0)
|
| Title | Stage III: Cmax of Midazolam |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 20 |
| With cobimetinib - Cycle 1 Day15 (n=17) |
11.5
(64.0)
|
| Without cobimetinib - Cycle 1 Day 1(n=20) |
10.9
(79.0)
|
| Title | Stage III: AUC0-24 of Midazolam |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 14 |
| With cobimetinib - Cycle 1 Day 15 (n=14) |
33.0
(74.0)
|
| Without cobimetinib - Cycle 1 Day 1 (n=11) |
33.4
(88.0)
|
| Title | Stage III: AUC0-inf of Midazolam |
|---|---|
| Description | 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. |
| Time Frame | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 19 |
| With cobimetinib - Cycle 1 Day 15 (n=17) |
34.9
(77.0)
|
| Without cobimetinib Cycle 1 Day 1 (n=19) |
35.7
(91.0)
|
Adverse Events
| Time Frame | 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) . | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||||||||||||||||||||||
| Arm/Group Title | Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | |||||||||||||||
| Arm/Group Description | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | |||||||||||||||
All Cause Mortality |
||||||||||||||||||||||||||||||
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | ||||||||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | |||||||||||||||
Serious Adverse Events |
||||||||||||||||||||||||||||||
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | ||||||||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/4 (50%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 3/6 (50%) | 3/7 (42.9%) | 5/7 (71.4%) | 7/21 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 4/8 (50%) | 3/6 (50%) | 11/22 (50%) | 8/20 (40%) | |||||||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||||||||||||
| Anaemia | 1/4 (25%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Febrile neutropenia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Cardiac disorders | ||||||||||||||||||||||||||||||
| Cardio-respiratory arrest | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Atrial fibrillation | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Cardiac arrest | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Supraventricular tachycardia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Eye disorders | ||||||||||||||||||||||||||||||
| Vision blurred | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||||||||||||
| Abdominal pain | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Diarrhoea | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastrointestinal haemorrhage | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Ileus | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Intestinal obstruction | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Faecal incontinence | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastritis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastrointestinal obstruction | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastrointestinal perforation | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Impaired gastric emptying | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Small intestinal obstruction | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Vomiting | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| General disorders | ||||||||||||||||||||||||||||||
| Chest pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Fatigue | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 2/22 (9.1%) | 0/20 (0%) | |||||||||||||||
| Generalised oedema | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hepatobiliary disorders | ||||||||||||||||||||||||||||||
| Bile duct obstruction | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Hepatic failure | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Infections and infestations | ||||||||||||||||||||||||||||||
| Pneumonia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Cellulitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Tonsillitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Urinary tract infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Injury, poisoning and procedural complications | ||||||||||||||||||||||||||||||
| Feeding tube complication | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Gastrointestinal stoma complication | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Investigations | ||||||||||||||||||||||||||||||
| Alanine aminotransferase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Aspartate aminotransferase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Blood bilirubin increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Blood creatine phosphokinase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Troponin increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Metabolism and nutrition disorders | ||||||||||||||||||||||||||||||
| Dehydration | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hyponatraemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||||||||||||||||||
| Arthralgia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||||||||||||
| Malignant neoplasm progression | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Colon cancer | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Lung neoplasm malignant | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Metastases to central nervous system | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Ovarian cancer | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Pancreatic carcinoma | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Nervous system disorders | ||||||||||||||||||||||||||||||
| Syncope | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hepatic encephalopathy | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||||||||||
| Respiratory arrest | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 2/20 (10%) | |||||||||||||||
| Dyspnoea | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Acute respiratory failure | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Chronic obstructive pulmonary disease | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Pleural effusion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Pulmonary oedema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Respiratory distress | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Respiratory failure | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Surgical and medical procedures | ||||||||||||||||||||||||||||||
| Pleurodesis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Vascular disorders | ||||||||||||||||||||||||||||||
| Deep vein thrombosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hypotension | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Peripheral artery thrombosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||||||||||||||||||
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) | Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) | Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan | ||||||||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/4 (100%) | 3/3 (100%) | 3/3 (100%) | 3/3 (100%) | 3/3 (100%) | 6/6 (100%) | 7/7 (100%) | 7/7 (100%) | 20/21 (95.2%) | 3/3 (100%) | 3/3 (100%) | 8/8 (100%) | 6/6 (100%) | 21/22 (95.5%) | 18/20 (90%) | |||||||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||||||||||||
| Anaemia | 2/4 (50%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 2/6 (33.3%) | 1/7 (14.3%) | 2/7 (28.6%) | 1/21 (4.8%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 0/6 (0%) | 3/22 (13.6%) | 6/20 (30%) | |||||||||||||||
| Thrombocytopenia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 2/7 (28.6%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Leukopenia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Leukocytosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 2/20 (10%) | |||||||||||||||
| Lymphopenia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Neutropenia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Lymphadenopathy | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Cardiac disorders | ||||||||||||||||||||||||||||||
| Tachycardia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Atrial fibrillation | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Bradycardia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Sinus tachycardia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Ear and labyrinth disorders | ||||||||||||||||||||||||||||||
| Vertigo | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Eye disorders | ||||||||||||||||||||||||||||||
| Vision blurred | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 3/6 (50%) | 2/22 (9.1%) | 1/20 (5%) | |||||||||||||||
| Visual impairment | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 2/6 (33.3%) | 3/22 (13.6%) | 1/20 (5%) | |||||||||||||||
| Periorbital oedema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 2/7 (28.6%) | 1/21 (4.8%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 0/6 (0%) | 2/22 (9.1%) | 0/20 (0%) | |||||||||||||||
| Macular degeneration | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 1/6 (16.7%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Vitreous floaters | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Abnormal sensation in eye | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Cataract | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Ocular icterus | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Uveitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Diplopia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Eye pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||||||||||||
| Diarrhoea | 2/4 (50%) | 1/3 (33.3%) | 1/3 (33.3%) | 2/3 (66.7%) | 2/3 (66.7%) | 3/6 (50%) | 4/7 (57.1%) | 4/7 (57.1%) | 13/21 (61.9%) | 1/3 (33.3%) | 1/3 (33.3%) | 6/8 (75%) | 6/6 (100%) | 17/22 (77.3%) | 12/20 (60%) | |||||||||||||||
| Nausea | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 1/6 (16.7%) | 3/7 (42.9%) | 3/7 (42.9%) | 7/21 (33.3%) | 0/3 (0%) | 2/3 (66.7%) | 6/8 (75%) | 1/6 (16.7%) | 9/22 (40.9%) | 4/20 (20%) | |||||||||||||||
| Vomiting | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 1/3 (33.3%) | 2/6 (33.3%) | 3/7 (42.9%) | 1/7 (14.3%) | 5/21 (23.8%) | 0/3 (0%) | 2/3 (66.7%) | 4/8 (50%) | 2/6 (33.3%) | 12/22 (54.5%) | 5/20 (25%) | |||||||||||||||
| Abdominal pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) | 1/6 (16.7%) | 0/7 (0%) | 2/7 (28.6%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 5/8 (62.5%) | 1/6 (16.7%) | 9/22 (40.9%) | 3/20 (15%) | |||||||||||||||
| Constipation | 1/4 (25%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 1/3 (33.3%) | 1/6 (16.7%) | 3/7 (42.9%) | 0/7 (0%) | 3/21 (14.3%) | 0/3 (0%) | 1/3 (33.3%) | 2/8 (25%) | 0/6 (0%) | 6/22 (27.3%) | 4/20 (20%) | |||||||||||||||
| Stomatitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/6 (33.3%) | 0/7 (0%) | 2/7 (28.6%) | 3/21 (14.3%) | 0/3 (0%) | 1/3 (33.3%) | 2/8 (25%) | 1/6 (16.7%) | 2/22 (9.1%) | 1/20 (5%) | |||||||||||||||
| Abdominal distension | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 4/20 (20%) | |||||||||||||||
| Gastrooesophageal reflux disease | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/7 (14.3%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Abdominal pain upper | 1/4 (25%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Flatulence | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Ascites | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 2/20 (10%) | |||||||||||||||
| Dry mouth | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 0/22 (0%) | 2/20 (10%) | |||||||||||||||
| Dyspepsia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Haematochezia | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Dysphagia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 2/7 (28.6%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Rectal haemorrhage | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Retching | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 3/21 (14.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Abdominal pain lower | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Oral pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Abdominal discomfort | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Anorectal discomfort | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Aphthous stomatitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Faecal incontinence | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastrointestinal sounds abnormal | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Haemorrhoids | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Impaired gastric emptying | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Tongue disorder | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Toothache | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Upper gastrointestinal haemorrhage | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| General disorders | ||||||||||||||||||||||||||||||
| Fatigue | 2/4 (50%) | 2/3 (66.7%) | 0/3 (0%) | 2/3 (66.7%) | 1/3 (33.3%) | 2/6 (33.3%) | 4/7 (57.1%) | 3/7 (42.9%) | 10/21 (47.6%) | 0/3 (0%) | 2/3 (66.7%) | 6/8 (75%) | 2/6 (33.3%) | 14/22 (63.6%) | 8/20 (40%) | |||||||||||||||
| Oedema peripheral | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/6 (16.7%) | 4/7 (57.1%) | 5/7 (71.4%) | 6/21 (28.6%) | 1/3 (33.3%) | 0/3 (0%) | 5/8 (62.5%) | 1/6 (16.7%) | 5/22 (22.7%) | 4/20 (20%) | |||||||||||||||
| Pyrexia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/6 (16.7%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 1/3 (33.3%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 3/22 (13.6%) | 2/20 (10%) | |||||||||||||||
| Oedema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 1/3 (33.3%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 3/22 (13.6%) | 0/20 (0%) | |||||||||||||||
| Asthenia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 1/22 (4.5%) | 2/20 (10%) | |||||||||||||||
| Chills | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 2/22 (9.1%) | 0/20 (0%) | |||||||||||||||
| Face oedema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 2/21 (9.5%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Chest pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Malaise | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Feeling hot | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Generalised oedema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Early satiety | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Gait disturbance | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Hypothermia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Influenza like illness | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Injection site pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Irritability | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Localised oedema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Non-cardiac chest pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Tenderness | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hepatobiliary disorders | ||||||||||||||||||||||||||||||
| Hyperbilirubinaemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Jaundice | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Immune system disorders | ||||||||||||||||||||||||||||||
| Hypersensitivity | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Infections and infestations | ||||||||||||||||||||||||||||||
| Urinary tract infection | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/7 (14.3%) | 3/21 (14.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 3/22 (13.6%) | 2/20 (10%) | |||||||||||||||
| Upper respiratory tract infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Hordeolum | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Gastroenteritis viral | 1/4 (25%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Oral candidiasis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Oral herpes | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Rhinitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Sinusitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Bacteraemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Bronchitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Clostridium difficile colitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Escherichia infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Groin infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Herpes virus infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Nail bed infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Peritonitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Pharyngitis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Pneumonia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Rash pustular | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Respiratory tract infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Syphilis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Viral upper respiratory tract infection | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Injury, poisoning and procedural complications | ||||||||||||||||||||||||||||||
| Contusion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Procedural pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Procedural site reaction | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Laceration | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Animal bite | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Fall | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hand fracture | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Incision site pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Joint injury | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Meniscus injury | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Muscle strain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Investigations | ||||||||||||||||||||||||||||||
| Aspartate aminotransferase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 3/21 (14.3%) | 0/3 (0%) | 0/3 (0%) | 3/8 (37.5%) | 0/6 (0%) | 2/22 (9.1%) | 2/20 (10%) | |||||||||||||||
| Alanine aminotransferase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 2/20 (10%) | |||||||||||||||
| Blood creatinine increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 3/21 (14.3%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Blood lactate dehydrogenase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 2/20 (10%) | |||||||||||||||
| Blood creatine phosphokinase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 4/20 (20%) | |||||||||||||||
| Blood alkaline phosphatase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 3/20 (15%) | |||||||||||||||
| Electrocardiogram QT prolonged | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 2/20 (10%) | |||||||||||||||
| Weight decreased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 2/22 (9.1%) | 1/20 (5%) | |||||||||||||||
| Gamma-glutamyltransferase increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Blood bilirubin increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Weight increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Activated partial thromboplastin time prolonged | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Ammonia increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Blood potassium decreased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Blood pressure increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Blood urine present | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Carbon dioxide decreased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Electrocardiogram QRS complex abnormal | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Haemoglobin | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Haemoglobin decreased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Oxygen saturation decreased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Platelet count increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Protein total decreased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Waist circumference increased | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Metabolism and nutrition disorders | ||||||||||||||||||||||||||||||
| Decreased appetite | 1/4 (25%) | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/7 (0%) | 5/21 (23.8%) | 0/3 (0%) | 2/3 (66.7%) | 2/8 (25%) | 0/6 (0%) | 7/22 (31.8%) | 6/20 (30%) | |||||||||||||||
| Dehydration | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 2/7 (28.6%) | 2/7 (28.6%) | 6/21 (28.6%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 1/6 (16.7%) | 9/22 (40.9%) | 2/20 (10%) | |||||||||||||||
| Hypokalaemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 3/6 (50%) | 2/7 (28.6%) | 0/7 (0%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 5/22 (22.7%) | 1/20 (5%) | |||||||||||||||
| Hyponatraemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 2/6 (33.3%) | 0/7 (0%) | 1/7 (14.3%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 2/20 (10%) | |||||||||||||||
| Hypoalbuminaemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 4/20 (20%) | |||||||||||||||
| Hypophosphataemia | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 2/6 (33.3%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Hyperglycaemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Hyperkalaemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 2/20 (10%) | |||||||||||||||
| Hypomagnesaemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hypermagnesaemia | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Cachexia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Diabetes mellitus | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Electrolyte imbalance | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Hypocalcaemia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Iron deficiency | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||||||||||||||||||
| Back pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/6 (16.7%) | 2/7 (28.6%) | 1/7 (14.3%) | 2/21 (9.5%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 0/6 (0%) | 3/22 (13.6%) | 1/20 (5%) | |||||||||||||||
| Pain in extremity | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 2/7 (28.6%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 3/8 (37.5%) | 1/6 (16.7%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Arthralgia | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Muscular weakness | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 0/22 (0%) | 4/20 (20%) | |||||||||||||||
| Myalgia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 1/6 (16.7%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Flank pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 2/6 (33.3%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Muscle spasms | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 1/6 (16.7%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Musculoskeletal pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Musculoskeletal stiffness | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Neck pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Critical illness myopathy | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Groin pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Intervertebral disc protrusion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Joint swelling | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Muscle fatigue | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||||||||||||
| Melanocytic naevus | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Nervous system disorders | ||||||||||||||||||||||||||||||
| Dizziness | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 2/6 (33.3%) | 1/7 (14.3%) | 3/7 (42.9%) | 3/21 (14.3%) | 0/3 (0%) | 0/3 (0%) | 3/8 (37.5%) | 0/6 (0%) | 5/22 (22.7%) | 3/20 (15%) | |||||||||||||||
| Headache | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 2/7 (28.6%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 1/6 (16.7%) | 2/22 (9.1%) | 2/20 (10%) | |||||||||||||||
| Neuropathy peripheral | 1/4 (25%) | 0/3 (0%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Dysgeusia | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Hypoaesthesia | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 2/20 (10%) | |||||||||||||||
| Syncope | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Convulsion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Tremor | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Ataxia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Cerebral haemorrhage | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Drug withdrawal headache | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hemiparesis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Hyperreflexia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Loss of proprioception | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Paraesthesia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Speech disorder | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Vocal cord paralysis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Psychiatric disorders | ||||||||||||||||||||||||||||||
| Insomnia | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 2/7 (28.6%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Confusional state | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Depression | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 2/22 (9.1%) | 1/20 (5%) | |||||||||||||||
| Hallucination, visual | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Disorientation | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Mental status changes | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Mood swings | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Restlessness | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Renal and urinary disorders | ||||||||||||||||||||||||||||||
| Haematuria | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 2/22 (9.1%) | 0/20 (0%) | |||||||||||||||
| Dysuria | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Proteinuria | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Urinary retention | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Costovertebral angle tenderness | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hydronephrosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Nocturia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Renal artery stenosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Renal failure acute | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Reproductive system and breast disorders | ||||||||||||||||||||||||||||||
| Pelvic pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Scrotal oedema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Vaginal discharge | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Breast pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Genital rash | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Menstruation irregular | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Oedema genital | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Vulvovaginal erythema | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||||||||||
| Cough | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 3/21 (14.3%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 2/22 (9.1%) | 1/20 (5%) | |||||||||||||||
| Dyspnoea | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 2/22 (9.1%) | 2/20 (10%) | |||||||||||||||
| Epistaxis | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 2/20 (10%) | |||||||||||||||
| Haemoptysis | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Nasal congestion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Productive cough | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Paranasal sinus hypersecretion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Pulmonary embolism | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Dysphonia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Pleuritic pain | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Rhinorrhoea | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Sinus congestion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Throat irritation | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Upper-airway cough syndrome | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||||||||||||||||||
| Rash | 1/4 (25%) | 1/3 (33.3%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 3/6 (50%) | 5/7 (71.4%) | 5/7 (71.4%) | 13/21 (61.9%) | 2/3 (66.7%) | 2/3 (66.7%) | 4/8 (50%) | 3/6 (50%) | 11/22 (50%) | 6/20 (30%) | |||||||||||||||
| Dry skin | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 2/3 (66.7%) | 0/3 (0%) | 1/6 (16.7%) | 2/7 (28.6%) | 3/7 (42.9%) | 1/21 (4.8%) | 1/3 (33.3%) | 0/3 (0%) | 1/8 (12.5%) | 1/6 (16.7%) | 2/22 (9.1%) | 1/20 (5%) | |||||||||||||||
| Dermatitis acneiform | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 2/21 (9.5%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 2/6 (33.3%) | 3/22 (13.6%) | 5/20 (25%) | |||||||||||||||
| Pruritus | 0/4 (0%) | 2/3 (66.7%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 1/6 (16.7%) | 0/7 (0%) | 1/7 (14.3%) | 1/21 (4.8%) | 0/3 (0%) | 1/3 (33.3%) | 1/8 (12.5%) | 1/6 (16.7%) | 1/22 (4.5%) | 3/20 (15%) | |||||||||||||||
| Skin fissures | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 2/20 (10%) | |||||||||||||||
| Alopecia | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 2/8 (25%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Hyperhidrosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Swelling face | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Ecchymosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 1/20 (5%) | |||||||||||||||
| Erythema | 0/4 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Pain of skin | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Photosensitivity reaction | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Pruritus generalised | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 1/3 (33.3%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Rash maculo-papular | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Skin exfoliation | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Urticaria | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Acne | 0/4 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Drug eruption | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Facial wasting | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Hyperkeratosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Nail discolouration | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Papule | 1/4 (25%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Rash erythematous | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Rash generalised | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Rash macular | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Skin disorder | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 1/3 (33.3%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Skin hyperpigmentation | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 1/6 (16.7%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Skin lesion | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Skin reaction | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 1/20 (5%) | |||||||||||||||
| Yellow skin | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Surgical and medical procedures | ||||||||||||||||||||||||||||||
| Wisdom teeth removal | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Vascular disorders | ||||||||||||||||||||||||||||||
| Hypertension | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/7 (0%) | 1/21 (4.8%) | 0/3 (0%) | 0/3 (0%) | 1/8 (12.5%) | 0/6 (0%) | 1/22 (4.5%) | 2/20 (10%) | |||||||||||||||
| Hypotension | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/7 (0%) | 0/7 (0%) | 4/21 (19%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 1/22 (4.5%) | 0/20 (0%) | |||||||||||||||
| Bloody discharge | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Haematoma | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/7 (0%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
| Thrombosis | 0/4 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/3 (0%) | 0/6 (0%) | 0/7 (0%) | 1/7 (14.3%) | 0/21 (0%) | 0/3 (0%) | 0/3 (0%) | 0/8 (0%) | 0/6 (0%) | 0/22 (0%) | 0/20 (0%) | |||||||||||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffmann-LaRoche |
| Phone | 1-800-821-8590 |
| genentech@druginfo.com |
Responsible Party:
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00467779
Other Study ID Numbers:
- MEK4592g
- GO01329
- XL518-001
First Posted:
May 1, 2007
Last Update Posted:
Aug 26, 2016
Last Verified:
Jul 1, 2016