Solid Tumor
Conditions
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.
Interventions
DRUGcobimetinib
Repeating oral dose
DRUGdextromethorphan
In Stage III only: single dose of dextromethorphan
DRUGmidazolam
In Stage III only: single dose of midazolam
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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: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 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 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. |
| 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 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. |
Countries
United States
Participant flow
Pre-assignment details
Study included following stages: Stage 1, Stage 1A, Stage 2, Stage 2A, and Stage 3. Different participants were recruited in each stage.
Participants by arm
| Arm | Count |
|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) Participants received cobimetinib 0.05 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 4 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) Participants received cobimetinib 0.10 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) Participants received cobimetinib 0.20 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) Participants received cobimetinib 10 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) Participants received cobimetinib 20 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) Participants received cobimetinib 40 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 6 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 7 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 7 |
| Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7) Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-21 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 21 |
| Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment \[14/14 schedule\]). Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 |
| Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) Participants received cobimetinib 80 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 3 |
| Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 8 |
| Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) Participants received cobimetinib 125 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 6 |
| Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14) Participants received cobimetinib 100 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. | 22 |
| Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan Participants received a single dose of midazolam (2 mg of midazolam syrup) and dextromethorphan (30 mg tablet) on Cycle 1 Day 1, in the absence of cobimetinib. After a 2-day washout period, participants received 21 consecutive daily doses of cobimetinib (60-mg) followed by a 7-day washout period.Participants received another single dose of midazolam and dextromethorphan on Cycle 1 Day 15, in the presence of steady-state cobimetinib concentrations. In Cycle 2 and beyond received cobimetinib alone, administered as a 60-mg daily dose for 21 consecutive days in 28-day cycles. | 20 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Stage 1 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Disease Progression | 2 | 2 | 2 | 3 | 2 | 2 | 4 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Unspecified Reason | 1 | 0 | 1 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 1A | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Stage 1A | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Stage 1A | Disease Progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 5 | 2 | 0 | 0 |
| Stage 1A | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Stage 1A | Unspecified Reason | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Stage 1A | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 |
| Stage 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 2 | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 2 | Disease Progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 16 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 2 | Unspecified Reason | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Stage 2A | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Stage 2A | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Stage 2A | Disease Progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 10 | 0 |
| Stage 2A | Unspecified Reason | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 7 | 0 |
| Stage 2A | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Stage 3 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Stage 3 | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Stage 3 | Disease Progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 9 |
| Stage 3 | Unspecified Reason | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 66.0 years STANDARD_DEVIATION 11.52 | 60.7 years STANDARD_DEVIATION 19.73 | 51.3 years STANDARD_DEVIATION 6.35 | 66.0 years STANDARD_DEVIATION 10.82 | 60.7 years STANDARD_DEVIATION 9.61 | 62.0 years STANDARD_DEVIATION 12.38 | 63.9 years STANDARD_DEVIATION 5.87 | 54.4 years STANDARD_DEVIATION 8.4 | 59.7 years STANDARD_DEVIATION 13.08 | 52.7 years STANDARD_DEVIATION 13.2 | 49.7 years STANDARD_DEVIATION 21.08 | 55.1 years STANDARD_DEVIATION 13.46 | 61.5 years STANDARD_DEVIATION 13.61 | 61.1 years STANDARD_DEVIATION 11.45 | 57.1 years STANDARD_DEVIATION 15.6 | 59.1 years STANDARD_DEVIATION 12.8 |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 11 Participants | 1 Participants | 3 Participants | 4 Participants | 4 Participants | 10 Participants | 9 Participants | 59 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants | 4 Participants | 10 Participants | 2 Participants | 0 Participants | 4 Participants | 2 Participants | 12 Participants | 11 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 7 / 7 | 7 / 7 | 20 / 21 | 3 / 3 | 3 / 3 | 8 / 8 | 6 / 6 | 21 / 22 | 18 / 20 |
| serious Total, serious adverse events | 2 / 4 | 0 / 3 | 1 / 3 | 0 / 3 | 1 / 3 | 3 / 6 | 3 / 7 | 5 / 7 | 7 / 21 | 0 / 3 | 1 / 3 | 4 / 8 | 3 / 6 | 11 / 22 | 8 / 20 |
Outcome results
Primary
Stage 1A: MTD of Cobimetinib in 14/14 Schedule
AEs were graded according to NCI-CTCAE v3.0. A DLT was the basis for determining MTD in Stage 1A participants. The participants of Stage 1A are dose-escalation cohorts, starting at the MTD of the 21/7 schedule, were treated on a 14/14 schedule to determine the MTD. A DLT was defined as either of the following occurring during the Study Treatment Period: Occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants to risk of irreversible medical harm; Nonhematologic toxicity: Grade 3 or 4 events, including Grade 3 nausea and/or vomiting and/or Grade 3 diarrhea, despite prophylaxis and/or treatment; Hematologic toxicity: Grade 4 thrombocytopenia. Grade 4 neutropenia of more than 4 days' duration; Grade 4 neutropenia of any duration with fever or documented infection. AEs (Grade 3 or higher) for which a clinical cause unrelated to cobimetinib was evident was not considered DLTs.
Time frame: Stage 1A: Days 1 to 28 of Cycle 1
Population: Safety population; Stage 1A participants only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: MTD of Cobimetinib in 14/14 Schedule | 100 mg |
Primary
Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs)
Adverse events (AE) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0. DLT was defined as either of the following occurring during the Study Treatment Period. The occurrence of a drug-related AE that, in the opinion of the cohort review committee (CRC), was of potential clinical significance such that further dose escalation would expose participants in higher dose cohorts to risk of irreversible medical harm or require medical treatment to avoid irreversible medical harm or non-hematologic toxicity * 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
Population: Safety population; Stages 1 and 1A participants only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 1 participants |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 1 participants |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 participants |
| Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) | Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 participants |
Primary
Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1
The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samples. AUC is measured as hours times nanograms per milliliter (h\*ng/mL).
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
Population: Safety population; Stage 1 participants only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 56.2 h*ng/mL | Standard Deviation 65 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 68.0 h*ng/mL | Standard Deviation 47 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 203.0 h*ng/mL | Standard Deviation 130 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 242.0 h*ng/mL | Standard Deviation 64 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 440.0 h*ng/mL | Standard Deviation 870 |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 785.0 h*ng/mL | Standard Deviation 560 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 1620.0 h*ng/mL | Standard Deviation 830 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1 | 3060.0 h*ng/mL | Standard Deviation 950 |
Primary
Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on Day 1, Cycle 1 in Stage 1 and was measured as nanograms per milliliter (ng/mL).
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
Population: Safety population; Stage 1 participants only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 4.51 ng/mL | Standard Deviation 5.8 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 6.92 ng/mL | Standard Deviation 3.8 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 18.3 ng/mL | Standard Deviation 13 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 18.8 ng/mL | Standard Deviation 5.1 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 30.8 ng/mL | Standard Deviation 69 |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 71.7 ng/mL | Standard Deviation 57 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 163.0 ng/mL | Standard Deviation 79 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1 | 261.0 ng/mL | Standard Deviation 110 |
Primary
Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule
AEs were graded according to the NCI-CTCAE v3.0. A DLT was determined from clinical findings during the Study Treatment Period (Cycle 1, Days 1). MTD was defined as the dose at which no DLTs were observed. DLT was defined as either of the following occurring during the Study Treatment Period. The occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants in higher dose cohorts to risk of irreversible medical harm or require medical treatment to avoid irreversible medical harm or non-hematologic toxicity * 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
Population: Safety population; Stage 1 participants only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule | 60 milligrams (mg) |
Primary
Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1
Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1.
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
Population: Safety population; Stage 1 participants only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 2.0 hours |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 1.0 hours |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 1.5 hours |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 3.0 hours |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 4.0 hours |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 2.5 hours |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 2.0 hours |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1 | 2.0 hours |
Secondary
Stage 1A: Accumulation Ratio of Cobimetinib at Steady State
Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.
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)
Population: Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: Accumulation Ratio of Cobimetinib at Steady State | 2.32 ratio | Standard Deviation 0.448 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: Accumulation Ratio of Cobimetinib at Steady State | 3.14 ratio | Standard Deviation 1.77 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: Accumulation Ratio of Cobimetinib at Steady State | 2.6 ratio | Standard Deviation 2.32 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: Accumulation Ratio of Cobimetinib at Steady State | 5.15 ratio | Standard Deviation 2.08 |
Secondary
Stage 1A: Apparent Clearance of Cobimetinib at Steady State
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.
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)
Population: Safety population; Stage 1A participants only. Number pf participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: Apparent Clearance of Cobimetinib at Steady State | 25.1 L/hr | Standard Deviation 13.5 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: Apparent Clearance of Cobimetinib at Steady State | 14.9 L/hr | Standard Deviation 8.33 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: Apparent Clearance of Cobimetinib at Steady State | 21.9 L/hr | Standard Deviation 20.3 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: Apparent Clearance of Cobimetinib at Steady State | 6.9 L/hr | Standard Deviation 3.22 |
Secondary
Stage 1A: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
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)
Population: Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: AUC 0-24/D of Cobimetinib at Steady State | 49.8 ng*hr/mL/mg | Standard Deviation 29.2 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: AUC 0-24/D of Cobimetinib at Steady State | 84.2 ng*hr/mL/mg | Standard Deviation 47.8 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: AUC 0-24/D of Cobimetinib at Steady State | 115.0 ng*hr/mL/mg | Standard Deviation 105 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: AUC 0-24/D of Cobimetinib at Steady State | 172.0 ng*hr/mL/mg | Standard Deviation 90.4 |
Secondary
Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1
AUC0-24 for stage 1A was calculated on Day 1 with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
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
Population: Safety population; Stage 1A participants only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | 1140 h*ng/mL | Standard Deviation 1150 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | 2130 h*ng/mL | Standard Deviation 70.1 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | 4020 h*ng/mL | Standard Deviation 2000 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | 7190 h*ng/mL | Standard Deviation 3640 |
Secondary
Stage 1A: AUC 0-24 of Cobimetinib at Steady State
The area under the AUC0-24 for steady state in stage 1A was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
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)
Population: Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Steady State | 2990.0 h*ng/mL | Standard Deviation 1750 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Steady State | 6740.0 h*ng/mL | Standard Deviation 3830 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Steady State | 11500.0 h*ng/mL | Standard Deviation 10500 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: AUC 0-24 of Cobimetinib at Steady State | 21500.0 h*ng/mL | Standard Deviation 11300 |
Secondary
Stage 1: Accumulation Ratio of Cobimetinib at Steady State
Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.
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)
Population: Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 3.56 ratio | Standard Deviation 1.76 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 3.66 ratio | Standard Deviation 0.901 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 2.65 ratio | Standard Deviation 0.886 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 3.23 ratio | Standard Deviation 1.03 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 2.96 ratio | — |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 3.61 ratio | Standard Deviation 2.27 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 2.87 ratio | Standard Deviation 0.787 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Accumulation Ratio of Cobimetinib at Steady State | 3.26 ratio | Standard Deviation 2.1 |
Secondary
Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on on Day 1 in Stage 1A and was measured as ng/mL.
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
Population: Safety population; Stage 1A participants only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1 | 78.4 ng/mL | Standard Deviation 88 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1 | 167.0 ng/mL | Standard Deviation 63 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1 | 258.0 ng/mL | Standard Deviation 140 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1 | 533.0 ng/mL | Standard Deviation 347 |
Secondary
Stage 1A: Cmax of Cobimetinib at Steady State
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1A and was measured in steady state as ng/mL.
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)
Population: Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: Cmax of Cobimetinib at Steady State | 180.0 ng/mL | Standard Deviation 101 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: Cmax of Cobimetinib at Steady State | 494.0 ng/mL | Standard Deviation 175 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: Cmax of Cobimetinib at Steady State | 640.0 ng/mL | Standard Deviation 511 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: Cmax of Cobimetinib at Steady State | 1160.0 ng/mL | Standard Deviation 540 |
Secondary
Stage 1: Apparent Clearance of Cobimetinib at Steady State
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.
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)
Population: Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 22.4 Liters per hour (L/hr) | Standard Deviation 17.2 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 34.0 Liters per hour (L/hr) | Standard Deviation 14.2 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 37.1 Liters per hour (L/hr) | Standard Deviation 11.1 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 13.5 Liters per hour (L/hr) | Standard Deviation 2.71 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 22.6 Liters per hour (L/hr) | — |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 14.0 Liters per hour (L/hr) | Standard Deviation 10.1 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 11.8 Liters per hour (L/hr) | Standard Deviation 5.71 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Apparent Clearance of Cobimetinib at Steady State | 11.6 Liters per hour (L/hr) | Standard Deviation 5.42 |
Secondary
Stage 1A: t1/2 of Cobimetinib at Steady State
t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1A in steady state.
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)
Population: Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: t1/2 of Cobimetinib at Steady State | 59.4 hours |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: t1/2 of Cobimetinib at Steady State | 44.1 hours |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: t1/2 of Cobimetinib at Steady State | 51.6 hours |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: t1/2 of Cobimetinib at Steady State | 47.7 hours |
Secondary
Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1
Tmax is defined as the time to reach Cmax during stage 1A at Day 1.
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
Population: Safety population; Stage 1A participants only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1 | 3.0 hours |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1 | 4.0 hours |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1 | 3.5 hours |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1 | 2.5 hours |
Secondary
Stage 1A: Tmax of Cobimetinib at Steady State
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)
Population: Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1A: Tmax of Cobimetinib at Steady State | 2.0 hours |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1A: Tmax of Cobimetinib at Steady State | 2.0 hours |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1A: Tmax of Cobimetinib at Steady State | 3 hours |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1A: Tmax of Cobimetinib at Steady State | 6 hours |
Secondary
Stage 1: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
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)
Population: Safety Population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 62.4 ng*hr/mL/mg | Standard Deviation 36.3 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 34 ng*hr/mL/mg | Standard Deviation 16.9 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 28.2 ng*hr/mL/mg | Standard Deviation 8.43 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 76.3 ng*hr/mL/mg | Standard Deviation 16.8 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 44.3 ng*hr/mL/mg | — |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 134 ng*hr/mL/mg | Standard Deviation 115 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 104 ng*hr/mL/mg | Standard Deviation 59.1 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: AUC 0-24/D of Cobimetinib at Steady State | 132 ng*hr/mL/mg | Standard Deviation 131 |
Secondary
Stage 1: AUC 0-24 of Cobimetinib at Steady State
The area under the AUC0-24 for steady state in stage 1 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
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)
Population: Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 202.0 h*ng/mL | Standard Deviation 158 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 288.0 h*ng/mL | Standard Deviation 200 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 411.0 h*ng/mL | Standard Deviation 199 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 763.0 h*ng/mL | Standard Deviation 168 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 886.0 h*ng/mL | — |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 5370.0 h*ng/mL | Standard Deviation 4600 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 6250.0 h*ng/mL | Standard Deviation 3540 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: AUC 0-24 of Cobimetinib at Steady State | 10500.0 h*ng/mL | Standard Deviation 10500 |
Secondary
Stage 1: Cmax of Cobimetinib at Steady State
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1 and was measured at steady state in ng/mL.
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)
Population: Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 13.5 ng/mL | Standard Deviation 9.53 |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 19.8 ng/mL | Standard Deviation 15.2 |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 28.7 ng/mL | Standard Deviation 8.63 |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 53.0 ng/mL | Standard Deviation 5.4 |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 54.7 ng/mL | — |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 341.0 ng/mL | Standard Deviation 244 |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 401.0 ng/mL | Standard Deviation 214 |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Cmax of Cobimetinib at Steady State | 641.0 ng/mL | Standard Deviation 514 |
Secondary
Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State
t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1 in steady state.
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)
Population: Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 80.0 hours |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 64.0 hours |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 47.8 hours |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 66.0 hours |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 50.5 hours |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 41.3 hours |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 51.3 hours |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State | 60.0 hours |
Secondary
Stage 1: Tmax of Cobimetinib at Steady State
Tmax is defined as the time to reach Cmax during stage 1 in steady state. Steady state was reached when overall intake of cobimetinib was in dynamic equilibrium with its elimination.
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)
Population: Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 4.0 hours |
| Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 1.0 hours |
| Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 2.25 hours |
| Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 4.0 hours |
| Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 3.0 hours |
| Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 2.0 hours |
| Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 3.0 hours |
| Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) | Stage 1: Tmax of Cobimetinib at Steady State | 2.5 hours |
Secondary
Stage 2A: Accumulation Ratio of Cobimetinib at Steady State
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
Population: Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2A: Accumulation Ratio of Cobimetinib at Steady State | 2.3 ratio | Standard Deviation 1.2 |
Secondary
Stage 2A: Apparent Clearance of Cobimetinib at Steady State
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
Population: Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2A: Apparent Clearance of Cobimetinib at Steady State | 11.8 L/hr | Standard Deviation 5.2 |
Secondary
Stage 2A: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
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
Population: Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2A: AUC 0-24/D of Cobimetinib at Steady State | 84.8 h*ng/mL | Standard Deviation 52 |
Secondary
Stage 2: Accumulation Ratio of Cobimetinib at Steady State
Accumulation ratio is AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.
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
Population: Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2: Accumulation Ratio of Cobimetinib at Steady State | 2.5 ratio | Standard Deviation 0.9 |
Secondary
Stage 2A: Cmax of Cobimetinib at Steady State
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
Population: Analysis population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2A: Cmax of Cobimetinib at Steady State | 315.0 ng/mL | Standard Deviation 220 |
Secondary
Stage 2A: Half-Life of Cobimetinib at 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
Population: Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2A: Half-Life of Cobimetinib at Steady State | 42.7 hours |
Secondary
Stage 2: Apparent Clearance of Cobimetinib at Steady State
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.
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
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2: Apparent Clearance of Cobimetinib at Steady State | 9.8 L/hr | Standard Deviation 9.9 |
Secondary
Stage 2A: Tmax of Cobimetinib at Steady State
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
Population: Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2A: Tmax of Cobimetinib at Steady State | 3.0 hours |
Secondary
Stage 2: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
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
Population: Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2: AUC 0-24/D of Cobimetinib at Steady State | 102.0 h*ng/mL | Standard Deviation 56.3 |
Secondary
Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1
The area under the AUC0-24 on Day 1 in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
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
Population: Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1 | 3060.0 h*ng/mL | Standard Deviation 2110 |
Secondary
Stage 2: AUC 0-24 of Cobimetinib at Steady State
The area under the AUC0-24 for steady state in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
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
Population: Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2: AUC 0-24 of Cobimetinib at Steady State | 10200.0 h*ng/mL | Standard Deviation 5630 |
Secondary
Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 2 and was measured in ng/mL.
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
Population: Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1 | 184.0 ng/mL | Standard Deviation 160 |
Secondary
Stage 2:Half-Life of Cobimetinib at Steady State
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
Population: Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2:Half-Life of Cobimetinib at Steady State | 53.4 hours |
Secondary
Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1
Tmax is defined as the time to reach Cmax during stage 2 on Day 1.
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
Population: Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1 | 3.0 hours |
Secondary
Stage 2: Tmax of Cobimetinib at Steady State
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
Population: Safety population; Stage 2 participants only; Number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage 2: Tmax of Cobimetinib at Steady State | 4.0 hours |
Secondary
Stage III: AUC 0-24 of Dextromethorphan
AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was determined both in presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC 0-24 of Dextromethorphan | With cobimetinib - Cycle 1 Day 1 (n=17) | 24.8 h*ng/mL | Standard Deviation 180 |
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC 0-24 of Dextromethorphan | Without cobimetinib - Cycle 1 Day1 (n=19) | 25.8 h*ng/mL | Standard Deviation 240 |
Secondary
Stage III: AUC0-24 of Midazolam
AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was calculated both in the presence (Cycle 1 Day 15) and absence (CXycle 1 Day 1) of cobimetinib.
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC0-24 of Midazolam | With cobimetinib - Cycle 1 Day 15 (n=14) | 33.0 h*ng/mL | Standard Deviation 74 |
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC0-24 of Midazolam | Without cobimetinib - Cycle 1 Day 1 (n=11) | 33.4 h*ng/mL | Standard Deviation 88 |
Secondary
Stage III: AUC 0-inf of Dextromethorphan
AUC0-inf is AUC from time 0 to infinity and was calculated both in presence Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC 0-inf of Dextromethorphan | With cobimetinib - Cycle 1 Day 15 (n=13) | 29.1 h*ng/mL | Standard Deviation 250 |
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC 0-inf of Dextromethorphan | Without cobimetinib - Cycle 1 Day1 (n=19) | 18.9 h*ng/mL | Standard Deviation 124 |
Secondary
Stage III: AUC0-inf of Midazolam
AUC0-inf is the AUC from time 0 to infinity and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC0-inf of Midazolam | With cobimetinib - Cycle 1 Day 15 (n=17) | 34.9 h*ng/mL | Standard Deviation 77 |
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: AUC0-inf of Midazolam | Without cobimetinib Cycle 1 Day 1 (n=19) | 35.7 h*ng/mL | Standard Deviation 91 |
Secondary
Stage III: Cmax of Dextromethorphan
Cmax is defined as maximum observed plasma concentration and was determined both in the presence (Cycle 1 Day 15) and absence of cobimetinib (Cycle 1 Day 1).
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
Population: Safety population; Stage 3 participants only. n=number of participants analyzed for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: Cmax of Dextromethorphan | With cobimetinib - Cycle 1 Day 15(n=17) | 3.44 ng/mL | Standard Deviation 150 |
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: Cmax of Dextromethorphan | Without cobimetinib - Cycle 1 Day 1 (n=20) | 3.16 ng/mL | Standard Deviation 273 |
Secondary
Stage III: Cmax of Midazolam
Cmax is the maximum observed plasma concentration and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: Cmax of Midazolam | With cobimetinib - Cycle 1 Day15 (n=17) | 11.5 ng/mL | Standard Deviation 64 |
| Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) | Stage III: Cmax of Midazolam | Without cobimetinib - Cycle 1 Day 1(n=20) | 10.9 ng/mL | Standard Deviation 79 |