Study of Cobimetinib in Participants With Solid Tumors

Eksperymentalny: 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.

Lek: cobimetinib

Repeating oral dose

Inne nazwy:

• GDC-0973/XL518

Eksperymentalny: 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.

Lek: cobimetinib

Repeating oral dose

Inne nazwy:

• GDC-0973/XL518

Eksperymentalny: 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.

Lek: cobimetinib

Repeating oral dose

Inne nazwy:

• GDC-0973/XL518

Eksperymentalny: 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.

Lek: cobimetinib

Repeating oral dose

Inne nazwy:

• GDC-0973/XL518

Eksperymentalny: 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).

Lek: cobimetinib

Repeating oral dose

Inne nazwy:

• GDC-0973/XL518

Lek: dextromethorphan

In Stage III only: single dose of dextromethorphan

Lek: midazolam

In Stage III only: single dose of midazolam

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

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

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.

Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1

Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on Day 1, Cycle 1 in Stage 1 and was measured as nanograms per milliliter (ng/mL).

Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1

The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samples. AUC is measured as hours times nanograms per milliliter (h*ng/mL).

Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1

Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1.

Stage 1: Tmax of Cobimetinib at Steady State

Tmax is defined as the time to reach Cmax during stage 1 in steady state. Steady state was reached when overall intake of cobimetinib was in dynamic equilibrium with its elimination.

Stage 1: AUC 0-24 of Cobimetinib at Steady State

The area under the AUC0-24 for steady state in stage 1 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.

Stage 1: AUC 0-24/D of Cobimetinib at Steady State

AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.

Stage 1: Accumulation Ratio of Cobimetinib at Steady State

Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.

Stage 1: Apparent Clearance of Cobimetinib at Steady State

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.

Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State

t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1 in steady state.

Stage 1: Cmax of Cobimetinib at Steady State

Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1 and was measured at steady state in ng/mL.

Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1

Tmax is defined as the time to reach Cmax during stage 1A at Day 1.

Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1

Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on on Day 1 in Stage 1A and was measured as ng/mL.

Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1

AUC0-24 for stage 1A was calculated on Day 1 with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.

Stage 1A: t1/2 of Cobimetinib at Steady State

t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1A in steady state.

Stage 1A: Tmax of Cobimetinib at Steady State

Tmax is defined as the time to reach Cmax during stage 1A in steady state.

Stage 1A: Apparent Clearance of Cobimetinib at Steady State

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.

Stage 1A: Accumulation Ratio of Cobimetinib at Steady State

Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.

Stage 1A: AUC 0-24 of Cobimetinib at Steady State

The area under the AUC0-24 for steady state in stage 1A was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.

Stage 1A: AUC 0-24/D of Cobimetinib at Steady State

AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.

Stage 1A: Cmax of Cobimetinib at Steady State

Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1A and was measured in steady state as ng/mL.

Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1

Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 2 and was measured in ng/mL.

Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1

The area under the AUC0-24 on Day 1 in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.

Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1

Tmax is defined as the time to reach Cmax during stage 2 on Day 1.

Stage 2: Tmax of Cobimetinib at Steady State

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

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

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

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

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

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

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

Accumulation Ratio AUC0-24 is ratio of AUC on Day 20: Day 1.

Stage 2A: Apparent Clearance of Cobimetinib at Steady State

Apparent clearance is the plasma clearance of absorbed drug.

Stage 2A: Half-Life of Cobimetinib at Steady State

Stage 2A: Tmax of Cobimetinib at Steady State

Tmax is defined as the time to reach Cmax during stage 2A in steady state.

Stage 2A: Cmax of Cobimetinib at Steady State

Cmax is the maximum plasma concentration achieved following the Day 20 dose in Stage 2A.

Stage III: Cmax of Dextromethorphan

Cmax is defined as maximum observed plasma concentration and was determined both in the presence (Cycle 1 Day 15) and absence of cobimetinib (Cycle 1 Day 1).

Stage III: AUC 0-24 of Dextromethorphan

AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was determined both in presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.

Stage III: AUC 0-inf of Dextromethorphan

AUC0-inf is AUC from time 0 to infinity and was calculated both in presence Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.

Stage III: Cmax of Midazolam

Cmax is the maximum observed plasma concentration and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.

Stage III: AUC0-24 of Midazolam

AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was calculated both in the presence (Cycle 1 Day 15) and absence (CXycle 1 Day 1) of cobimetinib.

Stage III: 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.