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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.

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.

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.

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.

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).

cobimetinib

In Stage III only: single dose of dextromethorphan

dextromethorphan

In Stage III only: single dose of midazolam

midazolam

Clinical Trials

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.

Study of Cobimetinib in Participants With Solid Tumors

A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of GDC-0973/XL518 Administered Orally Daily to Subjects With Solid Tumors

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

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

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.

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).

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).

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

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.

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.

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

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.

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.

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

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

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.

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

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

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.

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

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.

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

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

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.

T1/2 half-life of cobimetinib measured over the terminal phase by noncompartmental analysis.

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

Apparent clearance is the plasma clearance of absorbed drug.

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

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

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).

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.

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.

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.

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.

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.

Genentech, Inc.

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.

Stage 1 Cohort 01 - Cobimetinib 0.05 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.

Stage 1 Cohort 02 - Cobimetinib 0.10 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.

Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (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.

Stage 1 Cohort 04 - Cobimetinib 10 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.

Stage 1 Cohort 05 - Cobimetinib 20 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.

Stage 1 Cohort 06 - Cobimetinib 40 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.

Stage 1 Cohort 07 - Cobimetinib 60 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.

Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7)

Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7)

Participants received cobimetinib 60 mg via solution or capsule, once daily for Days 1-14 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.

Stage 1A Cohort 01A - Cobimetinib 60 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.

Stage 1A Cohort 02A - Cobimetinib 80 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.

Stage 1A Cohort 03A - Cobimetinib 100 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.

Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14)

Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14)

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.

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.

Total

Age, Continuous

Sex: Female, Male

Safety population consisted of all participants who received at least 1 dose of study drug.

Medical Communications

Participants received cobimetinib (GDC-0973/XL518) 0.05 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment \[21/7 schedule\]). Treatment was continued until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor.

Safety population; Stages 1 and 1A participants only.

Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs)

Participants received cobimetinib via solution or capsule, once daily for Days 1-21 of each 28-day cycle and were on 21-days-on and 7-days-off schedule. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor.

Stage 1 All Cohorts (21/7)

Safety population; Stage 1 participants only.

Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule

Participants received cobimetinib via solution or capsule, once daily for Days 1-14 of each 28-day cycle and were on a 14-days-on and 14-days-off schedule. Treatment was continued until PD or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor.

Stage 1A - All Cohorts (14/14)

Safety population; Stage 1A participants only.

Stage 1A: MTD of Cobimetinib in 14/14 Schedule

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

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

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

Safety population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.

Stage 1: Tmax of Cobimetinib at Steady State

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

Safety Population; Stage 1 participants only. Number of participants analyzed = participants who were evaluable for this outcome.

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

Stage 1: Accumulation Ratio of Cobimetinib at Steady State

Stage 1: Apparent Clearance of Cobimetinib at Steady State

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

Stage 1: Cmax of Cobimetinib at Steady State

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

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

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

Safety population; Stage 1A participants only. Number of participants analyzed = participants who were evaluable for this outcome.

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

Stage 1A: Tmax of Cobimetinib at Steady State

Safety population; Stage 1A participants only. Number pf participants analyzed = participants who were evaluable for this outcome.

Stage 1A: Apparent Clearance of Cobimetinib at Steady State

Stage 1A: Accumulation Ratio of Cobimetinib at Steady State

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

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

Stage 1A: Cmax of Cobimetinib at Steady State

Safety population; Stage 2 participants only. Number of participants analyzed = participants who were evaluable for this outcome.

Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1

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

Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1

Safety population; Stage 2 participants only; Number of participants analyzed = participants who were evaluable for this outcome.

Stage 2: Tmax of Cobimetinib at Steady State

Stage 2: AUC 0-24 of Cobimetinib at Steady State

Stage 2: AUC 0-24/D of Cobimetinib at Steady State

Stage 2: Accumulation Ratio of Cobimetinib at Steady State

Stage 2: Apparent Clearance of Cobimetinib at Steady State

Stage 2:Half-Life of Cobimetinib at Steady State

Safety population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.

Stage 2A: AUC 0-24/D of Cobimetinib at Steady State

Stage 2A: Accumulation Ratio of Cobimetinib at Steady State

Stage 2A: Apparent Clearance of Cobimetinib at Steady State

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

Stage 2A: Tmax of Cobimetinib at Steady State

Analysis population; Stage 2A participants only. Number of participants analyzed = participants who were evaluable for this outcome.

Stage 2A: Cmax of Cobimetinib at Steady State

With cobimetinib - Cycle 1 Day 15(n=17)

Without cobimetinib - Cycle 1 Day 1 (n=20)

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.

Safety population; Stage 3 participants only. n=number of participants analyzed for specified category.

Stage III: Cmax of Dextromethorphan

With cobimetinib - Cycle 1 Day 1 (n=17)

Without cobimetinib - Cycle 1 Day1 (n=19)

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.

Stage III: AUC 0-24 of Dextromethorphan

With cobimetinib - Cycle 1 Day 15 (n=13)

Stage III: AUC 0-inf of Dextromethorphan

With cobimetinib - Cycle 1 Day15 (n=17)

Without cobimetinib - Cycle 1 Day 1(n=20)

Stage III: Cmax of Midazolam

With cobimetinib - Cycle 1 Day 15 (n=14)

Without cobimetinib - Cycle 1 Day 1 (n=11)

Stage III: AUC0-24 of Midazolam

With cobimetinib - Cycle 1 Day 15 (n=17)

Without cobimetinib Cycle 1 Day 1 (n=19)

Stage III: AUC0-inf of Midazolam

Participants received cobimetinib (GDC-0973/XL518) 0.05 milligrams per kilograms (mg/kg) via solution or capsule, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment \[21/7 schedule\]). Treatment was continued until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor.

Spots Global Cancer Trial Database for Study of Cobimetinib in Participants With Solid Tumors

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Study Description

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