Solid TumorPhase 1NCT00467779

Study of Cobimetinib in Participants With Solid Tumors

A Phase 1 study testing cobimetinib, dextromethorphan and midazolam in people with Solid Tumor, run by Genentech, Inc. at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Solid Tumor
What is being tested?: cobimetinib, dextromethorphan and midazolam
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 119 participants
Where: 4 sitesUnited States
Study dates: May 2007to Apr 2014
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

4 sites in 1 country.

United States4 sites

Study site
Buffalo, New York, 14263
Study site
Detroit, Michigan, 48201
Study site
Los Angeles, California, 90095
Study site
Stanford, California, 94305-5821

Other trials in United States

About this study

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

Conditions: Solid Tumor
Being tested: cobimetinib, dextromethorphan, midazolam

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

cobimetinibDrug
Also called GDC-0973/XL518
Repeating oral dose
dextromethorphanDrug
In Stage III only: single dose of dextromethorphan
midazolamDrug
In Stage III only: single dose of midazolam

Study groups in NCT00467779
Study group	Role	What they receive
Stage 1: Cobimetinib Dose Escalation (21/7 Schedule)	Experimental	Participants will receive cobimetinib (GDC-0973/XL518) at the starting dose of 0.05 mg/kg via solution or capsule, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment [21/7 schedule]). Treatment will continue until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. Receives: Drug: cobimetinib
Stage 1A: Cobimetinib Dose Escalation (14/14 Schedule)	Experimental	Participants will receive cobimetinib at the starting dose of 60 mg via solution or capsule, once daily for Days 1-14 of each 28-day cycle (14 days on drug followed by 14 days off treatment [14/14 schedule]). Treatment will continue until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. Receives: Drug: cobimetinib
Stage 2: Cobimetinib Expansion (21/7 Schedule)	Experimental	Participants will receive cobimetinib at the maximum tolerated dose (MTD) established in Stage 1, once daily for Days 1-21 of each 28-day cycle (21 days on drug followed by 7 days off treatment [21/7 schedule]). Treatment will continue until progressive disease (PD) or unacceptable toxicity for up to 1 year at the discretion of investigator and beyond 1 year with the agreement of the sponsor. Receives: Drug: cobimetinib
Stage 2 A: Cobimetinib Expansion (14/14 Schedule)	Experimental	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. Receives: Drug: cobimetinib
Stage 3: Cobimetinib+Midazolam+Dextromethorphan	Experimental	Participants will receive a single dose of midazolam (2 mg of midazolam syrup) and dextromethorphan (30 mg tablet) on Cycle 1 Day 1, in the absence of cobimetinib. After a 2-day washout period, participants will receive 21 consecutive daily doses of cobimetinib (60-mg) followed by a 7-day washout period. Participants will receive another single dose of midazolam and dextromethorphan on Cycle 1 Day 15, in the presence of steady-state cobimetinib concentrations. In Cycle 2 and beyond participants will receive cobimetinib alone, administered as a 60-mg daily dose for 21 consecutive days in 28-day cycles (21/7 schedule). Receives: Drug: cobimetinib; Drug: dextromethorphan; Drug: midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: Stage 1 and 1A: Days 1 to 28 of Cycle 1
Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule
AEs were graded according to the NCI-CTCAE v3.0. A DLT was determined from clinical findings during the Study Treatment Period (Cycle 1, Days 1). MTD was defined as the dose at which no DLTs were observed. DLT was defined as either of the following occurring during the Study Treatment Period. The occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants in higher dose cohorts to risk of irreversible medical harm or require medical treatment to avoid irreversible medical harm or non-hematologic toxicity
- 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
Measured: Stage 1: Days 1 to 28 of Cycle 1
Stage 1A: MTD of Cobimetinib in 14/14 Schedule
AEs were graded according to NCI-CTCAE v3.0. A DLT was the basis for determining MTD in Stage 1A participants. The participants of Stage 1A are dose-escalation cohorts, starting at the MTD of the 21/7 schedule, were treated on a 14/14 schedule to determine the MTD. A DLT was defined as either of the following occurring during the Study Treatment Period:
Occurrence of a drug-related AE that, in the opinion of the CRC, was of potential clinical significance such that further dose escalation would expose participants to risk of irreversible medical harm; Nonhematologic toxicity: Grade 3 or 4 events, including Grade 3 nausea and/or vomiting and/or Grade 3 diarrhea, despite prophylaxis and/or treatment; Hematologic toxicity: Grade 4 thrombocytopenia. Grade 4 neutropenia of more than 4 days' duration; Grade 4 neutropenia of any duration with fever or documented infection. AEs (Grade 3 or higher) for which a clinical cause unrelated to cobimetinib was evident was not considered DLTs.
Measured: Stage 1A: Days 1 to 28 of Cycle 1
Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on Day 1, Cycle 1 in Stage 1 and was measured as nanograms per milliliter (ng/mL).
Measured: Stage 1: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1 and pre-dose on Cycle 1 Day 2
Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1
The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samples. AUC is measured as hours times nanograms per milliliter (h*ng/mL).
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2
Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1
Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1.
Measured: 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

Secondary outcomes (38)

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.
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: AUC 0-24 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.
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: Accumulation Ratio of Cobimetinib at Steady State
Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 1, Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: Apparent Clearance of Cobimetinib at Steady State
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State
t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1 in steady state.
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: Cmax of Cobimetinib at Steady State
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1 and was measured at steady state in ng/mL.
Measured: Stage 1: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12-18 hours post-dose on Cycle 1 Day 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1
Tmax is defined as the time to reach Cmax during stage 1A at Day 1.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2
Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib on on Day 1 in Stage 1A and was measured as ng/mL.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2
Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1
AUC0-24 for stage 1A was calculated on Day 1 with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2
Stage 1A: t1/2 of Cobimetinib at Steady State
t1/2 is the half-life of cobimetinib measured over the terminal phase by noncompartmental analysis in stage 1A in steady state.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: Tmax of Cobimetinib at Steady State
Tmax is defined as the time to reach Cmax during stage 1A in steady state.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: Apparent Clearance of Cobimetinib at Steady State
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: Accumulation Ratio of Cobimetinib at Steady State
Accumulation Ratio: AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: AUC 0-24 of Cobimetinib at Steady State
The area under the AUC0-24 for steady state in stage 1A was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: Cmax of Cobimetinib at Steady State
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 1A and was measured in steady state as ng/mL.
Measured: Stage 1A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1
Cmax is defined as the maximum plasma concentration achieved after administration of cobimetinib in Stage 2 and was measured in ng/mL.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2
Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1
The area under the AUC0-24 on Day 1 in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2
Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1
Tmax is defined as the time to reach Cmax during stage 2 on Day 1.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 1, pre-dose on Cycle 1 Day 2
Stage 2: Tmax of Cobimetinib at Steady State
Tmax is defined as the time to reach Cmax during stage 2 in steady state.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28
Stage 2: AUC 0-24 of Cobimetinib at Steady State
The area under the AUC0-24 for steady state in stage 2 was calculated with the measured data points from the time of administration of cobimetinib up to 24 h after administration by the trapezoidal formula. AUC 0-24 is the truncated AUC over a 24-hour sampling interval. The concentration-time curve is the result of time points of blood sampling and its measured concentration of free cobimetinib in the blood samplings.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28
Stage 2: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28
Stage 2: Accumulation Ratio of Cobimetinib at Steady State
Accumulation ratio is AUC0-24 at steady state divided by AUC0-24 on Cycle 1 Day 1. It was calculated only for participants who had a quantifiable AUC 0-24 at steady state.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28
Stage 2: Apparent Clearance of Cobimetinib at Steady State
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent clearance was calculated only for participants who had a quantifiable AUC 0-24 in steady state.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28
Stage 2:Half-Life of Cobimetinib at Steady State
T1/2 half-life of cobimetinib measured over the terminal phase by noncompartmental analysis.
Measured: Stage 2: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 21, 24 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22), and between Cycle 1 Days 26-28
Stage 2A: AUC 0-24/D of Cobimetinib at Steady State
AUC 0-24/D is the dose normalized truncated AUC over a 24-hour sampling interval.
Measured: Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28
Stage 2A: Accumulation Ratio of Cobimetinib at Steady State
Accumulation Ratio AUC0-24 is ratio of AUC on Day 20: Day 1.
Measured: Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28
Stage 2A: Apparent Clearance of Cobimetinib at Steady State
Apparent clearance is the plasma clearance of absorbed drug.
Measured: Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28
Stage 2A: Half-Life of Cobimetinib at Steady State
Measured: Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28
Stage 2A: Tmax of Cobimetinib at Steady State
Tmax is defined as the time to reach Cmax during stage 2A in steady state.
Measured: Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28
Stage 2A: Cmax of Cobimetinib at Steady State
Cmax is the maximum plasma concentration achieved following the Day 20 dose in Stage 2A.
Measured: Stage 2A: Pre-dose & 0.5, 1, 1.5, 2, 3, 4, 6 hours post-dose on Cycle 1 Day 14, 24 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15), and between Cycle 1 Days 26-28
Stage III: Cmax of Dextromethorphan
Cmax is defined as maximum observed plasma concentration and was determined both in the presence (Cycle 1 Day 15) and absence of cobimetinib (Cycle 1 Day 1).
Measured: Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1
Stage III: AUC 0-24 of Dextromethorphan
AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was determined both in presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
Measured: Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1
Stage III: AUC 0-inf of Dextromethorphan
AUC0-inf is AUC from time 0 to infinity and was calculated both in presence Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
Measured: Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1
Stage III: Cmax of Midazolam
Cmax is the maximum observed plasma concentration and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
Measured: Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1
Stage III: AUC0-24 of Midazolam
AUC0-24 is the area under the plasma drug concentration curve over a 24-hour sampling interval and was calculated both in the presence (Cycle 1 Day 15) and absence (CXycle 1 Day 1) of cobimetinib.
Measured: Stage III: Predose, 0.5, 1, 1.5, 2, 4, 6, 8, and 24 hours after dextromethorphan administration on Days 1 and 15 of Cycle 1
Stage III: AUC0-inf of Midazolam
AUC0-inf is the AUC from time 0 to infinity and was calculated both in the presence (Cycle 1 Day 15) and absence (Cycle 1 Day 1) of cobimetinib.
Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

May 2007Apr 2014

First posted1 May 2007 (estimated)
Study startMay 2007
Primary completionApr 2014
Study completionApr 2014

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Solid TumorStudies of the same condition, open and under way.
More trials run by Genentech, Inc.The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 119 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00467779
Sponsor's protocol ID: MEK4592g
Other IDs: GO01329, XL518-001
Status last verified: Jul 2016
First submitted: 18 Apr 2007
Last updated: 26 Aug 2016
Results posted: Yes, on ClinicalTrials.gov

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See locations

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Study at a glance

From the registry record, last updated by the sponsor on 26 Aug 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of GDC-0973/XL518 Administered Orally Daily to Subjects With Solid Tumors
ClinicalTrials.gov ID: NCT00467779
Acronym / sponsor ID: MEK4592g
Conditions: Solid Tumor
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 119 participants (actual)
Lead sponsor: Genentech, Inc.Industry (pharma, biotech, devices)
Study start: May 2007
Primary completion: Apr 2014 (actual)
Study completion: Apr 2014 (actual)
First posted: 1 May 2007 (estimated)
Results: Posted 22 Jul 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 5

Arm	Type	Receives
Stage 1: Cobimetinib Dose Escalation (21/7 Schedule)	Experimental	Drug: cobimetinibParticipants 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.
Stage 1A: Cobimetinib Dose Escalation (14/14 Schedule)	Experimental	Drug: cobimetinibParticipants 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.
Stage 2: Cobimetinib Expansion (21/7 Schedule)	Experimental	Drug: cobimetinibParticipants 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.
Stage 2 A: Cobimetinib Expansion (14/14 Schedule)	Experimental	Drug: cobimetinibParticipants 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.
Stage 3: Cobimetinib+Midazolam+Dextromethorphan	Experimental	Drug: cobimetinib, Drug: dextromethorphan, Drug: midazolamParticipants 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).

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

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

Key exclusion criteria (7 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
cobimetinibAlso: GDC-0973/XL518Repeating oral dose	Drug	Stage 1: Cobimetinib Dose Escalation (21/7 Schedule), Stage 1A: Cobimetinib Dose Escalation (14/14 Schedule), Stage 2 A: Cobimetinib Expansion (14/14 Schedule), Stage 2: Cobimetinib Expansion (21/7 Schedule), Stage 3: Cobimetinib+Midazolam+Dextromethorphan
dextromethorphanIn Stage III only: single dose of dextromethorphan	Drug	Stage 3: Cobimetinib+Midazolam+Dextromethorphan
midazolamIn Stage III only: single dose of midazolam	Drug	Stage 3: Cobimetinib+Midazolam+Dextromethorphan

Primary outcome

Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs)
Time frame: 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
Time frame: 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
Time frame: 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
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
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
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
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
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
Tmax is defined as the time to reach Cmax during stage 1 at Day 1 Cycle 1.

38 secondary outcomes

Stage 1: Tmax of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: AUC 0-24 of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: AUC 0-24/D of Cobimetinib at Steady State
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)
Stage 1: Accumulation Ratio of Cobimetinib 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)
Stage 1: Apparent Clearance of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State
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)
Stage 1: Cmax of Cobimetinib 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 21, 24, 48, and 72 hours post Cycle 1 Day 21 dose (Cycle 1 Day 22, 23, and 24, respectively)
Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1
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
Stage 1A: Cmax of Cobimetinib at Cycle 1 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
Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 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
Stage 1A: t1/2 of Cobimetinib 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 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: Tmax of Cobimetinib at Steady State
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)
Stage 1A: Apparent Clearance of Cobimetinib 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 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: Accumulation Ratio of Cobimetinib at Steady State
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)
Stage 1A: AUC 0-24 of Cobimetinib 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 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 1A: AUC 0-24/D of Cobimetinib at Steady State
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)
Stage 1A: Cmax of Cobimetinib 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 14, 24, 48, 72 hours post Cycle 1 Day 14 dose (Cycle 1 Day 15, 16, and 17, respectively)
Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1
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
Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 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
Stage 2: Tmax of Cobimetinib at Cycle 1 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
Stage 2: Tmax of Cobimetinib 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
Stage 2: AUC 0-24 of Cobimetinib 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
Stage 2: AUC 0-24/D of Cobimetinib 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
Stage 2: Accumulation Ratio of Cobimetinib 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
Stage 2: Apparent Clearance of Cobimetinib 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
Stage 2:Half-Life of Cobimetinib 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
Stage 2A: AUC 0-24/D 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
Stage 2A: Accumulation Ratio 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
Stage 2A: Apparent Clearance 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
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
Stage 2A: Tmax 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
Stage 2A: Cmax 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
Stage III: Cmax of Dextromethorphan
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
Stage III: AUC 0-24 of Dextromethorphan
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
Stage III: AUC 0-inf of Dextromethorphan
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
Stage III: Cmax of Midazolam
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
Stage III: AUC0-24 of Midazolam
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
Stage III: AUC0-inf of Midazolam
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

Results and safety

Results posted to the registry on 22 Jul 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7)	4	0
Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7)	3	0
Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7)	3	0
Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7)	3	0
Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7)	3	0
Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7)	6	1
Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7)	7	0
Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7)	7	0
Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7)	0	0
Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14)	0	0
Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14)	0	0
Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14)	0	0
Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14)	0	0
Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14)	0	0
Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan	0	0

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

Time frame: Stage 1 and 1A: Days 1 to 28 of Cycle 1. Number. Unit: participants

Measure	Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) n = 4	Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) n = 3	Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) n = 3	Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) n = 3	Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) n = 3	Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) n = 6	Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) n = 7	Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) n = 7	Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14) n = 3	Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14) n = 3	Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14) n = 8	Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14) n = 6
Value	0	0	0	0	0	1	1	2	0	0	0	2

Population analysed: Safety population; Stages 1 and 1A participants only.

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

Time frame: Stage 1: Days 1 to 28 of Cycle 1. Number. Unit: milligrams (mg)

Measure	Stage 1 All Cohorts (21/7) n = 36
Value	60

Population analysed: Safety population; Stage 1 participants only.

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

Time frame: Stage 1A: Days 1 to 28 of Cycle 1. Number. Unit: mg

Measure	Stage 1A - All Cohorts (14/14) n = 20
Value	100

Population analysed: Safety population; Stage 1A participants only.

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

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. Geometric mean (Standard Deviation). Unit: ng/mL

Measure	Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7) n = 4	Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7) n = 3	Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7) n = 3	Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7) n = 3	Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7) n = 3	Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7) n = 6	Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7) n = 7	Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7) n = 7
Value	4.51 (5.8)	6.92 (3.8)	18.3 (13.0)	18.8 (5.1)	30.8 (69.0)	71.7 (57.0)	163.0 (79.0)	261.0 (110.0)

Population analysed: Safety population; Stage 1 participants only.

38 secondary outcomes are reported in the full results.

Adverse events

Time frame: AEs were recorded from the Day 1 of treatment period until the 30 plus or minus 4 days after the last treatment (up to approximately 6 years) .. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Stage 1 Cohort 01 - Cobimetinib 0.05 mg/kg (21/7)	2 of 4 (50%)	4 of 4 (100%)	Not reported
Stage 1 Cohort 02 - Cobimetinib 0.10 mg/kg (21/7)	0 of 3 (0%)	3 of 3 (100%)	Not reported
Stage 1 Cohort 03 - Cobimetinib 0.20 mg/kg (21/7)	1 of 3 (33.3%)	3 of 3 (100%)	Not reported
Stage 1 Cohort 04 - Cobimetinib 10 mg (21/7)	0 of 3 (0%)	3 of 3 (100%)	Not reported
Stage 1 Cohort 05 - Cobimetinib 20 mg (21/7)	1 of 3 (33.3%)	3 of 3 (100%)	Not reported
Stage 1 Cohort 06 - Cobimetinib 40 mg (21/7)	3 of 6 (50%)	6 of 6 (100%)	Not reported
Stage 1 Cohort 07 - Cobimetinib 60 mg (21/7)	3 of 7 (42.9%)	7 of 7 (100%)	Not reported
Stage 1 Cohort 08 - Cobimetinib 80 mg (21/7)	5 of 7 (71.4%)	7 of 7 (100%)	Not reported
Stage 2 Cohort 20 - Cobimetinib 60 mg (Expansion) (21/7)	7 of 21 (33.3%)	20 of 21 (95.2%)	Not reported
Stage 1A Cohort 01A - Cobimetinib 60 mg (14/14)	0 of 3 (0%)	3 of 3 (100%)	Not reported
Stage 1A Cohort 02A - Cobimetinib 80 mg (14/14)	1 of 3 (33.3%)	3 of 3 (100%)	Not reported
Stage 1A Cohort 03A - Cobimetinib 100 mg (14/14)	4 of 8 (50%)	8 of 8 (100%)	Not reported
Stage 1A Cohort 04A - Cobimetinib 125 mg (14/14)	3 of 6 (50%)	6 of 6 (100%)	Not reported
Stage 2A Cohort 30 - Cobimetinib 100 mg (Expansion) (14/14)	11 of 22 (50%)	21 of 22 (95.5%)	Not reported
Stage 3 Cohort 40 - Cobimetinib+Midazolam+Dextromethorphan	8 of 20 (40%)	18 of 20 (90%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 26 Aug 2016.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Clinical Trials study director

Genentech, Inc.

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing cobimetinib, dextromethorphan and midazolam in people with Solid Tumor, run by Genentech, Inc. at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Jul 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs) (time frame: Stage 1 and 1A: Days 1 to 28 of Cycle 1). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00467779.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Aug 2016.