Study of Cobimetinib in Participants With Solid Tumors

NCT00467779 | Completed Phase 1 Results

• 3 other identifiers: MEK4592gGO01329XL518-001
• Study Type: interventional
• Target: 119
• Locations: 1 country
• Sites: 4

Brief Summary

This non-randomized, open-label, study will determine the highest safe dose of cobimetinib, how often it should be taken, how well participants with cancer tolerate cobimetinib and will assess the pharmacokinetic effect of midazolam and dextromethorphan on the study drug.

Conditions

Solid Tumor

Outcome Measures

Primary Outcomes (6)

• 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 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

  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.

  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).

  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).

  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.

  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

  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

  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

  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

  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

  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)

Study Arms (5)

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.

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.

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.

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.

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).

Drug: cobimetinib; Drug: dextromethorphan; Drug: midazolam

Interventions

cobimetinib DRUG

Repeating oral dose

Also known as: GDC-0973/XL518

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

dextromethorphan DRUG

In Stage III only: single dose of dextromethorphan

Stage 3: Cobimetinib+Midazolam+Dextromethorphan

midazolam DRUG

In Stage III only: single dose of midazolam

Stage 3: Cobimetinib+Midazolam+Dextromethorphan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (4)

Unknown Facility

Los Angeles, California, 90095, United States

Location

Unknown Facility

Stanford, California, 94305-5821, United States

Location

Unknown Facility

Detroit, Michigan, 48201, United States

Location

Unknown Facility

Buffalo, New York, 14263, United States

Location

MeSH Terms

Interventions

cobimetinib; Dextromethorphan; Midazolam

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-LaRoche

genentech@druginfo.com

1-800-821-8590

Study Officials

• Clinical Trials

  Genentech, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2007
• First Posted: May 1, 2007
• Study Start: May 1, 2007
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: August 26, 2016
• Results First Posted: July 22, 2016

Record last verified: 2016-07

Locations

US (4)