Study of Cobimetinib in Participants With Solid Tumors

Genentech

Status and phase: Completed; Phase 1

Conditions: Solid Tumor

Treatments: Drug: dextromethorphan; Drug: cobimetinib; Drug: midazolam

Study type: Interventional

Funder types: Industry

Identifiers

NCT00467779

MEK4592g

GO01329 (Other Identifier)

XL518-001 (Other Identifier)

Details and patient eligibility

About

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.

Enrollment: 119 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically confirmed solid tumor that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective, and there are no known therapies to prolong survival
• Disease that is measurable according to Response Evaluation Criteria in Solid Tumors (RECIST)
• Adequate organ and marrow function
• Sexually active participants must use medically acceptable methods of contraception during the course of the study and at least 11 days after the last dose of study treatment
• Female participants of childbearing potential must have a negative serum pregnancy test at screening
• No other history of/or ongoing malignancy that would potentially interfere with the interpretation of the pharmacodynamic or efficacy assays

Exclusion criteria

• Anticancer treatment (e.g., chemotherapy, radiotherapy, cytokines, or hormones) within 28 days (6 weeks for nitrosoureas or mitomycin C, or 14 days for hormonal therapy or kinase inhibitors) before the first dose of study drug
• The participant has not recovered to Grade </=1 from adverse events (AEs) or to within 10% of baseline values due to investigational or other agents administered more than 28 days prior to study enrollment
• The participant has received another investigational agent within 28 days of the first dose of study drug
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, diabetes, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
• The participant is pregnant or breastfeeding
• The participant is known to be positive for the human immunodeficiency virus (HIV)
• Allergy or hypersensitivity to components of the cobimetinib formulation

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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119 participants in 5 patient groups

Stage 1: Cobimetinib Dose Escalation (21/7 Schedule)

Experimental group

Description:

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.

Treatment:

Drug: cobimetinib

Stage 1A: Cobimetinib Dose Escalation (14/14 Schedule)

Experimental group

Description:

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.

Treatment:

Drug: cobimetinib

Stage 2: Cobimetinib Expansion (21/7 Schedule)

Experimental group

Description:

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.

Treatment:

Drug: cobimetinib

Stage 2 A: Cobimetinib Expansion (14/14 Schedule)

Experimental group

Description:

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.

Treatment:

Drug: cobimetinib

Stage 3: Cobimetinib+Midazolam+Dextromethorphan

Experimental group

Description:

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).

Treatment:

Drug: cobimetinib

Drug: dextromethorphan

Drug: midazolam