Clinical trial NCT00467779: Study of Cobimetinib in Participants With Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2007-05-01
Enrollment: 119
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Stage 1 and 1A: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Stage 1 and 1A: Days 1 to 28 of Cycle 1
measure: Stage 1: Maximum Tolerated Dose (MTD) of Cobimetinib in 21/7 Schedule
timeFrame: Stage 1: Days 1 to 28 of Cycle 1
measure: Stage 1A: MTD of Cobimetinib in 14/14 Schedule
timeFrame: Stage 1A: Days 1 to 28 of Cycle 1
measure: Stage 1: Maximum Observed Concentration (Cmax) of Cobimetinib at Day 1, Cycle 1
timeFrame: 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
measure: Stage 1: Area Under the Plasma Cobimetinib Concentration Curve From Time 0 to 24 Hours (AUC 0-24) Day 1, Cycle 1
timeFrame: 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
measure: Stage 1: Time to Maximum Concentration (Tmax) of Cobimetinib at Day 1, Cycle 1
timeFrame: 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:
measure: Stage 1: Tmax of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1: AUC 0-24 of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1: AUC 0-24/D of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1: Accumulation Ratio of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1: Apparent Clearance of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1: Half-Life (t1/2) of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1: Cmax of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1A: Tmax of Cobimetinib at Cycle 1 Day 1
timeFrame: 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
measure: Stage 1A: Cmax of Cobimetinib at Cycle 1 Day 1
timeFrame: 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
measure: Stage 1A: AUC 0-24 of Cobimetinib at Cycle 1 Day 1
timeFrame: 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
measure: Stage 1A: t1/2 of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1A: Tmax of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1A: Apparent Clearance of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1A: Accumulation Ratio of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1A: AUC 0-24 of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1A: AUC 0-24/D of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 1A: Cmax of Cobimetinib at Steady State
timeFrame: 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)
measure: Stage 2: Cmax of Cobimetinib at Cycle 1 Day 1
timeFrame: 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
measure: Stage 2:AUC 0-24 of Cobimetinib at Cycle 1 Day 1
timeFrame: 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
measure: Stage 2: Tmax of Cobimetinib at Cycle 1 Day 1
timeFrame: 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
measure: Stage 2: Tmax of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2: AUC 0-24 of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2: AUC 0-24/D of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2: Accumulation Ratio of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2: Apparent Clearance of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2:Half-Life of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2A: AUC 0-24/D of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2A: Accumulation Ratio of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2A: Apparent Clearance of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2A: Half-Life of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2A: Tmax of Cobimetinib at Steady State
timeFrame: 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
measure: Stage 2A: Cmax of Cobimetinib at Steady State
timeFrame: 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
measure: Stage III: Cmax of Dextromethorphan
timeFrame: 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
measure: Stage III: AUC 0-24 of Dextromethorphan
timeFrame: 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
measure: Stage III: AUC 0-inf of Dextromethorphan
timeFrame: 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
measure: Stage III: Cmax of Midazolam
timeFrame: 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
measure: Stage III: AUC0-24 of Midazolam
timeFrame: 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
measure: Stage III: AUC0-inf of Midazolam
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
state: California
city: Stanford
country: United States
state: California
city: Detroit
country: United States
state: Michigan
city: Buffalo
country: United States
state: New York
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References: