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A Study to Evaluate Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Participants

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ClinicalTrials.gov Identifier: NCT01929876
Recruitment Status : Completed
First Posted : August 28, 2013
Results First Posted : August 4, 2016
Last Update Posted : August 4, 2016
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label)
Condition Healthy Participants
Interventions Drug: Cobimetinib
Drug: Itraconazole
Enrollment 16
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description Cobimetinib 10 milligram (mg) (two 5 mg capsules) administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Period Title: Period 1
Started 16
Completed 16
Not Completed 0
Period Title: Period 2
Started 16
Completed 15
Not Completed 1
Reason Not Completed
Non-Compliance             1
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Baseline Participants 16
Hide Baseline Analysis Population Description
Safety population consisted of all participants who received at least 1 dose of cobimetinib and had at least 1 postdose safety assessment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants
38  (9.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants
Female
5
  31.3%
Male
11
  68.8%
1.Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole
Hide Description Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.
Time Frame Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) population consisted of all participants who received at least 1 dose of cobimetinib and had evaluable PK data.
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanogram per milliliter (ng/mL)
Period 1: Cobimetinib Alone
5.21
(38.1%)
Period 2: Cobimetinib With Itraconazole
16.5
(27.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cobimetinib + Itraconazole
Comments Ratio of Least squares (LS) means (Cobimetinib with Itraconazole/Cobimetinib alone) of natural log-transformed parameter (expressed as a percent).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of least squares means
Estimated Value 316.6
Confidence Interval (2-Sided) 90%
268.1 to 374.0
Estimation Comments LS means from analysis of variance (ANOVA), calculated by transforming the natural log means back to the linear scale (that is, geometric LS mean).
2.Primary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole
Hide Description AUC (0 - inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf) of cobimetinib with and without itraconazole, assessed using a model independent approach.
Time Frame Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 14
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Period 1: Cobimetinib Alone (n=14)
241
(51.5%)
Period 2: Cobimetinib With Itraconazole (n=12)
1596
(23.0%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cobimetinib + Itraconazole
Comments Only participants with PK parameter data from both Period 1 Day 1 and Period 2 Day 4 (n=11) were included for statistical analyses.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of LS means
Estimated Value 672.3
Confidence Interval (2-Sided) 90%
563.7 to 801.9
Estimation Comments Ratio of LS means (Cobimetinib with Itraconazole/Cobimetinib alone) of natural log-transformed parameter (expressed as a percent). LS means from ANOVA, calculated by transforming the natural log means back to the linear scale.
3.Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole
Hide Description Time to reach maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.
Time Frame Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 15
Median (Full Range)
Unit of Measure: hours
Period1: Cobimetinib Alone
2.00
(1.00 to 6.05)
Period 2: Cobimetinib With Itraconazole
4.00
(2.00 to 8.02)
4.Secondary Outcome
Title Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole
Hide Description AUC (0-t) = Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (0-t) of cobimetinib with and without itraconazole was assessed. It was calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations using a model independent approach.
Time Frame Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanogram*hour per milliliter (ng*hr/mL)
Period 1: Cobimetinib Alone
209
(49.4%)
Period 2: Cobimetinib With Itraconazole
1220
(24.0%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cobimetinib + Itraconazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of LS means
Estimated Value 583.9
Confidence Interval (2-Sided) 90%
488.2 to 698.2
Estimation Comments Ratio of LS means (Cobimetinib with Itraconazole/Cobimetinib alone) of natural log-transformed parameter (expressed as a percent). LS means from ANOVA, calculated by transforming the natural log means back to the linear scale.
5.Secondary Outcome
Title Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole
Hide Description Plasma half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 14
Median (Full Range)
Unit of Measure: hours
Period1: Cobimetinib Alone (n=14)
58.6
(25.9 to 89.2)
Period 2: Cobimetinib With Itraconazole (n=12)
118
(83.1 to 170)
6.Secondary Outcome
Title Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole
Hide Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated using a model independent approach.
Time Frame Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 14
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter per hour (L/hr)
Period1: Cobimetinib Alone (n=14)
41.4
(51.5%)
Period 2: Cobimetinib With Itraconazole (n=12)
6.27
(23.0%)
7.Secondary Outcome
Title Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole
Hide Description Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction of drug absorbed.
Time Frame Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 14
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter (L)
Period1: Cobimetinib Alone (n=14)
3233
(27.5%)
Period 2: Cobimetinib With Itraconazole (n=12)
1065
(36.1%)
8.Secondary Outcome
Title Cmax of Itraconazole and Hydroxy-Itraconazole
Hide Description Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.
Time Frame Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Itraconazole
1480
(42.6%)
Hydroxy-Itraconazole
1243
(26.4%)
9.Secondary Outcome
Title Tmax of Itraconazole and Hydroxy-Itraconazole
Time Frame Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 15
Median (Full Range)
Unit of Measure: hours
Itraconazole
2.00
(1.00 to 24.0)
Hydroxy-Itraconazole
4.00
(2.00 to 6.00)
10.Secondary Outcome
Title Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole
Hide Description AUC (0-24) = Area under the plasma concentration versus time curve from time zero (predose) to 24 hours postdose (0-24) of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.
Time Frame Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4
Hide Outcome Measure Data
Hide Analysis Population Description
PK population
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description:
Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
Overall Number of Participants Analyzed 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Itraconazole
15607
(26.8%)
Hydroxy-Itraconazole
23176
(23.2%)
Time Frame approximately 2 months
Adverse Event Reporting Description Safety population
 
Arm/Group Title Cobimetinib + Itraconazole
Hide Arm/Group Description Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2.
All-Cause Mortality
Cobimetinib + Itraconazole
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Cobimetinib + Itraconazole
Affected / at Risk (%)
Total   0/16 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cobimetinib + Itraconazole
Affected / at Risk (%)
Total   6/16 (37.50%) 
Gastrointestinal disorders   
Abdominal pain * 1  1/16 (6.25%) 
Diarrhoea * 1  1/16 (6.25%) 
Dyspepsia * 1  1/16 (6.25%) 
Infections and infestations   
Rhinitis * 1  1/16 (6.25%) 
Investigations   
Alanine aminotransferase increased * 1  1/16 (6.25%) 
Aspartate aminotransferase increased * 1  1/16 (6.25%) 
Musculoskeletal and connective tissue disorders   
Back pain * 1  1/16 (6.25%) 
Nervous system disorders   
Dizziness * 1  1/16 (6.25%) 
Headache * 1  1/16 (6.25%) 
Skin and subcutaneous tissue disorders   
Erythema * 1  1/16 (6.25%) 
Rash macular * 1  1/16 (6.25%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (15.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800-821-8590
EMail: genentech@druginfo.com
Layout table for additonal information
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01929876     History of Changes
Other Study ID Numbers: GP28620
First Submitted: August 22, 2013
First Posted: August 28, 2013
Results First Submitted: June 22, 2016
Results First Posted: August 4, 2016
Last Update Posted: August 4, 2016