Trial Outcomes & Findings for A Study to Evaluate Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Participants (NCT NCT01929876)

NCT ID: NCT01929876

Last Updated: 2016-08-04

Results Overview

Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

16 participants

Primary outcome timeframe

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

Results posted on

2016-08-04

Participant Flow

Participant milestones

Participant milestones
Measure	Cobimetinib + Itraconazole 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 1 STARTED	16
Period 1 COMPLETED	16
Period 1 NOT COMPLETED	0
Period 2 STARTED	16
Period 2 COMPLETED	15
Period 2 NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Cobimetinib + Itraconazole 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 2 Non-Compliance	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cobimetinib + Itraconazole n=16 Participants 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.
Age, Continuous	38 years STANDARD_DEVIATION 9.9 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Population: Pharmacokinetic (PK) population consisted of all participants who received at least 1 dose of cobimetinib and had evaluable PK data.

Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=15 Participants 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.
Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole Period 1: Cobimetinib Alone	5.21 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 38.1
Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole Period 2: Cobimetinib With Itraconazole	16.5 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 27.7

PRIMARY outcome

Timeframe: 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

Population: PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.

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.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=14 Participants 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.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole Period 1: Cobimetinib Alone (n=14)	241 ng*hr/mL Geometric Coefficient of Variation 51.5
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole Period 2: Cobimetinib With Itraconazole (n=12)	1596 ng*hr/mL Geometric Coefficient of Variation 23.0

SECONDARY outcome

Timeframe: 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

Population: PK population

Time to reach maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=15 Participants 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.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole Period1: Cobimetinib Alone	2.00 hours Interval 1.0 to 6.05
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole Period 2: Cobimetinib With Itraconazole	4.00 hours Interval 2.0 to 8.02

SECONDARY outcome

Timeframe: 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

Population: PK population

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.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=15 Participants 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.
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole Period 1: Cobimetinib Alone	209 nanogramhour per milliliter (nghr/mL) Geometric Coefficient of Variation 49.4
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole Period 2: Cobimetinib With Itraconazole	1220 nanogramhour per milliliter (nghr/mL) Geometric Coefficient of Variation 24.0

SECONDARY outcome

Timeframe: 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

Population: PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.

Plasma half-life is the time measured for the plasma concentration to decrease by one half.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=14 Participants 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.
Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole Period1: Cobimetinib Alone (n=14)	58.6 hours Interval 25.9 to 89.2
Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole Period 2: Cobimetinib With Itraconazole (n=12)	118 hours Interval 83.1 to 170.0

SECONDARY outcome

Timeframe: 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

Population: PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.

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.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=14 Participants 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.
Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole Period1: Cobimetinib Alone (n=14)	41.4 liter per hour (L/hr) Geometric Coefficient of Variation 51.5
Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole Period 2: Cobimetinib With Itraconazole (n=12)	6.27 liter per hour (L/hr) Geometric Coefficient of Variation 23.0

SECONDARY outcome

Timeframe: 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

Population: PK population. "Number of Participants Analyzed" indicates participants evaluable for this outcome measure and "n" signifies participants evaluable for specified category.

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.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=14 Participants 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.
Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole Period1: Cobimetinib Alone (n=14)	3233 liter (L) Geometric Coefficient of Variation 27.5
Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole Period 2: Cobimetinib With Itraconazole (n=12)	1065 liter (L) Geometric Coefficient of Variation 36.1

SECONDARY outcome

Timeframe: 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

Population: PK population

Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=15 Participants 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.
Cmax of Itraconazole and Hydroxy-Itraconazole Itraconazole	1480 ng/mL Geometric Coefficient of Variation 42.6
Cmax of Itraconazole and Hydroxy-Itraconazole Hydroxy-Itraconazole	1243 ng/mL Geometric Coefficient of Variation 26.4

SECONDARY outcome

Timeframe: 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

Population: PK population

Time to reach maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=15 Participants 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.
Tmax of Itraconazole and Hydroxy-Itraconazole Itraconazole	2.00 hours Interval 1.0 to 24.0
Tmax of Itraconazole and Hydroxy-Itraconazole Hydroxy-Itraconazole	4.00 hours Interval 2.0 to 6.0

SECONDARY outcome

Timeframe: Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4

Population: PK population

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.

Outcome measures

Outcome measures
Measure	Cobimetinib + Itraconazole n=15 Participants 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.
Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole Itraconazole	15607 ng*hr/mL Geometric Coefficient of Variation 26.8
Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole Hydroxy-Itraconazole	23176 ng*hr/mL Geometric Coefficient of Variation 23.2

Adverse Events

Cobimetinib + Itraconazole

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Cobimetinib + Itraconazole n=16 participants at risk 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.
Gastrointestinal disorders Abdominal pain	6.2% 1/16 • approximately 2 months Safety population
Gastrointestinal disorders Diarrhoea	6.2% 1/16 • approximately 2 months Safety population
Gastrointestinal disorders Dyspepsia	6.2% 1/16 • approximately 2 months Safety population
Skin and subcutaneous tissue disorders Erythema	6.2% 1/16 • approximately 2 months Safety population
Skin and subcutaneous tissue disorders Rash macular	6.2% 1/16 • approximately 2 months Safety population
Investigations Alanine aminotransferase increased	6.2% 1/16 • approximately 2 months Safety population
Investigations Aspartate aminotransferase increased	6.2% 1/16 • approximately 2 months Safety population
Nervous system disorders Dizziness	6.2% 1/16 • approximately 2 months Safety population
Nervous system disorders Headache	6.2% 1/16 • approximately 2 months Safety population
Infections and infestations Rhinitis	6.2% 1/16 • approximately 2 months Safety population
Musculoskeletal and connective tissue disorders Back pain	6.2% 1/16 • approximately 2 months Safety population

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER