A Study of the Effects of Posaconazole on Alectinib (RO5424802) Pharmacokinetics in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
This open-label study will investigate whether multiple oral doses of posaconazole affect the single dose pharmacokinetics of alectinib in healthy volunteers.

Official Title
-----------------
An Open-Label, Three-Period, Fixed Sequence Study to Investigate the Effect of Multiple Oral Doses of Posaconazole, a Potent Cytochrome P450 3A Inhibitor, on the Single Dose Pharmacokinetics of RO5424802 in Healthy Subjects

Conditions
-----------------
Healthy Volunteer

Intervention / Treatment
-----------------
* Drug: Alectinib
* Drug: Posaconazole


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Body mass index (BMI) between 18 to 32 kilogram per square meter (kg/m^2) Male volunteers must use effective contraception as outlined in the protocol Willingness to abstain from alcohol and xanthine-containing beverages or food (coffee, tea, cola, chocolate and energy drinks) from 72 hours prior to the first dose until discharged Willingness to avoid prolonged sun exposure and guard against sunburn during study and follow-up Exclusion Criteria: Clinically significant medical history or findings in physical examination, vital signs, or laboratory test results prior to study start Positive screening tests for hepatitis B or C, human immunodeficiency virus (HIV), alcohol, drugs of abuse, or tobacco Women of childbearing potential, or males with pregnant or lactating partners Regular smoking within 6 months prior to first dosing. Participants should avoid smoky environments for at least 1 week prior to each cotinine screen Excessive alcohol consumption Use of any metabolic inducers (including herbals such as St. John's Wort) within 4 weeks or 5 half-lives (whichever is longer) before the first dose of study medication, including but not limited to: rifampin, rifabutin, glucocorticoids, carbamazepine, phenytoin and phenobarbital Strenuous activity, sunbathing, or contact sports are not allowed from 4 days prior to entry into the clinical site until study follow-up Participation in an investigational drug or device study within 45 days (or 6 months for biologic therapies) prior to first dosing

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>There will be 3 dosing periods in the study: Period 1 (Days 1 to 7), Period 2 (Days 8 to 14), and Period 3 (Days 15 to 18). Alectinib will be administered as a 40 milligrams (mg) single oral dose on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants). On Days 8 to 14 (Period 2) and Days 15 to 18 (Period 3) posaconazole will be administered as a 400-mg twice daily (BID) oral dose after a high-fat meal. The follow-up assessments will occur within 10 to 14 days after the last dose of posaconazole. | Drug: Alectinib<br>* Alectinib will be administered as a single oral dose on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants).<br>* Other names: RO5424802;Drug: Posaconazole<br>* Posaconazole will be administered as a 400-mg BID oral dose after a high-fat meal on Days 8 to 14 (Period 2) and Days 15 to 18 or 21 (Period 3).<br>|
| Experimental: Cohort B<br>There will be 3 dosing periods in the study: Period 1 (Days 1 to 7), Period 2 (Days 8 to 14), and Period 3 (Days 15 to 21). Alectinib will be administered as a single oral dose at the dose selected based on Cohort A data on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants). On Days 8 to 14 (Period 2) and Days 15 to 21 (Period 3) posaconazole will be administered as a 400-mg BID oral dose after a high-fat meal. The follow-up assessments will occur within 10 to 14 days after the last dose of posaconazole. | Drug: Alectinib<br>* Alectinib will be administered as a single oral dose on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants).<br>* Other names: RO5424802;Drug: Posaconazole<br>* Posaconazole will be administered as a 400-mg BID oral dose after a high-fat meal on Days 8 to 14 (Period 2) and Days 15 to 18 or 21 (Period 3).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Alectinib: Cohort A |  | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Alectinib: Cohort A | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| Cmax of Alectinib: Cohort B |  | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| AUClast of Alectinib: Cohort B | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of RO5424802: Cohort B | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of RO5468924: Cohort A | RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| AUClast of RO5468924: Cohort A | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| AUC0-inf of RO5468924: Cohort A | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| Cmax of RO5468924: Cohort B | RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| AUClast of RO5468924: Cohort B | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| AUC0-inf of RO5468924: Cohort B | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib: Cohort A |  | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| Tmax of Alectinib: Cohort B |  | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| Tmax of RO5468924: Cohort A | RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| Tmax of RO5468924: Cohort B | RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| Metabolite/Parent Ratio for AUC0-inf: Cohort B | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of Alectinib. The ratio is molecular weight adjusted. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| Metabolite/Parent Ratio for Cmax: Cohort B | RO5468924 is M4 metabolite of Alectinib. The ratio is molecular weight adjusted. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| Terminal Half-life (t1/2) of Alectinib: Cohort A | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| t1/2 of Alectinib: Cohort B | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing | 
| t1/2 of RO5468924: Cohort A | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | 
| t1/2 of RO5468924: Cohort B | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of Alectinib. | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing |