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A Study to Evaluate How Daily Dosing With Enzalutamide Affects the Metabolism of Caffeine and Dextromethorphan in Men With Prostate Cancer

Primary Purpose

Pharmacokinetics of Dextromethorphan, Pharmacokinetics of Caffeine, Prostate Cancer

Status

Completed

Phase

Phase 1

Locations

Moldova, Republic of

Study Type

Interventional

Intervention

Caffeine

Dextromethorphan

Enzalutamide

Enzalutamide Placebo to Match (PTM)

About this trial

This is an interventional basic science trial for Pharmacokinetics of Dextromethorphan focused on measuring Safety, Dextromethorphan, CYP2D6, Phase 1, Prostate cancer, CYP1A2, Pharmacokinetics, Drug-drug interactions, Caffeine, Enzalutamide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Subject is a male aged 18 years old or older (at screening) with histologically confirmed prostate cancer (all stages) for whom androgen deprivation therapy is indicated (except when indicated in a neoadjuvant/adjuvant setting). Subjects may be on ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or have undergone prior bilateral orchiectomy at screening.
Subject has progressive disease by prostate-specific antigen (PSA) or imaging.
Subject has received no more than 2 prior chemotherapy regimens.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
Male subject must use a condom if having sex with a pregnant woman.
Male subject and their female spouse/partners who are of childbearing potential must use 2 acceptable methods of birth control starting at screening and continuing throughout the study period and for 3 months after final study drug administration.
Subject has an estimated life expectancy of at least 6 months.

Exclusion Criteria:

Subject has confirmed CYP2D6 poor metabolizer, or CYP2D6 ultrarapid metabolizer status based on genotyping analysis.
Subject has known metastases in the liver or any hepatic disorder that could affect drug metabolism deemed clinically significant by the investigator after discussion with the sponsor.
Subject has undergone major surgery within 4 weeks prior to day 1.
Subject received treatment with chemotherapy within 4 weeks prior to enrollment (day 1 visit) or plans to initiate treatment with chemotherapy during the study.
Subject uses concomitant medications that are potent inducers and/or inhibitors of CYP1A2, CYP2C8, CYP2D6, or CYP3A4.

Sites / Locations

Arensia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

1:Caffeine, Dextromethorphan and Enzalutamide

Arm Description

1-sequence crossover here

Outcomes

Primary Outcome Measures

PK measured by Pharmacokinetic parameter Maximum concentration (Cmax)

For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.

PK measured by Pharmacokinetic parameter Area under the curve (AUC) from the time of dosing to the last measurable concentration (AUC0-t)

For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.

PK measured by PK parameter area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf)

For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.

Secondary Outcome Measures

PK measured by PK parameters tmax, terminal elimination half-life (t1/2), apparent total systemic clearance after oral dosing (CL/F), apparent volume of distribution during terminal elimination phase (Vz/F) and extrapolated AUC (%AUC)

Tmax is time to maximum concentration. These PK parameters will be measured for the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.

PK measured by PK parameters Cmax, AUC0-t, AUC0-inf, %AUC, tmax and t1/2

For 1,7-dimethylxanthine (metabolite caffeine), dextrorphan (metabolite dextromethorphan).

PK measured by PK parameters Cmax, trough concentrations (Ctrough) at Days 28, 52, 53, 54 and 55, tmax, AUC during the time interval between consecutive dosing (AUCtau), CL/F (parent only) and peak-to-trough ratio (PTR)

For Enzalutamide, N-desmethyl enzalutamide (M2) and sum of enzalutamide + M2.

Safety and tolerability measured by vital signs, adverse events, laboratory assessments and electrocardiogram

Full Information

NCT ID

NCT02225093

First Posted

August 22, 2014

Last Updated

June 26, 2017

Sponsor

Astellas Pharma Europe B.V.

Collaborators

Medivation, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02225093

Brief Title

A Study to Evaluate How Daily Dosing With Enzalutamide Affects the Metabolism of Caffeine and Dextromethorphan in Men With Prostate Cancer

Official Title

A Phase 1 Open-label Study to Evaluate the Effect of Multiple Doses of Enzalutamide on the Pharmacokinetics of Substrates for CYP1A2 and CYP2D6 in Male Subjects With Prostate Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Completed

Study Start Date

October 2, 2013 (Actual)

Primary Completion Date

February 3, 2014 (Actual)

Study Completion Date

February 3, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Astellas Pharma Europe B.V.

Collaborators

Medivation, Inc.

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study evaluates how once daily enzalutamide affects the metabolism of caffeine and dextromethorphan in men with prostate cancer by measuring concentrations of these drugs and their metabolites in plasma.

Detailed Description

This is an open-label, fixed-sequence, crossover drug-drug interaction study in subjects with prostate cancer. Screening takes place between Day -28 and Day -7, and subjects are admitted to the clinic on Day -1 where they remain until Day 4. On Day 1, they receive a single oral cocktail containing caffeine and dextromethorphan plus a dose of enzalutamide placebo in order to assess possible effects of excipients of the enzalutamide formulation. On Days 1 to 3 blood samples for pharmacokinetic (PK) assessment are collected. From Days 4 to 54, (or Day 55 if the subject rolls over into the extension study) the subjects take a daily oral dose of enzalutamide. On Day 28, the subjects return to the clinic where a plasma sample is taken to determine enzalutamide PK exposure. From Days 52 to 55 they are re-admitted to the clinic where a plasma sample is collected on Day 52 for enzalutamide PK exposure.On Day 53, subjects receive a single oral cocktail of caffeine and dextromethorphan concomitantly with enzalutamide. PK samples are collected from Days 53 to 55. From Day 55 onwards, subjects experiencing clinical benefit may roll over into an extension study. Only subjects who enroll into the extension study continue to receive enzalutamide otherwise daily dosing with enzalutamide is discontinued on Day 54. An End of Study Visit (ESV) takes place approximately 30 days (±7 days) after the last dose of enzalutamide.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pharmacokinetics of Dextromethorphan, Pharmacokinetics of Caffeine, Prostate Cancer

Keywords

Safety, Dextromethorphan, CYP2D6, Phase 1, Prostate cancer, CYP1A2, Pharmacokinetics, Drug-drug interactions, Caffeine, Enzalutamide

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

1:Caffeine, Dextromethorphan and Enzalutamide

Arm Type

Experimental

Arm Description

1-sequence crossover here

Intervention Type

Drug

Intervention Name(s)

Caffeine

Other Intervention Name(s)

CYP1A2 substrate

Intervention Description

Oral

Intervention Type

Drug

Intervention Name(s)

Dextromethorphan

Other Intervention Name(s)

CYP2D6 substrate

Intervention Description

Oral /.L

Intervention Type

Drug

Intervention Name(s)

Enzalutamide

Other Intervention Name(s)

Xtandi, MDV3100, ASP9785

Intervention Description

Oral

Intervention Type

Drug

Intervention Name(s)

Enzalutamide Placebo to Match (PTM)

Intervention Description

Oral

Primary Outcome Measure Information:

Title

PK measured by Pharmacokinetic parameter Maximum concentration (Cmax)

Description

For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.

Time Frame

Day 1 and Day 53 (28 times)

Title

PK measured by Pharmacokinetic parameter Area under the curve (AUC) from the time of dosing to the last measurable concentration (AUC0-t)

Description

For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.

Time Frame

Day 1 and Day 53 (28 times)

Title

PK measured by PK parameter area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf)

Description

For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.

Time Frame

Day 1 and Day 53 (28 times)

Secondary Outcome Measure Information:

Title

Description

Time Frame

Day 1 and Day 53 (28 times)

Title

PK measured by PK parameters Cmax, AUC0-t, AUC0-inf, %AUC, tmax and t1/2

Description

For 1,7-dimethylxanthine (metabolite caffeine), dextrorphan (metabolite dextromethorphan).

Time Frame

Day 1 and Day 53 (28 times)

Title

Description

For Enzalutamide, N-desmethyl enzalutamide (M2) and sum of enzalutamide + M2.

Time Frame

Day 28 (± 1 day), and Days 52 to 55 (15 times)

Title

Safety and tolerability measured by vital signs, adverse events, laboratory assessments and electrocardiogram

Time Frame

Screening (Day -28 to Day -7) to ESV (>153 times)

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject is a male aged 18 years old or older (at screening) with histologically confirmed prostate cancer (all stages) for whom androgen deprivation therapy is indicated (except when indicated in a neoadjuvant/adjuvant setting). Subjects may be on ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or have undergone prior bilateral orchiectomy at screening. Subject has progressive disease by prostate-specific antigen (PSA) or imaging. Subject has received no more than 2 prior chemotherapy regimens. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Male subject must use a condom if having sex with a pregnant woman. Male subject and their female spouse/partners who are of childbearing potential must use 2 acceptable methods of birth control starting at screening and continuing throughout the study period and for 3 months after final study drug administration. Subject has an estimated life expectancy of at least 6 months. Exclusion Criteria: Subject has confirmed CYP2D6 poor metabolizer, or CYP2D6 ultrarapid metabolizer status based on genotyping analysis. Subject has known metastases in the liver or any hepatic disorder that could affect drug metabolism deemed clinically significant by the investigator after discussion with the sponsor. Subject has undergone major surgery within 4 weeks prior to day 1. Subject received treatment with chemotherapy within 4 weeks prior to enrollment (day 1 visit) or plans to initiate treatment with chemotherapy during the study. Subject uses concomitant medications that are potent inducers and/or inhibitors of CYP1A2, CYP2C8, CYP2D6, or CYP3A4.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Astellas Pharma Europe B.V.

Official's Role

Study Director

Facility Information:

Facility Name

Arensia

City

Chisinau

ZIP/Postal Code

2025

Country

Moldova, Republic of

12. IPD Sharing Statement

Links:

URL

https://www.astellasclinicalstudyresults.com/study.aspx?ID=43

Description

Link to results on Astellas Clinical Study Results website

Learn more about this trial

A Study to Evaluate How Daily Dosing With Enzalutamide Affects the Metabolism of Caffeine and Dextromethorphan in Men With Prostate Cancer

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