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A Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Participants With Castration-Resistant Prostate Cancer

Primary Purpose

Prostatic Neoplasms, Castration-Resistant

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
JNJ 56021927
Drug Cocktail
Pioglitazone
Rosuvastatin
Sponsored by
Aragon Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prostatic Neoplasms, Castration-Resistant focused on measuring JNJ-56021927, Prostatic Neoplasms, Castration-Resistant

Eligibility Criteria

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

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
  • Adenocarcinoma of the prostate
  • Participants with non-metastatic castration-resistant prostate cancer (NM-CRPC) or metastatic castration-resistant prostate cancer (mCRPC), who in the opinion of the investigator may benefit from treatment with JNJ-56021927
  • Surgically or medically castrated, with testosterone levels of <50 nanogram per deciliter (ng/dL)
  • If the participant is being treated with a gonadotropin-releasing hormone (GnRHa) (ie, participant who has not undergone bilateral orchiectomy), then this therapy must have been initiated at least 4 weeks prior to the Cycle 1 Day 1 visit and must be continued throughout the study
  • Adequate bone marrow and organ function defined as: Hemoglobin (>=9.0 g/dL, independent of transfusion or growth factor support within the prior 7 days); Absolute neutrophil count (>=1000/mm^3 independent of growth factor support within the prior 7 days); Platelet count (>=75,000/mm^3 independent of transfusion or growth factor support within the prior 7 days); Serum albumin (>=3.0 g/dL); Serum creatinine (<=1.5*upper limit of normal (ULN) or calculated creatinine clearance >=50 mL/min/1.73m^2); Total bilirubin [<1.5*ULN (participants with Gilbert's Syndrome may be enrolled if the total bilirubin is <4 mg/dL with predominance of indirect bilirubin >=80% of total bilirubin]); Aspartate aminotransferase or alanine aminotransferase (<=3.0*ULN); Prothrombin time (PT) or partial thromboplastin time (PTT) or international normalized ratio (INR) (PT <=15 sec or INR <=1.2 PTT <=40 sec).

Exclusion Criteria:

  • Known brain metastases
  • Chemotherapy or immunotherapy for the treatment of prostate cancer within 4 weeks of the Study Day 15 (Cycle 1 Day 1) visit
  • Prior treatment with enzalutamide within 8 weeks before first dose of drug probes
  • Therapies that must be discontinued or substituted prior to study visit Day 1, or must be temporarily interrupted during the course of the study, include the following: a) Medications known to lower the seizure threshold within 4 weeks before Study Day 15 (Cycle 1 Day 1) and b) Medications known to induce or inhibit drug metabolizing enzymes (CYP3A4, CYP2C9, CYP2C19 and CYP2C8) or transporter proteins (P-gp, BRCP, OATP1B1, and OATPB3)
  • Participant has known allergies, hypersensitivity, or intolerance to any of the study drugs/drug probes or excipients
  • History of seizure or any condition that may predispose to seizure within 12 months prior to enrollment (Study Day 1); brain arteriovenous malformation; or intercranial masses such as schwannoma or meningioma that is causing edema or mass effect
  • Participants with poor metabolizer genotype for CYP2C9 (*2, *3), or CYP2C19 (*2, *3, *4, *8)

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

JNJ 56021927

Arm Description

Participants will receive drug cocktail (comprising of midazolam [2 milligram {mg}], warfarin [10 mg], vitamin K (10 mg), omeprazole (40 mg), and fexofenadine [30 mg]) orally on Study Day 1 and 43 (Cycle 2 Day 1). On Study Day 8 and 50, pioglitazone 15 mg will be administered orally and on Study Day 9 and 51, rosuvastatin 10 mg will be administered orally. JNJ 56021927, 240 mg once daily will be administered on Study Day 15 up to disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, the participant is no longer receiving clinical benefit in the opinion of the Investigator, the start of subsequent anticancer therapy, or the Sponsor ends the study.

Outcomes

Primary Outcome Measures

Maximum Observed Plasma Concentration (Cmax)
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Cmax for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC [0-last])
The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time. AUC (0-last) for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity])
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. AUC[0-infinity]) for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.

Secondary Outcome Measures

Time to Reach Maximum Observed Plasma Concentration (Tmax)
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. Tmax for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Elimination Rate Constant (Lambda[z])
Lambda(z) is first-order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve. Lambda[z]) for midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Elimination Half-Life (t1/2)
The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z). t1/2 for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Apparent Clearance (CL/F)
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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Maximum Observed Plasma Concentration (Cmax) for JNJ-56021927
The Cmax is the maximum observed plasma concentration.
Time to Reach Maximum Observed Plasma Concentration (Tmax) for JNJ-56021927
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24])
The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours.
Trough Plasma Concentration (Ctrough)
The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen.
Number of Participants with Adverse Events

Full Information

First Posted
October 29, 2015
Last Updated
February 14, 2023
Sponsor
Aragon Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02592317
Brief Title
A Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Participants With Castration-Resistant Prostate Cancer
Official Title
Drug-drug Interaction Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Subjects With Castration-Resistant Prostate Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
February 12, 2016 (Actual)
Primary Completion Date
November 7, 2016 (Actual)
Study Completion Date
January 18, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Aragon Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the effects of repeat dosing of JNJ-56021927 on the pharmacokinetics for single-dose multiple cytochrome P450 (CYP450) enzymes (CYP3A4, CYP2C9, CYP2C19, CYP2C8) and transporter (P-gp and BRCP) substrates in participants with castration-resistant prostate cancer (CRPC).
Detailed Description
This is a Phase 1, multicenter, open-label study in participants with CRPC. The study will consist of a Screening Phase to determine eligibility, a Pretreatment Phase, a Treatment Phase, and a Follow-up Phase. The study is designed to estimate the magnitude of the effects of JNJ-56021927 on the pharmacokinetics of probe substrates. In vitro studies have indicated that JNJ-56021927 and its active metabolite JNJ-56142060 (M3) have the potential to affect multiple cytochrome P450 (CYP) enzymes (CYP3A4, CYP2C9, CYP2C19, and CYP2C8) and drug transporters proteins (P-glycoprotein [P-gp] and breast cancer resistance protein [BRCP]) via inhibition or induction. In human hepatocytes, JNJ 56021927 and JNJ-56142060 (M3) were found to be inducers of CYP3A4. The induction of CYP3A4 suggests that JNJ-56021927 and M3 will induce other CYP isozymes and drug transporters (eg, CYP2C and P-gp via activation of pregnane X receptor). The study is designed to confirm the in vivo significance of these non-clinical findings.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostatic Neoplasms, Castration-Resistant
Keywords
JNJ-56021927, Prostatic Neoplasms, Castration-Resistant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
JNJ 56021927
Arm Type
Experimental
Arm Description
Participants will receive drug cocktail (comprising of midazolam [2 milligram {mg}], warfarin [10 mg], vitamin K (10 mg), omeprazole (40 mg), and fexofenadine [30 mg]) orally on Study Day 1 and 43 (Cycle 2 Day 1). On Study Day 8 and 50, pioglitazone 15 mg will be administered orally and on Study Day 9 and 51, rosuvastatin 10 mg will be administered orally. JNJ 56021927, 240 mg once daily will be administered on Study Day 15 up to disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, the participant is no longer receiving clinical benefit in the opinion of the Investigator, the start of subsequent anticancer therapy, or the Sponsor ends the study.
Intervention Type
Drug
Intervention Name(s)
JNJ 56021927
Intervention Description
JNJ 56021927 will be administered once daily orally in a dose of 240 mg from Study Day 15 up to disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, the participant is no longer receiving clinical benefit in the opinion of the Investigator, the start of subsequent anticancer therapy, or the Sponsor ends the study.
Intervention Type
Drug
Intervention Name(s)
Drug Cocktail
Intervention Description
Drug cocktail comprise of midazolam (2 mg), warfarin (10 mg), vitamin K (10 mg), omeprazole (40 mg), and fexofenadine (30 mg) will be administered on Study Day 1 and 43.
Intervention Type
Drug
Intervention Name(s)
Pioglitazone
Intervention Description
Pioglitazone 15 mg will be administered orally on Study Day 8 and 50.
Intervention Type
Drug
Intervention Name(s)
Rosuvastatin
Intervention Description
Rosuvastatin 15 mg will be administered orally on Study Day 9 and 51.
Primary Outcome Measure Information:
Title
Maximum Observed Plasma Concentration (Cmax)
Description
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Cmax for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Time Frame
Day 1, 8, 9, 43, 50, and 51
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC [0-last])
Description
The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time. AUC (0-last) for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Time Frame
Day 1, 8, 9, 43, 50, and 51
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity])
Description
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. AUC[0-infinity]) for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Time Frame
Day 1, 8, 9, 43, 50, and 51
Secondary Outcome Measure Information:
Title
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Description
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. Tmax for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Time Frame
Days 1, 8, 9, 43, 50, and 51
Title
Elimination Rate Constant (Lambda[z])
Description
Lambda(z) is first-order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve. Lambda[z]) for midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Time Frame
Day 1, 8, 9, 43, 50, and 51
Title
Elimination Half-Life (t1/2)
Description
The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z). t1/2 for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Time Frame
Days 1, 8, 9, 43, 50, and 51
Title
Apparent Clearance (CL/F)
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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F for Midazolam, S-warfarin, omeprazole, fexofenadine, pioglitazone, rosuvastatin will be assessed along with the metabolites of Midazolam, S-warfarin, omeprazole and pioglitazone.
Time Frame
Days 1, 8, 9, 43, 50, and 51
Title
Maximum Observed Plasma Concentration (Cmax) for JNJ-56021927
Description
The Cmax is the maximum observed plasma concentration.
Time Frame
Day 43
Title
Time to Reach Maximum Observed Plasma Concentration (Tmax) for JNJ-56021927
Description
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
Time Frame
Day 43
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24])
Description
The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours.
Time Frame
Day 43
Title
Trough Plasma Concentration (Ctrough)
Description
The (Ctrough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen.
Time Frame
Day 43, 50 and 51
Title
Number of Participants with Adverse Events
Time Frame
Up to 6 years 6 months

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 Adenocarcinoma of the prostate Participants with non-metastatic castration-resistant prostate cancer (NM-CRPC) or metastatic castration-resistant prostate cancer (mCRPC), who in the opinion of the investigator may benefit from treatment with JNJ-56021927 Surgically or medically castrated, with testosterone levels of <50 nanogram per deciliter (ng/dL) If the participant is being treated with a gonadotropin-releasing hormone (GnRHa) (ie, participant who has not undergone bilateral orchiectomy), then this therapy must have been initiated at least 4 weeks prior to the Cycle 1 Day 1 visit and must be continued throughout the study Adequate bone marrow and organ function defined as: Hemoglobin (>=9.0 g/dL, independent of transfusion or growth factor support within the prior 7 days); Absolute neutrophil count (>=1000/mm^3 independent of growth factor support within the prior 7 days); Platelet count (>=75,000/mm^3 independent of transfusion or growth factor support within the prior 7 days); Serum albumin (>=3.0 g/dL); Serum creatinine (<=1.5*upper limit of normal (ULN) or calculated creatinine clearance >=50 mL/min/1.73m^2); Total bilirubin [<1.5*ULN (participants with Gilbert's Syndrome may be enrolled if the total bilirubin is <4 mg/dL with predominance of indirect bilirubin >=80% of total bilirubin]); Aspartate aminotransferase or alanine aminotransferase (<=3.0*ULN); Prothrombin time (PT) or partial thromboplastin time (PTT) or international normalized ratio (INR) (PT <=15 sec or INR <=1.2 PTT <=40 sec). Exclusion Criteria: Known brain metastases Chemotherapy or immunotherapy for the treatment of prostate cancer within 4 weeks of the Study Day 15 (Cycle 1 Day 1) visit Prior treatment with enzalutamide within 8 weeks before first dose of drug probes Therapies that must be discontinued or substituted prior to study visit Day 1, or must be temporarily interrupted during the course of the study, include the following: a) Medications known to lower the seizure threshold within 4 weeks before Study Day 15 (Cycle 1 Day 1) and b) Medications known to induce or inhibit drug metabolizing enzymes (CYP3A4, CYP2C9, CYP2C19 and CYP2C8) or transporter proteins (P-gp, BRCP, OATP1B1, and OATPB3) Participant has known allergies, hypersensitivity, or intolerance to any of the study drugs/drug probes or excipients History of seizure or any condition that may predispose to seizure within 12 months prior to enrollment (Study Day 1); brain arteriovenous malformation; or intercranial masses such as schwannoma or meningioma that is causing edema or mass effect Participants with poor metabolizer genotype for CYP2C9 (*2, *3), or CYP2C19 (*2, *3, *4, *8)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Research & Development, LLC Clinical Trial
Organizational Affiliation
Janssen Research & Development, LLC
Official's Role
Study Director
Facility Information:
City
Chisinau
Country
Moldova, Republic of
City
Barcelona
Country
Spain
City
Sevilla
Country
Spain

12. IPD Sharing Statement

Learn more about this trial

A Study to Evaluate the Effect of Multiple Doses of JNJ-56021927 on the Pharmacokinetics of Multiple Cytochrome P450 and Transporter Substrates in Participants With Castration-Resistant Prostate Cancer

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