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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

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

NCT ID

NCT02592317

First Posted

October 29, 2015

Last Updated

February 14, 2023

Sponsor

Aragon Pharmaceuticals, Inc.

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

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

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

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

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

Time Frame

Day 1, 8, 9, 43, 50, and 51

Secondary Outcome Measure Information:

Title

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Description

Time Frame

Days 1, 8, 9, 43, 50, and 51

Title

Elimination Rate Constant (Lambda[z])

Description

Time Frame

Day 1, 8, 9, 43, 50, and 51

Title

Elimination Half-Life (t1/2)

Description

Time Frame

Days 1, 8, 9, 43, 50, and 51

Title

Apparent Clearance (CL/F)

Description

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

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

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