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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02592317
Recruitment Status : Active, not recruiting
First Posted : October 30, 2015
Last Update Posted : May 24, 2019
Sponsor:
Information provided by (Responsible Party):
Aragon Pharmaceuticals, Inc.

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).

Condition or disease Intervention/treatment Phase
Prostatic Neoplasms, Castration-Resistant Drug: JNJ 56021927 Drug: Drug Cocktail Drug: Pioglitazone Drug: Rosuvastatin Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 2016
Actual Primary Completion Date : November 2016
Estimated Study Completion Date : February 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: JNJ 56021927
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.
Drug: JNJ 56021927
JNJ 56021927 will be adminitered 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.

Drug: Drug Cocktail
Drug cocktail comprise of midazolam (2 mg), warfarin (10 mg), vitamin K (10 mg), omeprazole (40 mg), and fexofenadine (30 mg) will be administerd on Study Day 1 and 43.

Drug: Pioglitazone
Pioglitazone 15 mg will be administered orally on Study Day 8 and 50.

Drug: Rosuvastatin
Rosuvastatin 15 mg will be administered orally on Study Day 9 and 51.




Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Day 1, 8, 9, 43, 50, and 51 ]
    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.

  2. Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC [0-last]) [ Time Frame: Day 1, 8, 9, 43, 50, and 51 ]
    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.

  3. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) [ Time Frame: Day 1, 8, 9, 43, 50, and 51 ]
    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 :
  1. Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Days 1, 8, 9, 43, 50, and 51 ]
    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.

  2. Elimination Rate Constant (Lambda[z]) [ Time Frame: Day 1, 8, 9, 43, 50, and 51 ]
    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.

  3. Elimination Half-Life (t1/2) [ Time Frame: Days 1, 8, 9, 43, 50, and 51 ]
    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.

  4. Apparent Clearance (CL/F) [ Time Frame: Days 1, 8, 9, 43, 50, and 51 ]
    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.

  5. Maximum Observed Plasma Concentration (Cmax) for JNJ-56021927 [ Time Frame: Day 43 ]
    The Cmax is the maximum observed plasma concentration.

  6. Time to Reach Maximum Observed Plasma Concentration (Tmax) for JNJ-56021927 [ Time Frame: Day 43 ]
    The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.

  7. Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) [ Time Frame: Day 43 ]
    The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours.

  8. Trough Plasma Concentration (Ctrough) [ Time Frame: Day 43, 50 and 51 ]
    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.

  9. Number of Participants with Adverse Events [ Time Frame: up to 30 days after last dose of study drug ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02592317


Locations
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Moldova, Republic of
Chisinau, Moldova, Republic of
Spain
Barcelona, Spain
Sevilla, Spain
Sponsors and Collaborators
Aragon Pharmaceuticals, Inc.
Investigators
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Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

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Responsible Party: Aragon Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02592317     History of Changes
Other Study ID Numbers: CR108072
56021927PCR1020 ( Other Identifier: Janssen Research & Development, LLC )
2015-003691-72 ( EudraCT Number )
First Posted: October 30, 2015    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Aragon Pharmaceuticals, Inc.:
JNJ-56021927
Prostatic Neoplasms, Castration-Resistant

Additional relevant MeSH terms:
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Prostatic Neoplasms
Prostatic Neoplasms, Castration-Resistant
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Rosuvastatin Calcium
Pioglitazone
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Hypoglycemic Agents
Physiological Effects of Drugs