Caly Chien

Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration‐resistant prostate cancer

Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low‐fat or high‐fat meals was examined in healthy subjects and metastatic castration‐resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low‐fat meal, + high‐fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1–7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post–low‐fat (n = 6) or high‐fat meal (n = 18; days 8–14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration–time curve (AUC) increased ∼5‐ and ∼10‐fold, respectively, with low‐fat and high‐fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2‐fold higher with a high‐fat meal and similar with a low‐fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high‐fat/low‐fat meals or fasted/modified fasting state. Short‐term dosing with food did not alter abiraterone acetate safety.

An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma

Purpose: This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL). Experimental Design: Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics. Results: Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19–75) years, median number of prior systemic therapies 6 (range, 3–14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5–8 months). Median number of cycles: 4 (range, 1–16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing). Conclusions: JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL. Clin Cancer Res; 21(8); 1843–50. ©2015 AACR.

Impact on abiraterone pharmacokinetics and safety: Open-label drug–drug interaction studies with ketoconazole and rifampicin

We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11–16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8–13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax) and 15% for area under the plasma concentration–time curve from 0 to time of the last quantifiable concentration (AUClast) and AUC from time 0 to infinity (AUC∞) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.

Single‐dose pharmacokinetic studies of abiraterone acetate in men with hepatic or renal impairment

Three open‐label, single‐dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non‐cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end‐stage renal disease (ESRD), and age‐, BMI‐matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125‐ and 2,000‐mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4‐fold in patients with moderate hepatic impairment. Despite a 16‐fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single‐dose administration of abiraterone acetate was well‐tolerated.

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

Objective. To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy. Methods. In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16. Results. Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527–treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527–treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527–treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE. Conclusion. Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3–3.0 µM, 1.6–2.9 µM, 0.044–0.15 µM, and 5.4–5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9–156] for Cmax and 146 (90% CI, 126–171) for AUClast. Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.

Abstract CT302: Pharmacokinetics (PK) and safety of ARN-509 with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Background: ARN-509 and AA target the androgen axis via different mechanisms and may have complementary activity in mCRPC. ARN-509, a potent and selective androgen receptor (AR) antagonist, inhibits AR nuclear translocation and DNA binding without significant AR agonist properties (Clegg et al. Cancer Res. 2012). AA is the prodrug of abiraterone, which directly inhibits androgen biosynthesis. No overlapping toxicities are expected for the combination. This ongoing phase Ib study evaluates the potential PK drug-drug interaction and safety of ARN-509 in combination with AA + P. Methods: Pts had progressive mCRPC and ECOG score ≤ 2. Pts received AA (1000 mg/d) + P (5 mg BID) beginning on Cycle 1 Day 1 (C1D1) with the addition of ARN-509 (240 mg/d) on C1D8 in 28-day treatment cycles until disease progression or toxicity. Serial blood samples for PK analysis were collected on C1D7 and C2D8 for abiraterone analysis and on C2D8 for ARN-509 analysis. Primary objective: evaluate effect of ARN-509 on abiraterone PK. Secondary objective: evaluate safety of ARN-509 in combination with AA + P. Results: As of November 21, 2014, 28 pts have been enrolled. At baseline, the median age was 70 years (range: 49-83); median prostate-specific antigen was 56.8 μg/L (range: 4.1-2597.0 μg/L); bone, nodal, and visceral disease were present in 24 (86%), 17 (61%), and 8 (29%) pts; and 13 (46%) pts were pretreated with docetaxel, 11 (39%) with AA, and 12 (43%) with enzalutamide. 9 pts thus far completed 1 cycle, 6 completed 2 cycles, and 4 completed 3 cycles. 26 pts are continuing therapy. 10 pts were evaluable for PK assessment and 28 pts were evaluable for safety assessment. Most drug-related adverse events (AEs) were grade 1-2, and included fatigue (n = 5), diarrhea (n = 3), dysgeusia (n = 3), vomiting (n = 4), abdominal pain (n = 2), anorexia (n = 3), dyspepsia (n = 2), rash (n = 2) and nausea (n = 3). Grade 3 drug-related AEs included hyponatremia (n = 1), fatigue (n = 1), and increased alanine aminotransferase (n = 1), and were managed by drug interruption and supportive measures. Interim data indicate a small reduction in abiraterone PK exposure when AA + P is coadministered with ARN-509. PK of ARN-509 were consistent with historical data when ARN-509 was given as monotherapy. Conclusions: This ongoing phase Ib study (NCT02123758) indicates no clinically significant PK interaction between ARN-509 and AA + P. The combination is well tolerated in pts with mCRPC; interim AE data were consistent with those seen in the AA + P phase III trials (Fizazi et al. Lancet Oncol. 2012; Ryan et al. NEJM. 2013). These preliminary results justify further evaluation of the safety and efficacy of ARN-509 in combination with AA + P for mCRPC. Citation Format: Edwin M. Posadas, Kim N. Chi, Ronald de Wit, Maja JA de Jonge, Gerhardt Attard, Terence Friedlander, Margaret Yu, Peter Hellemans, Caly Chien, Charlene Abrams, Martha Gonzalez, Geralyn C. Trudel, Vijay Chauhan, Fred Saad. Pharmacokinetics (PK) and safety of ARN-509 with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT302. doi:10.1158/1538-7445.AM2015-CT302

THU0133 Results from A Phase 2A, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Parallel-Group Study of Jnj-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-Modifying Antirheumatic Drug Therapy

Background JNJ-40346527, an investigational agent, is a selective inhibitor of the colony stimulating factor-1 receptor (CSF-1R) kinase and acts to inhibit macrophage survival, proliferation and differentiation. Based on current understanding of their mechanisms of action, JNJ-40346527 and traditional DMARDS may have complementary effects in reducing inflammation in rheumatoid arthritis (RA). Objectives To assess the safety, tolerability, and efficacy of JNJ-40346527 compared with placebo (PBO) administered for 12wks to patients with active RA despite DMARD therapy. Methods In this randomized, double-blind, PBO-controlled, parallel-group study, adult RA patients were randomized (2:1) to receive JNJ-40346527 100mg or PBO twice daily. RA patients had active disease (persistent disease activity with ≥6 swollen/6 tender joints at screening and baseline and a CRP level ≥0.8mg/dL at screening) despite MTX, SSZ, and/or HCQ therapy at the time of screening. Patients had to be on MTX, SSZ, and/or HCQ therapy for ≥6 months prior to screening, with a stable dose for minimum of 8wks prior to screening; patients were to continue stable DMARD therapy through wk12. Primary endpoint was change from baseline in DAS28 (CRP) at wk12. Efficacy analyses were based on m-ITT, defined as all randomized patients who had received ≥1 study agent administration and who had a baseline and at least one post-baseline value. Pharmacokinetics (PK) and pharmacodynamics assessments were performed. Conclusions Despite evidence of adequate PK exposure and effective peripheral target engagement, no consistent evidence of efficacy was observed in the JNJ-40346527 group vs PBO in patients with active RA despite DMARD therapy. No statistically significant difference was observed between the groups in any of the efficacy parameters analyzed; treatment was generally well-tolerated. Disclosure of Interest : M. Genovese Grant/research support: Janssen Research & Development, LLC, E. Hsia Employee of: Janssen Research & Development, LLC, S. Belkowski Employee of: Janssen Research & Development, LLC, C. Chien Employee of: Janssen Research & Development, LLC, T. Masterson Employee of: Janssen Research & Development, LLC, R. Thurmond Employee of: Janssen Research & Development, LLC, C. Manthey Employee of: Janssen Research & Development, LLC, D. Yan Employee of: Janssen Research & Development, LLC, T. Ge Employee of: Janssen Research & Development, LLC, A. Greenspan Employee of: Janssen Research & Development, LLC DOI 10.1136/annrheumdis-2014-eular.2404