Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 18 Mar 2015 BAY / Page: 1 of 8 2. Synopsis Date of report: 18 MAR 2015 Study title: Sponsor s study number: NCT number: Single-center, open-label, non-randomized, two-period sequential treatment study to assess the effect of neomycin on the pharmacokinetics of regorafenib in healthy male subjects NCT EudraCT number: Sponsor: Clinical phase: Study objectives: Bayer HealthCare I Primary objective To investigate the effect of neomycin on the pharmacokinetics (PK) of regorafenib (BAY ). Secondary objectives To evaluate the safety and tolerability of regorafenib in healthy male subjects, To investigate the effect of neomycin on the pharmacokinetics (PK) of regorafenib's two pharmacologically active metabolites M-2 (BAY ) and M-5 (BAY ), To investigate the effect of neomycin on the amount of regorafenib excreted in urine as its pharmacologically inactive metabolites M-7 (BAY ) and M-8 (BAY ). Test drug: Regorafenib (Stivarga; BAY ) Name of active ingredient: Dose: Route of administration: Duration of treatment: Reference drug: Regorafenib Single dose of 160 mg (four 40 mg tablets) of regorafenib Oral Two single 160 mg doses of regorafenib administered on Day 1 of Period 1 and Period 2, separated by a washout period of 14 days None Background treatment: Neomycin Name of active ingredient: Neomycin sulphate

3 18 Mar 2015 BAY / Page: 2 of 8 Dose: Route of administration: Duration of treatment: Indication: Diagnosis and main criteria for inclusion: Study design: Methodology: Study center: Publication(s) based on the study (references): 1 gram three times a day Oral In Period 1: No treatment. In Period 2: 1 g thrice daily over 5 days, starting 4 days before Day 1 of Period 2. Refractory, locally advanced or metastatic solid tumors Healthy male subjects years of age with a body mass index at least 18 and below 30 kg/m²; use of adequate barrier birthcontrol measures, non-smokers (or former smokers who stopped smoking > 3 months) before the first study drug administration. Single-center, open-label, non-randomized, two-period, sequential-treatment study Pharmacokinetics: Plasma concentrations of regorafenib and its two pharmacologically active metabolites M-2 and M-5 were measured by using validated methods. Blood samples for pharmacokinetic assessment were collected before each treatment period and for up to 192 hours after drug administration. The glucuronide conjugates M-7 and M-8 were also measured in urine by validated methods. Urine samples were collected in three 24-hour intervals (up to 72 hours) from Day 1 to Day 4 in Periods 1 and 2. Single center in Germany None at the time of reporting Study period: First subject, first visit: 05 DEC 2013 Last subject, last visit: 23 APR 2014 Early termination No Number of subjects: Planned: At least 24 subjects valid for analysis. Criteria for evaluation Treated and analyzed: 27 subjects in Period 1, 26 in Periods 1 and 2. More details are given in the section on study subjects below.

4 18 Mar 2015 BAY / Page: 3 of 8 Clinical pharmacology: Primary PK variables (for regorafenib): AUC and Cmax Secondary PK variables for regorafenib: tmax, tlast, t1/2, AUC(0 24), AUC(0 tlast) for M-2 and M-5: AUC, Cmax, tmax, tlast, t1/2, AUC(0 24), AUC(0 tlast) for M-7 and M-8: AE, ur(0 24), AE, ur(0 48), AE, ur(0 72) Safety/tolerability: Statistical methods: Substantial protocol changes: Adverse events, clinical laboratory values, vital signs, electrocardiography, audiological/otological examination. For demography and safety: Standard descriptive statistics. For pharmacokinetic parameters: Standard pharmacokinetic analysis methods (non-compartmental). The bioavailability of regorafenib in the presence vis-à-vis the absence of neomycin was compared by the ratio (with neomycin : without neomycin) of AUC and Cmax. 90% confidence intervals were calculated by ANOVA, including subject and treatment effects. Protocol version 3.0, dated 24 Oct introduced the following changes: o Additional orientational otological examination and audiometry at Screening and Follow-Up as recommended by ethics o Change of contact information (telephone and fax number) of PI o Correction of information from integrated study protocol V 2.0 (non-substantial amendment 1) externalization of the Bayer Pharma AG internal Phase 1 Unit as part of the department Clinical Pharmacology to the CRO CRS as of 1 Jul 2013 Protocol version 4.0, dated 11 Nov introduced the following changes: o Change in reference ranges of blood pressure and heart rate as part of exclusion criteria Electrocardiogram (ECG), blood pressure, heart rate requested by Health authority (BfArM)

5 18 Mar 2015 BAY / Page: 4 of 8 Study subjects All 27 subjects in this study were healthy males, with a mean age of 36.4 years (range, years). All were of Caucasian ethnicity. Their mean body weight was 81.9 kg, mean body height was 181 cm and mean body mass index was 24.9 kg/m 2. All 27 subjects received the first treatment (regorafenib only), and 26 received the second treatment (regorafenib plus neomycin). All 27 subjects were included in the analysis sets for safety and for pharmacokinetics. Pharmacokinetic results The following tables summarize the results as geometric mean, coefficient of variation (% CV) and range of the pharmacokinetic parameters of regorafenib and its metabolites in plasma and urine by treatment. Pharmacokinetic parameters of regorafenib (BAY ) in plasma (geometric mean (%CV), [range]), following single oral dose of regorafenib without and with neomycin Parameter Unit N Regorafenib N Regorafenib + Neomycin AUC mg h/l (31) [ ] (36) [ ] AUC (0-24) mg h/l (20) [ ] (32) [ ] AUC (0-tlast) mg h/l (30) [ ] (35) [ ] Cmax mg/l (36) [ ] (39) [ ] t1/2 h (23) [ ] (26) [ ] tmax a h [ ] [ ] tlast a h [ ] [ ] a Median [range] There was no relevant change in mean AUC and Cmax of regorafenib (<10% decrease) when regorafenib was administered without and with neomycin. No change in elimination half-life was observed between the two treatment periods. The confidence intervals for regorafenib for the treatment ratio ((regorafenib+neomycin)/regorafenib) were calculated by analysis of variance and were also fully contained in the bioequivalence acceptance range of (0.8; 1.25) for both AUC and Cmax.

6 18 Mar 2015 BAY / Page: 5 of 8 Pharmacokinetic parameters of M-2 (BAY ) in plasma (geometric mean (%CV), [range]), following single oral dose of regorafenib without and with neomycin Parameter Unit N Regorafenib N Regorafenib + Neomycin AUC mg h/l (37) [ ] (61) [ ] AUC (0-24) mg h/l (32) [ ] (63) [ ] AUC (0-tlast) mg h/l (37) [ ] (64) [ ] Cmax mg/l (41) [ ] (66) [ ] t1/2 h (13) [ ] (20) [ ] tmax a h [ ] [ ] tlast a h [ ] [ ] a Median [range] Mean AUC and Cmax decreased by 77% and 82% respectively in the neomycin treatment period relative to the corresponding values observed with regorafenib alone. M-2 peak plasma concentrations were observed 4 hours after dosing in both treatment periods. Consistently, the confidence interval for M-2 for the treatment ratio ((regorafenib+neomycin)/ regorafenib) lay outside the bioequivalence acceptance range for both AUC and Cmax. No significant change in elimination half-life was observed between the two treatment periods.

7 18 Mar 2015 BAY / Page: 6 of 8 Pharmacokinetic parameters of M-5 (BAY ) in plasma (geometric mean (%CV), [range]), following single oral dose of regorafenib without and with neomycin Parameter Unit N Regorafenib N Regorafenib + Neomycin AUC mg h/l (55) [ ] (50) [ ] AUC (0-24) mg h/l (50) [ ] (51) [ ] AUC (0-tlast) mg h/l (55) [ ] (75) [ ] Cmax mg/l (52) [ ] (60) [ ] t1/2 h (21) [ ] (32) [ ] tmax a h [ ] [ ] tlast a h [ ] [96 192] a Median [range] The pharmacokinetics of metabolite M-5 (BAY ) were generally consistent with results observed for M-2. Following oral administration of regorafenib, median tmax was very variable, ranging between hours in Period 1 and hours in Period 2. Mean AUC and Cmax were reduced by more than 80% relative to the corresponding values observed with regorafenib alone. Consistently, the confidence interval for M-5 for the treatment ratio ((regorafenib+neomycin)/regorafenib) lay outside the bioequivalence acceptance range for AUC and Cmax. Pharmacokinetic parameters of cumulative amount of M-7 (BAY ) in urine (arithmetic mean (SD), [range]), following single oral dose of regorafenib without and with neomycin Parameter Unit N Regorafenib N Regorafenib + Neomycin Aeur (0-24) mg (1.756) [ ] (2.248) [ ] Aeur (0-48) mg (2.474) [ ] (3.447) [ ] Aeur (0-72) mg (3.10) [ ] (3.894) [ ] % Aeur % (1.425) [ ] (1.790) [ ] a Median [range] Mean maximum percentage recovery of the glucuronide of regorafenib (M-7) in urine over the 72 hours after dosing was ~7% in the regorafenib treatment period. In the neomycin treatment period, mean maximum percentage recovery of M-7 in urine over the 72 hours after

8 18 Mar 2015 BAY / Page: 7 of 8 dosing was 6.6%. There was no significant difference in urinary excretion of M-7 between the two periods. Pharmacokinetic parameters of cumulative amount of M-8 (BAY ) in urine (arithmetic mean (SD), [range]), following single oral dose of regorafenib without and with neomycin Parameter Unit N Regorafenib N Regorafenib + Neomycin Aeur (0-24) mg (0.9503) [ ] ( ) [ ] Aeur (0-48) mg (1.510) [ ] (0.6877) [ ] Aeur (0-72) mg (1.841) [ ] (1.048) [ ] % Aeur % (0.8219) [ ] (0.4085) [ ] a Median [range] Mean maximum percentage recovery of M-8, the glucuronide of the N-oxide metabolite (M-2), in urine over the 72 hours after dosing was ~2.8% in the regorafenib treatment period. In the neomycin treatment period, mean maximum percentage recovery of M-8 in urine over the 72 hours after dosing decreased to 0.8%. Urine recovery of M-8 in both treatment periods was 60 88% less than that observed for M-7. Overall, urinary excretion of M-8 was significantly inhibited (decreased by 73%) in the presence of neomycin. This finding was consistent with results observed for the N-oxide metabolite, M-2. Safety results No deaths or other serious adverse events occurred during this study. Adverse events during treatment with regorafenib plus neomycin were more frequent than during treatment with regorafenib only. In particular, gastro-intestinal disorders were not encountered during treatment with regorafenib only but affected >80% of subjects when neomycin was added to the treatment. More adverse events were considered related to neomycin than to regorafenib. Most of the adverse events were rated as mild ; all events resolved, or were resolving, with no change in the administration of study medication. The laboratory tests (hematology, hemostasis, clinical chemistry, urinalysis), the measurements of vital signs, electrocardiography and otological/audiometric examinations all failed to yield any grounds for concern about the safety of regorafenib administered with or without neomycin. No adverse events were recorded in connection with any of these. Overall conclusions The treatment with 160 mg oral regorafenib without and with neomycin (1 g three times daily) was found to be safe and well tolerated by all subjects. Neomycin had no relevant effect on the pharmacokinetics of regorafenib parent. Confidence intervals for the ratio ((regorafenib + neomycin) / regorafenib) included the value 1.0 for both AUC and Cmax, and were fully contained in the bioequivalence acceptance range of (0.8; 1.25) for regorafenib.

9 18 Mar 2015 BAY / Page: 8 of 8 However, pretreatment with neomycin significantly reduced exposure to M 2 and M 5 by approximately 80%. The confidence intervals for the treatment ratio ((regorafenib + neomycin) / regorafenib) for regorafenib and its pharmacologically active metabolites were: for regorafenib for AUC [0.857; 1.038]; for regorafenib for Cmax, [0.836; 1.107]; for M 2 for AUC [0.198; 0.283]; for M 2 for Cmax, [0.153; 0.222]; for M 5 for AUC [0.112; 0.177] and for M 5 for Cmax, [0.166; 0.230]. For the metabolites, none of these contained the number 1, and all lay outside the bioequivalence acceptance range (0.8; 1.25). Decreased M 2 could be a result of reduced enterohepatic recycling, due to inhibition of bacterial β-glucuronidase activity. Effects on M 5 may be the result of the lower M 2 exposure. The clinical significance of these findings is unknown but may result in decreased efficacy of regorafenib.

10 Document Date: 2015-Mar-18 Marketing Authorization Holder in Germany Investigational Site List Name Bayer Vital GmbH D Leverkusen Postal Address Germany Sponsor in Germany (if applicable) Legal Entity Name Postal Address Bayer Pharma AG D Leverkusen Germany List of Investigational Sites No Investigator Name Facility Name Street ZIP Code City Country 1 Hr. Dr. M Berse CRS Clinical Research Services Sellerstrasse 31 Gebäude P Berlin GERMANY Page 1 of 1

11 Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Drug Stivarga Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Regorafenib BAY Other Company Code(s) Chemical Description Other Product Aliases IUPAC Name: 4-[4-({[4-Chloro-3- (trifluoromethyl)phenyl]carbamoyl}amino)-3- fluorophenoxy]-n-methylpyridine-2-carboxamide Date of last Update/Change: 08 Aug 2013