SYNOPSIS - DIMDI

SYNOPSIS

Name of Sponsor/Company Aragon Pharmaceuticals, Inc

Name of Investigational Product JNJ-56021927 (apalutamide)

Status: Approved

Date: 25 September 2017

Prepared by: Janssen Research & Development, LLC

Protocol No.: ARN-509-003

Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study of ARN-509 in Men with Non-Metastatic (M0) Castration-Resistant Prostate CancerA Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study of ARN-509 in Men with Non-Metastatic (M0) Castration-Resistant Prostate Cancer

Study Name: Selective Prostate AR Targeting with ARN-509 (SPARTAN)

EudraCT Number: 2012-004322-24

NCT No.: NCT01946204

Clinical Registry No.: CR102931

Co-Principal Investigator(s): Matthew Raymond Smith, MD, PhD, Massachusetts General Hospital, Boston, MA, USA; Eric Small, MD, University of California San Francisco, San Francisco, CA, USA.

Study Center(s): Country (# sites): Australia (15), Austria (2), Belgium (3), Canada (27), Czech Republic (7), Denmark (4), Finland (3), France (18), Germany (19), Hungary (1), Israel (6), Italy (10), Japan (22), Netherlands (6), New Zealand (3), Norway (1), Poland (10), Romania (3), Russia (9), Slovakia (3), South Korea (11), Spain (27), Sweden (5), Taiwan (6), United Kingdom (15), United States of America (96)

Publications (Reference): none

Study Period: 19 September 2013 (first patient signed informed consent) to 19 May 2017 (data cut-off date for primary analysis)

Phase of Development: 3

Objectives:

Primary Objective:

To demonstrate superiority in the metastasis-free survival (MFS) of men with high risk non-metastatic castration-resistant prostate cancer (NM-CRPC) treated with apalutamide versus placebo

Secondary Objectives:

To compare the following parameters in men with high risk NM-CRPC treated with apalutamide versus placebo:

Time to metastasis (TTM)

Progression-free survival (PFS)

Time to symptomatic progression

Overall survival (OS)

Time to initiation of cytotoxic chemotherapy

Safety and tolerability

Methodology: Randomized, double-blind, placebo controlled study in subjects with high risk non-metastatic castrate resistant prostate cancer (NM-CRPC). Subjects received apalutamide or placebo at a dose of 240 mg given orally, daily until development of metastasis or other reason for treatment discontinuation with concurrent androgen deprivation therapy (ADT). Subjects who met the primary endpoint with confirmed distant metastases by Blinded Independent Central Review (BICR) were offered ZYTIGA® (abiraterone acetate + prednisone) as a subsequent treatment option. Medications prohibited while on study included agents known to decrease the seizure threshold and/or cause seizure.

Number of Subjects (planned and analyzed): 1200 subjects were planned; 1207 subjects were randomized; 1201 subjects received study drug and were included in the safety analysis.

Diagnosis and Main Criteria for Inclusion: Non-metastatic, histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features, with high risk for development of metastases, defined as a prostate-specific antigen doubling time (PSADT) ≤ 10 months.

Test Product, Dose and Mode of Administration, Batch No.: ARN-509 Capsule Formulation:, , , , , , , , ,

, , , , , , , , , , , , : ARN-509 Tablet Formulation: , , ,

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Reference Therapy, Dose and Mode of Administration, Batch No.: Placebo Capsule Formulation: , , , , , , , , ;

Placebo Tablet Formulation: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

Duration of Treatment: Subjects were to remain on study treatment until documented radiographic progression (development of distant metastases as assessed by BICR), withdrawal of consent, or the development of unacceptable toxicity.

Criteria for Evaluation: Subjects treated under the original protocol through Amendment 6 were seen every 28 days for evaluations that included a physical exam, vital signs, evaluation of adverse events, concomitant medications, complete blood counts, chemistries, testosterone, fasting lipid panel, thyroid stimulating hormone (TSH), Eastern Cooperative Oncology Group performance status (ECOG PS), patient-reported outcomes (PRO), and medical resource utilization (MRU). The original schedule for pharmacokinetic (PK) samples were collections on Day 1 of Cycles 1, 2, 3, 6, 12, 16, and 24; biomarker samples were collected on Day 1 of Cycles 1, 12, 18, 24 and 36. After Amendment 7, the visit schedule was modified for subjects to be seen every cycle (a cycle = 28 days) for the first 6 cycles, every other cycle for the next 6 cycles, then every 4 cycles starting with Cycle 13. Starting with Amendment 7, PK samples were collected on Day 1 of Cycles 1, 2, 3, 6, 11, 17, and 25; biomarker samples were collected on Day 1 of Cycles 1, 11, 17, 25 and 37. Radiographic scans (bone scans and computerized tomography [CT] or magnetic resonance imaging [MRI] of the chest, abdomen, and pelvis) were performed every 16 weeks from Day 1 of Cycle 1 for detection of metastasis throughout the study.

Statistical Methods: The primary efficacy analysis was event-driven and was to take place when approximately 372 MFS events had occurred. The study was designed with 90% power to detect a 30% reduction in the risk of developing metastases (HR = 0.70) for subjects receiving apalutamide, with a 2-sided α of 0.05. Based on an assumed median MFS of 25 months in the placebo arm, this treatment effect represents an increase in the median MFS of approximately 11 months (from 25 months to 36 months). Assuming an accrual period of 24 months (with 75% of the patients accrued in the second year), approximately 1,200 subjects were needed.

The study was also designed with 85% power to detect a 25% reduction (HR = 0.75) in the risk of death for subjects receiving apalutamide, based on an assumed median OS of 49 months in the placebo arm. This treatment effect represents an increase in the median OS of approximately 16 months (from 49 to 65 months).

If the primary efficacy endpoint of MFS is significant, the key secondary efficacy endpoints, TTM, PFS, time to symptomatic progression, OS, and time to initiation of cytotoxic chemotherapy were to be tested in that order according to the pre-specified hierarchical testing. While this is the final analysis for time to metastasis and progression free survival, it is the first interim analysis for the other endpoints and were to be tested with pre-specified O’Brian-Fleming alpha spending that provides strong control of family-wise type I error rate at 0.05 (2-sided).

RESULTS:

The Independent Data Monitoring Committee (IDMC) reviewed data from the 19 May 2017 clinical cut-off, the preplanned final analysis for MFS, and recommended to unblind the study based on a statistically significant and clinically meaningful treatment effect on MFS which crossed the pre-specified O’Brian-Fleming boundary for efficacy as well as a favorable benefit/ risk assessment. In addition, the IDMC recommended that subjects randomized to the placebo arm be allowed to cross-over and receive apalutamide. The sponsor plans to continue to follow all subjects for survival.

STUDY POPULATION: One thousand two hundred and seven (1,207) subjects were enrolled. Thirty-nine percent (39%) of subjects in the apalutamide arm and 70% of subjects in the placebo arm had discontinued treatment. The most common reason for treatment discontinuation was progressive disease (19% of subjects in the apalutamide arm and 53% of subjects in the placebo arm). Treatment discontinuation due to adverse events was reported for 11% of subjects in the apalutamide arm and 6% of subjects in the placebo arm. Withdrawal by subject choice was reported for 7% of subjects in the apalutamide arm and 10% of subjects in the placebo arm. Fewer than 1% of the subjects discontinued treatment due to a protocol violation or lost to follow-up.

Demographic characteristics were well balanced between the treatment arms. The median age of subjects was 74 years. Twenty-six percent of subjects were 80 years of age or older. Most subjects were white (66%); 12% of subjects were Asian.

The median treatment duration was estimated to be 16.9 months in the apalutamide arm and 11.2 months in the placebo arm. Seventy percent of subjects in the apalutamide arm and 45% of subjects in the placebo arm received at least 12 months of treatment; 26% and 11% received at least 24 months of treatment, respectively.

EFFICACY RESULTS: Substantial improvements were observed for the primary endpoint of MFS as well as all secondary endpoints.

Primary Endpoint: MFS

Treatment with apalutamide + ADT significantly decreased the risk of distant metastasis or death by 72% compared with placebo + ADT (HR=0.280; 95% CI: 0.227,0.346; p<0.0001) by BICR. The median MFS was 40.5 months for the apalutamide arm and 16.2 months for the placebo arm. Results were consistent among analyses of MFS by investigator, sensitivity analyses, and for all subgroups evaluated.

Secondary Endpoints:

Time to metastasis (TTM): Treatment with apalutamide + ADT significantly decreased the risk of distant metastasis by 73% compared with placebo + ADT (HR=0.271; 95% CI: 0.219,0.335; p<0.0001). The median time to metastasis was 40.5 months for the apalutamide arm and 16.6 months for the placebo arm.

Progression-free survival (PFS): Treatment with apalutamide + ADT significantly decreased the risk of disease progression inclusive of distant and locoregional disease or death by 71% compared with placebo + ADT (HR=0.291; 95% CI: 0.238,0.356; p<0.0001). The median PFS was 40.5 months for the apalutamide arm and 14.7 months for the placebo arm.

Time to symptomatic progression: Treatment with apalutamide + ADT significantly decreased the risk of symptomatic progression by 55% compared with placebo + ADT (HR=0.447; 95% CI: 0.315,0.634; p<0.0001). The median time to symptomatic progression was not estimable for either treatment arm while the lower boundary of the 95% CI was 36.8 months for the placebo arm.

Overall survival (OS): Treatment with apalutamide + ADT resulted in favorable OS compared with placebo + ADT (HR=0.700; 95% CI: 0.472, 1.038; p=0.0742). The median survival was not reached in the apalutamide arm and was 39.0 months in the placebo arm.

Time to initiation of cytotoxic chemotherapy: Treatment with apalutamide + ADT decreased the risk for initiation of subsequent treatment with cytotoxic chemotherapy by 56% compared with placebo + ADT (HR=0.435; 95% CI: 0.286,0.661; nominal p<0.0001).

Other Endpoints:

A confirmed prostate-specific antigen (PSA) response by Prostate Cancer Working group -2 (PCWG2) criteria was observed in 90% of subjects in the apalutamide arm and 2% of subjects in the placebo arm.

Treatment with apalutamide + ADT significantly decreased the risk of PSA progression by 94% compared with placebo + ADT (HR=0.064; 95% CI: 0.052, 0.080; p<0.0001). The median time to PSA progression was not estimable for the apalutamide arm and 3.7 months in the placebo arm.

PFS2 was defined as the time from randomization to investigator-assessed disease progression with the first subsequent anti-cancer therapy or death (due to any cause) prior to the start of the second subsequent anti-cancer therapy, whichever occurs first. PFS2 was significantly improved for subjects treated with apalutamide + ADT compared with placebo + ADT, with a 51% reduction in the risk of disease progression during the first subsequent therapy or death (HR=0.489; 95% CI: 0.361, 0.662; p<0.0001). The majority of study subjects on both treatment arms received approved therapy for mCRPC including ZYTIGA (provided as part of the study), enzalutamide, or docetaxel as the first subsequent therapy.

PRO results indicated that there was no detriment to overall health-related quality of life with the addition of apalutamide to ADT. Similar mean changes from baseline or median time to worsening in the FACT-P were observed in the 2 treatment arms. For nearly all time points, no differences between apalutamide and placebo were observed in change from baseline across the EQ-5D index or VAS.

PHARMACOKINETIC AND PHARMACODYNAMIC RESULTS: The population PK analysis and exposure- response analysis will be presented in separate reports.

SAFETY RESULTS: The safety results from this study demonstrated an acceptable safety profile for apalutamide plus ADT for the treatment of patients with NM-CRPC.

The most frequently reported treatment-emergent adverse events (TEAEs; ie, occurring in ≥15% of subjects in either arm) were fatigue (30% apalutamide versus 21% placebo), hypertension (25% versus 20%, respectively), skin rash as the grouped term (24% versus 5.5%), diarrhea (20% versus 15%), nausea (18% versus 16%), weight decreased (16% versus 6.3%), arthralgia (16% versus 7.5%), and fall (16% versus 9.0%).

Grade 3 or 4 TEAEs were reported in 45% of subjects in the apalutamide arm and 34% subjects in the placebo arm; SAEs were reported in 25% of subjects in the apalutamide arm compared with 23% of subjects in the placebo arm; TEAEs with an outcome of death were reported for 1.2% of subjects in the apalutamide arm compared with 0.3% of subjects in the placebo arm. The most commonly reported Grade 3 TEAE in both arms was hypertension (14% of subjects in the apalutamide arm and 12 % of subjects in the placebo arm). There was a higher incidence of Grade 3 TEAEs of skin rash in the apalutamide arm compared with the placebo arm (5.2% of subjects in the apalutamide arm and 0.3% of subjects in the placebo arm).

The percentage of subjects reported with TEAEs leading to treatment discontinuation was higher in the apalutamide arm (11%) compared with the placebo arm (7.0%), and skin rash as a grouped term was the event leading to the highest number of treatment discontinuations. All other TEAEs leading to treatment discontinuation occurred at a low rate (<1%) except for fatigue (1.0% apalutamide versus 0.3% placebo).

Adverse events (all grades) of special interest (apalutamide arm versus placebo arm) were skin rash (24% versus 5.5%), fall (16% versus 9.0%), fracture (12% versus 7.3%), seizure (0.2% versus 0.0%) and hypothyroidism (8.1% versus 2.0%). When adjusted for exposure (events/100 P-Y), the incidence of skin rash, fall, fracture and hypothyroidism still are higher in the apalutamide arm.

Most events of skin rash were Grade 1 or 2. Grade 3 events of skin rash were reported for 5.2% of apalutamide-treated subjects; there were no Grade 4 events. Two apalutamide-treated subjects were reported with an event of skin rash as a serious adverse event (SAE). Events of skin rash were the most frequently reported reason for treatment discontinuation (2.4% of apalutamide treated subjects). No event of skin rash led to death.

Most events of fracture and fall were Grade 1 or 2

Only 2 subjects in the apalutamide arm (1 subject Grade 1; 1 subject Grade 2) and no subjects in the placebo arm reported seizure, resulting in protocol-required discontinuation of study drug.

All events of hypothyroidism were Grade 1 or 2

After standardizing for the difference in duration of treatment exposure, the TEAEs (Grades 1-4) that were observed at an excess of 5 or more events/100 P-Y in the apalutamide arm compared with the placebo arm were fatigue, arthralgia, weight decreased, hypothyroidism (as a grouped term) and skin rash (as a grouped term). The TEAEs (Grades 1-4) observed at an excess of 5 or more events/100 P-Y in the placebo arm compared with the apalutamide arm were back pain, hematuria, constipation, urinary tract infection, urinary retention, and abdominal pain upper.

The only Grade 3-4 laboratory abnormality that occurred in at least 2% of subjects in either arm was hyperglycemia (2.4% for the apalutamide arm versus 1.0% for the placebo arm).

STUDY LIMITATIONS: No notable study limitations were identified by the Sponsor.

CONCLUSION(S): Apalutamide in combination with ADT showed superior efficacy in comparison

with ADT alone for patients with NM-CRPC. Apalutamide + ADT significantly improved MFS, TTM,

PFS, and time to symptomatic progression compared with ADT alone. Though survival data are not yet

mature at the time of this analysis for MFS, treatment with apalutamide + ADT resulted in favorable OS

compared with ADT alone. Additionally, a compelling result for time to initiation of cytotoxic chemotherapy was observed. Significant improvements were consistently observed across clinically

relevant endpoints including PSA response rate, time to PSA progression, and progression-free survival

during first subsequent therapy (PFS2). There was no detrimental effect or worsening of symptoms that

impacted the quality of life from the addition of apalutamide to ADT in this population of men with NM-

CRPC who are generally asymptomatic. With the exception of small numerical increases in skin rash, fall,

fracture, and hypothyroidism, when adjusted for exposure, apalutamide in combination with ADT did not

have a clinically meaningful increase in the incidence of TEAEs compared with subjects who received

ADT alone. The majority of TEAEs reported were Grade 1 or 2 and were not dose-limiting. Grade 3

events were manageable, being largely related to hypertension (in both treatment arms) and skin rash (as a

grouped term) in the apalutamide arm with a low rate of treatment discontinuation due to TEAEs in both

treatment arms (11% in the apalutamide arm versus 7% in the placebo arm). Collectively, the data

demonstrate a favorable benefit-risk profile of the apalutamide + ADT regimen for the treatment of

subjects with NM CRPC at high risk for metastasis.

Note: The batch numbers are not critical to the interpretation of results and are considered confidential.

Note:Name of Active Substance: JNJ-56021927 (apalutamide)Name of Finished Product: ERLEADA®

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Highlight

Clinical Study Report ARN-509-003

Protocol ID Country Investigators Site

ARN-509-003 Australia Royal Prince Alfred Hospital 119-143 Missenden Road Camperdown, 2050 Australia

ARN-509-003 Australia Royal Hobart Hospital Centre for Clinical Research 24 Campbell StreetHobart TAS 7000 Australia

ARN-509-003 Australia University Hospital Geelong 70 Swanston Street, Geelong Victoria 3220 Australia

ARN-509-003 Australia Haematology & Oncology Clinics of Australia 293 Vulture StreetSouth Brisbane QLD 4101 Australia

ARN-509-003 Australia Sir Charles Gairdner Hospital Hospital Avenue Nedlands WA 6009 Australia

ARN-509-003 Australia Peter MacCallum Cancer Centre Grattan Street, Parkville Melbourne VIC 3050 Australia

ARN-509-003 Australia Saint George Hospital 1 South StreetKogarah NSW 2217 Australia

ARN-509-003 Australia The Queen Elizabeth Hospital 28 Woodville RoadWoodville South SA 5011 Australia

ARN-509-003 Australia Royal Adelaide Hospital 28 Woodville RoadWoodville South SA 5011 Australia

ARN-509-003 Australia Liverpool Hospital 11 Elizabeth StreetLiverpool NSW 2170 Australia


Gosford HospitalHolden StreetGosford NSW 2250 Australia

ARN-509-003 Australia Wollongong Hospital Crown StreetWollongong NSW 2500 Australia

ARN-509-003 Australia Box Hill Hospital 5 Arnold StreetBox Hill VIC 3128 Australia

ARN-509-003 Australia Sydney Adventist Hospital 185 Fox Valley Road, Clark TowerWahroonga NSW 2076 Australia

ARN-509-003 Australia Sir Charles Gairdner Hospital Dept. of Medical Oncology Hospital Avenue Nedlands WA 6009 Australia

ARN-509-003 Austria Medizinische Universität Wien Währinger Gürtel 18-20 1090 WienAustria

ARN-509-003 Austria LKH - Universitätsklinikum Graz Auenbruggerplatz 298036 Graz Austria

ARN-509-003 Belgium AZ Groeninge Campus Kennedylaan President Kennedylaan 48500 KortrijkBelgium

ARN-509-003 Belgium Universitair Ziekenhuis Leuven Campus Gasthuisberg, Herestraat 493000 Leuven Belgium

ARN-509-003 Belgium Universitair Ziekenhuis Gent Corneel Heymanslaan 10 9000 Gent Belgium

ARN-509-003 Canada Centre Hospitalier de L'Universite de Montreal, Hopital Notre Dame 900 Rue Saint-Denis, Viger tower Montreal, Quebec City H2X 0A9 Canada

ARN-509-003 Australia


ARN-509-003 Canada London Health Sciences Centre 800 Commissioners Road EastLondon, Ontario N6A 5W9 Canada

ARN-509-003 Canada CHUS - Hospitalier Fleurimont Centre de Recherche Clinique 3001, 12e Avenue Nord, CRCSherbrooke, Quebec City J1H 5N4 Canada

ARN-509-003 Canada The Fe/Male Health Centre 407-1235 Trafalgar Road NorthOakville, Ontario L6H 3P1 Canada

ARN-509-003 Canada The University of British Columbia (UBC)-Vancouver General Hospital (VGH) - Vancouver Prostate Cen 2775 Laurel StreetVancouver, British Columbia V5Z 1M9 Canada

ARN-509-003 Canada Sunnybrook Health Sciences Centre 2075 Bayview AvenueToronto, Ontario M4N 3M5 Canada

ARN-509-003 Canada Recherches Cliniques Theradev 4 Robinson NordGranby, Quebec City J2G 8Z9 Canada

ARN-509-003 Canada Ultra-Med Inc. 175 Still view RoadPointe-Claire, Quebec City H9R 4S3 Canada

ARN-509-003 Canada Toronto University Health Network 610 University AvenueToronto, Ontario M5G 2M9 Canada

ARN-509-003 Canada British Columbia Cancer Agency Vancouver Island Cancer Centre 2410 Lee AvenueVictoria, British Columbia V8R 6V5 Canada

ARN-509-003 Canada Comite d'ethique de la recherche du CHU de Quebec 11 Cote du Palais, CRCEO 2643Quebec, Quebec City G1R 2J6 Canada

ARN-509-003 Canada Dalhousie University 5790 University AvenueHalifax, Nova Scotia B3H 1V7 Canada


ARN-509-003 Canada Urology South Shore Research 304-3234 boulevard TaschereauGreenfield Park, Quebec City J4V2H3 Canada

ARN-509-003 Canada Moncton Hospital 135 MacBeath AvenueMoncton, New Brunswick E1C 6Z8 Canada

ARN-509-003 Canada The Ottawa Hospital Regional Cancer Centre 501 Smyth RoadOttawa, Ontario K1H 8L6 Canada

ARN-509-003 Canada British Columbia Cancer Agency 399 Royal AvenueKelowna, British Columbia V1Y 5L3 Canada

ARN-509-003 Canada 2150935 Ontario Inc 1101 2nd Avenue EastOwen Sound, Ontario N4K 2J1 Canada

ARN-509-003 Canada Saint John Regional Hospital 400 University AvenueSaint John, New Brunswick E2L 4L2 Canada

ARN-509-003 Canada Exdeo Clinical Research Inc 302-32615 South Fraser WayAbbotsford, British Columbia V2T1X8 Canada

ARN-509-003 Canada Jewish General Hospital 3755 Chemin de la Cote Ste-CatherineMontreal, Quebec City H3T 1E2 Canada

ARN-509-003 Canada Prostate Cancer Center 6500-7007 14th Street SouthwestCalgary, Alberta C1A 8T5 Canada

ARN-509-003 Canada Jonathan Giddens Medicine Professional Corporation 18 Kensington RoadBrampton, Ontario L6T 4S5 Canada

ARN-509-003 Canada Brantford Urology Research 99 Wayne Gretzky ParkwayBrantford, Ontario N3S 6T6 Canada


ARN-509-003 Canada St. Joseph's Healthcare Hamilton 50 Charlton Avenue EastHamilton, Ontario L8N 4A6 Canada

ARN-509-003 Canada Juravinski Cancer Centre 699 Concession StreetHamilton, Ontario L8V 5C2 Canada

ARN-509-003 Canada UroLaval 300 Boul De La Concorde EastLaval, Quebec City H7G 2E6 Canada

ARN-509-003 Canada Centre integre de sante et de services sociaux de l'Outaouais 909 Boul de La Vérendrye, Cancerologie Gatineau, Quebec City J8P 7H2 Canada

ARN-509-003 Czech Republic

Fakultni Nemocnice Olomouc Onkologicka klinika, I.P. Pavlova 6 Olomouc- 779 00 Czech Republic


Slezska nemocnice v Opave Urologicke oddeleni, Olomoucka 86, Opava Severomoravsky Kraj- 746 01 Czech Republic


Urocentrum Praha s.r.o Karlovo namesti 3, Suite 319 Praha- 120 00 Czech Republic

ARN-509-003 CzechRepublic


Urologicka klinika VFN a 1. LF UK v Praze Ke Karlovu 6 Praha 2- 128 08 Czech Republic Krajska Nemocnice Liberec Husova 10, Liberec Severocesky Kraj- 460 63 Czech Republic


Fakultni nemocnice Motol Ustav patologie a molekularni mediciny, V Uvalu 84 Praha- 150 06 Czech Republic


Thomayerova Nemocnice Videnska 800, Prague 4 Praha- 140 59 Czech Republic


ARN-509-003 Denmark Rigshospitalet Department of Urology Research, 7521, Tagensvej 20 Copenhagen-2100 Denmark

ARN-509-003 Denmark Aalborg University Hospital, Aalborg Sygehus Nord Urologisk afd., Reberbansgade 15 Aalborg C- 9000 Denmark

ARN-509-003 Denmark Roskilde Sygehus Urologisk Ambulatorium, Kogevej 7-13 Roskilde- 4000 Denmark

ARN-509-003 Denmark Odense University Hospital Sdr. Boulevard 29 Odense C- 5000 Denmark

ARN-509-003 Finland Turku University Hospital Kiinamyllynkatu 4-8 Turku 20521 Finland

ARN-509-003 Finland Oulun Yliopistollinen Sairaala Kajaanintie 50 Oulu 90220 Finland

ARN-509-003 Finland Seinajoki Central Hospital Hanneksenrinne 7 Seinajoki 60220 Finland

ARN-509-003 France Hopital Europeen Georges-Pompidou 20 rue Leblanc, 4eme etage, Paris Cedex 15 ILE-DE-France- 75908 France

ARN-509-003 France Hopital Pontchaillou 2 rue Henri le Guiloux Rennes Cedex- 35033 France

ARN-509-003 France Hopital Claude Huriez 1 Place de Verdun, Lille cedex Nord Pas-De-Calais, 59037 France

ARN-509-003 France Hopital Charles Nicolle 1 rue de Germont, Pavillon Derocque, Rouen Haute-Normandie- 76031 France


ARN-509-003 France Centre Hospitalier Regional et Universitaire de Besançon Hopital Jean-Minjoz 3, boulevard Alexandre Fleming, Besancon Cedex Franche-Comte- 25030 France

ARN-509-003 France Institut de Cancerologie de l’Ouest - Site Rene Gauducheau Service d'Oncologie Médicale Boulevard Jacques Monod Saint Herblain cedex Pays De La Loire- 44805 France

ARN-509-003 France Centre de Lutte Contre le Cancer Francois Baclesse Comite Genito-Urinaire, 3 avenue du General Harris, Caen Cedex 05 Basse-Normandie- 14076 France

ARN-509-003 France Institut Curie 26 rue d'Ulm, Paris Cedex 05 Ile-De-France- 75248 France

ARN-509-003 France Institut Jean-Godinot 1 rue du General-Koenig, BP 171 Reims Cedex- 51056 France

ARN-509-003 France Centre Hospitalier Universitaire de Lyon-Hôpital Edouard Herriot 5 Place D Arsonval, Lyon Rhone-Alpes- 69003 France

ARN-509-003 France Centre Antoine Lacassagne 33, avenue de Valombrose, Nice Cedex 2 Provence Alpes Cote D'sur- 06189 France

ARN-509-003 France Institut Paoli Calmettes 232 Boulevard Sainte Marguerite, BP 156, Marseille Cedex 9 Provence Alpes Cote D'sur- 13273 France

ARN-509-003 France Les Hopitaux Universitaires de Strasbourg 1 place de l'Hopital, BP 426, Strasbourg Cedex Alsace- 67091 France

ARN-509-003 France Service d'Urologie Tripode Hopital Pellegrin Place Amelie Raba Leon, Bordeaux Aquitaine- 33000 France

ARN-509-003 France The Public Hospital Centre Hospitalier de Vendee Service d'Hematologie et d'Oncologie, boulevard Stephane Moreau


La Roche sur Yon Cedex 9- 85925 France

ARN-509-003 France Hopital Foch 40 rue Worth, Suresnes ILE-De-France- 92150 France

ARN-509-003 France Centre Jean Perrin 58, rue Montalembert, BP 392, Clermont Ferrand Cedex Auvergne- 63011 France

ARN-509-003 France Centre Hospitalier Prive Saint-Gregoire 6 Boulevard de la Boutiere, St Gregoire Bretagne- 35768 France

ARN-509-003 Germany Studienpraxis Urologie Steinengrabenstraße 17 72622 Nürtingen Germany

ARN-509-003 Germany Gemeinschaftspraxis für Dermatologie, Gynäkologie und Urologie Hofaue 91-9342103 Wuppertal Germany

ARN-509-003 Germany Klinik für Urologie und Urologische Onkologie Carl-Neuberg-Straβe 1 30625 Hannover Germany

ARN-509-003 Germany Urologische Universitätsklinik Im Neuenheimer Feld 110 69120 HeidelbergGermany

ARN-509-003 Germany Universitätsklinik Tübingen Klinik fur UrologieHoppe-Seyler-Straße 372076 Tübingen Germany

ARN-509-003 Germany Urologikum Hamburg Harksheider Strasse 3 22399 Hamburg Germany


ARN-509-003 Germany Praxisgemeinschaft für Urologie Friedrich-Paffrath-Strabe 9826389 Wilhelmshaven Germany

ARN-509-003 Germany Urologische GemeinschaftspraxisStuttgarter Str. 5673230 Kirchheim unter Teck Germany

ARN-509-003 Germany Universitätsklinikum Frankfurt Theodor-Stern-Kai 760590 Frankfurt Germany

ARN-509-003 Germany Universitätsklinikum Münster Albert-Schweitzer-Campus 148149 MünsterGermany

ARN-509-003 Germany Kliniken Nordoberpfalz Klinikum WeidenSollnerstraße 1692637 Weiden Germany

ARN-509-003 Germany Universitätsmedizin der Johannes Gutenberg Universität Mainz Langenbeckstraße 155131 Mainz Germany

ARN-509-003 Germany Urologie Neandertal Adlerstasse 140822 Mettmann Germany

ARN-509-003 Germany Urologie 24St. Theresien-Krankenhaus Nürnberg Karlstrasse 290513 Zirndorf Germany

ARN-509-003 Germany Duisburger Fachärztegemeinschaft UrologieKometenplatz 29-3347179 Duisburg Germany


Urologische Gemeinschaftspraxis Milchhofstr. 1b 79312 Emmendingen Germany

ARN-509-003 Germany Urologische Gemeinschaftspraxis Königstraße 4947051 Duisburg Germany

ARN-509-003 Germany Städtisches Klinikum Braunschweig Salzdahlumer Strasse 9038126 BraunschweigGermany

ARN-509-003 Germany Urologische Praxis Lietzenburger Strasse 54 10719 BerlinGermany

ARN-509-003 Hungary Soproni Erzsebet Oktato Korhaz es Rehabilitacios Intezet Urologiai Osztaly, Gyori ut 15, Sopron Gyor-Moson-Sopron 9400 Hungary

ARN-509-003 Israel Assaf Harofeh Medical Centre Tzrifin, Be’er Ya'ako Rehoboth 70300 Israel

ARN-509-003 Israel Bnai Zion Medical Center 47 Golomb Street Haifa 31048 Israel

ARN-509-003 Israel Rabin Medical Center 39 Jabotinski Street, Petach Tikvah Petah Tiqwa 4941492 Israel

ARN-509-003 Israel Rambam Health Corporation 8 Haaliya Street POB 9602, Bat-Galim Haifa 31096 Israel

ARN-509-003 Israel Meir Medical Center Meir MC, 59 Tchernichovsky St., Kfar Saba Sharon 4428164 Israel

ARN-509-003 Israel Tel Aviv Sourasky Medical Center 6 Weizman Street

ARN-509-003 Germany


Tel Aviv 64239 Israel

ARN-509-003 Italy Azienda Ospedaliera San Camillo Forlanini Circonvallazione Gianicolense 87Roma 00152 Italy

ARN-509-003 Italy Unità Operativa Complessa Oncologia Medica Via Pietro Nenni, 20 Arezzo Milano 52100 Italy

ARN-509-003 Italy Istituto Regina Elena Via Elio Chianesi, 53 Roma 00144 Italy

ARN-509-003 Italy Azienda Ospedaliera Universitaria-Maggiore della Carita di Novara Corso Mazzini, 18, SC Oncologia Novara 28100 Italy

ARN-509-003 Italy SC Oncologia Medica Via Stelvio 25 Sondrio 23100 Italy

ARN-509-003 Italy Azienda Ospedaliera Citta della Salute e della Scienza di Torino Via Genova 3Torino 10126 Italy

ARN-509-003 Italy Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Via P. Maroncelli, 40, Meldola Forli-Cesena 47014 Italy

ARN-509-003 Italy Azienda Ospedaliero - Universitaria San Luigi Gonzaga A.O.U. San Luigi Gonzaga di Orbassano, Regione Gonzole, 10, Orbassano Torino 10043 Italy

ARN-509-003 Italy Istituto Europeo di Oncologia Via Ripamonti 435 Milano 20141 Italy

ARN-509-003 Italy Azienda Ospedaliera San Giuseppe Moscati Via Circumvallazione, 68 Avellino 83100 Italy


Nagasaki University Hospital1-7-1 Sakamoto Nagasaki 852-8501 Japan

ARN-509-003 Japan Hokkaido University Hospital Kita 14-jo Nishi 5-chome, Kita-ku, Sapporo Hokkaido 060-8648 Japan

ARN-509-003 Japan National Hospital Organization Shikoku Cancer Center 160 Kou Minamiumemoto-machi, Matsuyama Ehime 791-0280 Japan

ARN-509-003 Japan Tokushima University Hospital 2-50-1 Kuramoto-cho, Tokushima-shi Tokushima 770-8503 Japan

ARN-509-003 Japan Kanazawa University Hospital 13-1 Takaramachi, Kanazawa Ishikawa 920-8641 Japan

ARN-509-003 Japan Osaka City University Hospital 1-5-7, Asahi-cho, Abeno-ku, Osaka-shi Osaka 176399 Japan

ARN-509-003 Japan Kitasato University Hospital 1-15-1,Kitasato,Minami-ku, Sagamihara Kanagawa 252-0375 Japan

ARN-509-003 Japan Nagoya City University Hospital 1 Mizuho-cho Mizuho-ku, Nagoya Aichi 467-8601 Japan

ARN-509-003 Japan Dokkyo Medical University Saitama Medical Center 2-1-50, Minamikoshigaya, Koshigaya Saitama 343-8555 Japan

ARN-509-003 Japan National Cancer Center Hospital East 6-5-1 Kashiwanoha, Kashiwa-shi Chiba 277-8577 Japan

ARN-509-003 Japan Yokohama City University Medical Center 3-9 Fukuura, Kanazawa-ku, Yokohama Kanagawa 236-0004 Japan

ARN-509-003 Japan


Asahikawa Medical University Hospital2-1-1-1 Midorigaoka-Higashi, Asahikawa Hokkaido 078-8510 Japan

ARN-509-003 Japan Kindai University Hospital 377-2 Ohno-higashi, Osakasayama-shi Osaka 589-8511 Japan

ARN-509-003 Japan Kurume University Hospital 67 Asahi-machi,Kurume-shi, Kurume Fukuoka 830-0011 Japan

ARN-509-003 Japan Tokyo Women's Medical University 8-1 Kawadacho, Sinjuku-ku Tokyo 162-8666 Japan

ARN-509-003 Japan Niigata University Medical & Dental Hospital 754 Ichibancho, Asahimachidori, Chuo-ku, Niigata-shi Niigata 951-8520 Japan

ARN-509-003 Japan Nationa l Hospital Organization Tokyo Medical Center 2-5-1 Higashigaoka, Meguro-ku Tokyo 152-8902 Japan

ARN-509-003 Japan OsakaCity General Hospital 2-13-22, Miyakojima Hon-dori, Miyakojima-ku Osaka-shi Osaka 534-0021 Japan

ARN-509-003 Japan

ARN-509-003 Japan

Yamaguchi University Hospital 1-1-1 Minami-kogushi, Ube Yamaguchi- 755-8505 Japan Nagano Municipal Hospital 1333-1 Tomitake, Nagano-shi Nagano 381-8551 Japan

ARN-509-003 Japan Akita University Hospital Hiroomote Aza Hasunuma 44-2 Akita 010-8543 Japan

ARN-509-003 Japan Hakodate Goryokaku Hospital 1 Hikariga-oka Fukushima 960-1295 Japan

ARN-509-003 Japan


ARN-509-003 Netherlands Catharina Ziekenhuis Michelangelolaan 2Eindhoven, Noord-Brabant 5623 EJ Netherlands

ARN-509-003 Netherlands Spaarne Ziekenhuis Spaarnepoort 1Hoofddorp, Noord-Holland 2134 TM Netherlands

ARN-509-003 Netherlands Sint Franciscus Gasthuis Kleiweg 500Rotterdam, Zuid-Holland 3045 PM Netherlands

ARN-509-003 Netherlands Medisch Centrum Haaglanden Location Antoniushove, Burg. Banninglaan 1Leidschendam, Zuid-Holland 2262 BA Netherlands

ARN-509-003 Netherlands Canisius-Wilhelmina Ziekenhuis Weg door Jonkerbos 100Nijmegen, Gelderland 6532 SZ Netherlands

ARN-509-003 Netherlands NoordWest Ziekenhuisgroep Locatie Alkmaar Wilhelminalaan 12Alkmaar, Noord-Holland 1815 JD Netherlands

ARN-509-003 New Zealand North Shore Hospital Private Bag 93-503Takapuna, Auckland 0740 New Zealand

ARN-509-003 New Zealand Canterbury Urology Research Trust 249 Papanui Road, Hiatt Chambers, Block 5 Christchurch 8014 New Zealand

ARN-509-003 New Zealand Cardinal Points Research 8 Percy Street, Whau Valley, Whangarei Northland 0145 New Zealand

ARN-509-003 Norway Akershus Universitets Sykehus Sykehusveien 25 Nordbyhagen, Akershus 1474 Norway

ARN-509-003 Poland Centrum Onkologii, Ambulatorium Chemioterapiiulica dr Izabeli Romanowskiej 2Bydgoszcz, Kujawsko-Pomorskie 85-796 Poland


ARN-509-003 Poland Wielkopolskie Centrum Onkologii im. Marii Sklodowskiej-Curie Oddzial Radioterapii I, ulica Garbary 15Poznan, Wielkopolskie 61-866 Poland

ARN-509-003 Poland Uniwersyteckie Centrum Kliniczne Klinika Onkologii i Radioterapii, ulica Debinki 7Gdansk, Pomorskie 80-952 Poland

ARN-509-003 Poland NZOZ Specjalista ulica 29-Listopada 37Kutno, Lodzkie 99-300 Poland

ARN-509-003 Poland Copernicus Podmiot Leczniczy Oddzial Chemioterapii, Aleja Zwycięstwa 31/32Gdansk, Pomorskie 80-219 Poland

ARN-509-003 Poland Szpital Kliniczny Dzieciątka Jezus Klinika Urologii Ogólnej, Onkologicznej i Czynnosciowej ulica Lindleya 4 Warszawa, Mazowieckie 02-005 Poland

ARN-509-003 Poland Centrum Onkologii, Oddział Urologii i Ogolnej i Onkologicznej, Batorego 17/19Toruń, Kujawsko-Pomorskie 87-100 Poland

ARN-509-003 Poland Szpital Kliniczny Dzieciatka Jezus Klinika Urologii Ogolnej, Onkologicznej i Czynnosciowejulica Lindleya 4Warszawa, Mazowieckie- 02-005 Poland

ARN-509-003 Poland Samodzielny Publiczny Szpital Kliniczny Nr 2 PUM w Szczecinie Aleja Powstancow Wielkopolskich 72, Klinika Urologii i Onkologii Urologicznej, Szczecin Zachodniopomorskie- 70-111 Poland

ARN-509-003 Poland Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu ulica Borowska 213, Wrocław Dolnoslaskie- 50-556 Poland

ARN-509-003 Romania MedLife Policlinica de Diagnos tic Rapid Strasse Turnului, Number 5 Brasov 500152 Romania


ARN-509-003 Romania Spitalul Clinic Judetean de Urgenta Targu Mureș P-ța Bernady Gyorgy, Number 6, Tirgu-Mureș Mures 540072 Romania

ARN-509-003 Romania S.C. Medisprof S.R.L. Piata 1 Mai, Numarul 3 Cluj- Napoca Cluj 400058 Romania

ARN-509-003 Russia Ivanovo Regional Oncological Dispensary 5, Lyubimova Str. Ivanovo 153040 Russia

ARN-509-003 Russia P.A. Hertzen Moscow Oncology Research Institute (MNIOI) 3, 2nd Botkinskiy proezdMoscow 125284 Russia

ARN-509-003 Russia Omsk Region Clinical Oncologic Dispensary 9, Zavertyaeva, Building 1Omsk 644013 Russia

ARN-509-003 Russia Regional State Budgetary Institution of Health Care - Altay Regional Oncological Dispensary 115, Matrosova strasse Barnaul 656052 Russia

ARN-509-003 Russia Sverdlovsk Regional Clinical Hospital #1 185, Volgogradskaya st, Ekaterinburg 620102 Russia

ARN-509-003 Russia Federal State Budget Institution Medical Radiological Research Center named after A.F. Tsyb 4 Koroleva Strasse, Obninsk Kaluga 249036 Russia

ARN-509-003 Russia Bashkirian State Medical University Clinical Hospital of Bashkirian State Medical University, 2, Shafieva str. Ufa 450096 Russia

ARN-509-003 Russia Ryazan State Medical University 13, Sportivnaya str. Ryazan 390011 Russia

ARN-509-003 Russia Leningrad Regional Oncology Dispensary 37-39, Liteiny prospect


Saint Petersburg 199104 Russia

ARN-509-003 Slovakia CUIMED- Urologicka ambulancia Ambulancia Petrzalka, Strecnianska 13 Bratislava 851 05 Slovakia

ARN-509-003 Slovakia Privatna urologicka ambulancia Piaristicka 257/8 Trencin 911 01 Slovakia

ARN-509-003 Slovakia Univerzitna nemocnica Martin Kollarova 2 Martin 03601 Slovakia

ARN-509-003 South Korea Gangnam Severance Hospital 211 Eonju-ro, Gangnam-gu Seoul 06273 South Korea

ARN-509-003 South Korea Samsung Medical Center Cancer Center B4, Cancer Center B4, Gangnam-gu Seoul 06351 South Korea

ARN-509-003 South Korea Pusan National University Hospital 179 Gudeok-ro, Seo-gu, Busan Gyeongsangnam-Do-49241 South Korea

ARN-509-003 South Korea Seoul National University Hospital 101 Daehak-ro, Jongno-gu, Seoul GyeonggI-Do 03080 South Korea

ARN-509-003 South Korea Seoul National University Bundang Hospital 82 Gumi-Ro 173 Beon-Gil, Bundang-gu, Seongnam-si Gyeonggi-Do 13620 South Korea

ARN-509-003 South Korea Asan Medical Center 88 Olympic-ro 43-gil, Songpa-gu Seoul 05505 South Korea

ARN-509-003 South Korea Seoul Saint Mary's Hospital 222 Banpo-daero, Seocho-gu Seoul 06591 South Korea

ARN-509-003 South Korea Keimyung University Dongsan Medical Center 56 Dalseong-ro, Jung-gu, Daegu


Gyeongsangnam-Do 41931 South Korea

ARN-509-003 South Korea Chonnam National University Hospital 42 Jebong-Ro, Dong-gu Dong-gu 61469 South Korea

ARN-509-003 South Korea Korea University Guro Hospital Gurodong-ro 148, Guro-gu Seoul 08308 South Korea

ARN-509-003 South Korea Kyungpook National University Chilgok Hospital 807 Hoguk-ro, Buk-gu, Daegu Gyeongsangbuk-Do 41404 South Korea

ARN-509-003 Spain HM Centro Integral Oncológico Clara Campal Calle Ona, 10, Planta -1 Madrid 28050 Spain

ARN-509-003 Spain Hospital Ramon y Cajal Carretera Colmenar Viejo, KM. 9,1, Planta -2, Derecha Madrid 28034 Spain

ARN-509-003 Spain Hospital Santa Creu i Sant Pau Calle Mas Casanovas 90, Planta -2 Barcelona 08041 Spain

ARN-509-003 Spain Hospital General Universitario Gregorio Maranon Calle Maiquez 7, Planta -1, Servicio Oncologia Madrid 28007 Spain

ARN-509-003 Spain Hospital Vall d´Hebron Paseo Vall d'Hebron, 119-129 Barcelona 08035 Spain

ARN-509-003 Spain Hospital Universitario 12 de Octubre Avenida de Cordoba, Km 5.4, Avenida de Cordoba, Km 5.4, Edificio de Maternidad, 2ª planta Madrid 28041 Spain

ARN-509-003 Spain Clinica Universidad de Navarra Avenida Pio XII 36, 5ª Fase, 8ºplanta, Pamplona Navarra 31008 Spain


Instituto Valenciano de Oncologia-Fundacion (IVO-FINCIVO) Calle Profesor Beltran Baguena, 8 Valencia 46009 Spain

ARN-509-003 Spain Hospital Universitari de Girona Doctor Josep Trueta Avenida de Francia, s/n, Planta 1 Gerona 17007 Spain

ARN-509-003 Spain Hospital Universitari Germans Trias i Pujol Carretera del Canyet, s/n, Edificio Maternal, 6ª planta, Badalona Barcelona 08916 Spain

ARN-509-003 Spain Corporacio Sanitaria Parc Tauli Parc Tauli s/n, Sabadell Barcelona 08208 Spain

ARN-509-003 Spain Hospital Universitario Son Espases Despacho 149, Nivel 1, Pasillo Q, Palma de Mallorca Las Palmas 07120 Spain

ARN-509-003 Spain Hospital Clínico Universitario Virgen de la Victoria Campus Universitario de Teatinos Malaga 29010 Spain

ARN-509-003 Spain Hospital Universitario de Guadalajara Calle Donantes de Sangre, s/n Guadalajara 19002 Spain

ARN-509-003 Spain Hospital Universitario Fundacion Jimenez Diaz Avenida Reyes Catolicos 2, Servicio de Oncologia Medica Madrid 28040 Spain

ARN-509-003 Spain Hospital San Carlos Madrid Calle Dr. Martin Lagos, s/n, Pabellon B Madrid 28040 Spain

ARN-509-003 Spain Hospital Puerta de Hierro Majadahonda C / Manuel de Falla, 1, Planta 3, Majadahonda Madrid 28222 Spain

ARN-509-003 Spain Hospital General de Jerez de la Frontera Ronda de Circunvalacion s/n, 4a planta, Jerez de la Frontera Cadiz 11407 Spain

ARN-509-003 Spain


Hospital Clinic de Barcelona Calle Villarroel n 170 Barcelona 08036 Spain

ARN-509-003 Spain Hospital Provincial de Castellon Avenida Dr. Clara, 19 Castellon 12002 Spain

ARN-509-003 Spain Hospital Universitario de Getafe Planta 4a Control C, A-42, Getafe Madrid 28905 Spain

ARN-509-003 Spain Hospital Infanta Sofia Paseo de Europa, 34, San Sebastian de los Reyes Madrid 28702 Spain

ARN-509-003 Spain Hospital Universitario Virgen del Rocio Avenida Manuel Siurot, s/n Sevilla 41013 Spain

ARN-509-003 Spain Complejo Hospitalario Universitario La Coruna Xubias de Arriba, 84, Planta 11, A Coruna La Coruna 15006 Spain

ARN-509-003 Spain Hospital Universitario Marqus de Valdecilla Avenida Valdecilla 25 Santander 39008 Spain

ARN-509-003 Spain Hospital Virgen de la Macarena Avenida Doctor Fedriani, 3, 2a planta del Hospital Virgen Macarena. Ala B - pasillo Sevilla 41009 Spain

ARN-509-003 Spain Hospital Universitario de Salamanca Paseo de San Vicente 182, Planta 2, ala derecha Salamanca 37003 Spain

ARN-509-003 Sweden Umea University Hospital Cancercentrum, Forskningsenheten Umea 901 85 Sweden

ARN-509-003 Sweden Universitetssjukhuset Orebro Örebro Orebro 70185 Sweden

ARN-509-003 Spain


ARN-509-003 Sweden Karolinska University Hospital Huddinge Urologkliniken, K62 Stockholm 14186 Sweden

ARN-509-003 Sweden University of California Irvine Medical Center Dept. of Urology Uppsala 751 85 Sweden

ARN-509-003 Sweden Sahlgrenska Universitetsjukhuset Department of Urology Göteborg 413 45 Sweden

ARN-509-003 Taiwan Kaohsiung Veterans General Hospital No. 386 Ta-Chung 1st Road Kaohsiung 81362 Taiwan

ARN-509-003 Taiwan Taipei Veterans General Hospital Number 201, Section 2, Shipai Road Beitou District Taipei 11217 Taiwan

ARN-509-003 Taiwan Taichung Veterans General Hospital No. 160, Sec. 3, Tai-Chung Kang Road, 1st Floor Taichung Taichung 40705 Taiwan

ARN-509-003 Taiwan Chang Gung Memorial Hospital No. 123 Ta-Pie Road, Niaosung District Kaohsiung 83301 Taiwan

ARN-509-003 Taiwan Chang Gung Memorial Hospital Linkou Branch 2F, Education Building, No. 5, Fushing Street, Kweishan Taoyuan 333 Taiwan

ARN-509-003 Taiwan National Taiwan University Hospital 7, Chung-Shan South Road Taipei 100 Taiwan

ARN-509-003 United Kingdom

Guy's and Saint Thomas NHS Foundation Trust Saint Thomas StreetLondon SE1 9RT United Kingdom


Nottingham City Hospital NHS Trust Nottingham City Hospital Campus, Hucknall RoadNottingham NG5 1PB United Kingdom



Beatson Cancer Centre Glasgow 1053 Great Western RoadGlasgow G12 0YN United Kingdom


The Royal Marsden NHS Foundation Trust Downs Road, SuttonSurrey SM2 5PT United Kingdom


Clatterbridge Centre for Oncology NHS Foundation Trust Clatterbridge Health Park, Clatterbridge Road, BebingtonWirral CH63 4JY United Kingdom


Royal Surrey County Hospital NHS Foundation Trust Daphne Jackson Road, The Leggett BuildingGuildford GU2 7WG United Kingdom


Addenbrooke's Hospital Box 193Cambridge CB2 0QQ United Kingdom


Saint James Hospital Level 4 Bexley, Beckett StreetLeeds LS9 7TF United Kingdom


Maidstone and Tunbridge Wells NHS Trust Hermitage LaneMaidstone ME16 9QQ United Kingdom


Ninewells Hospital Stefani Unit, Ward 32Dundee DD1 9SY United Kingdom


New Cross Hospital Wednesfield Road, Wolverhampton WV10 0QP United Kingdom


East Lancashire Hospitals NHS Trust Haslingden RoadBlackburn BB2 3HH United Kingdom


Southampton University Hospitals NHS Trust Tremona RoadSouthampton SO16 6YD United Kingdom



Singleton Hospital Sketty LaneSwansea SA2 8QA United Kingdom


Charing Cross Hospital Fulham Palace Road, Hammersmith London W6 8RF United Kingdom

ARN-509-003 United States Massachusetts General Hospital 55 Fruit StreetBoston Massachusetts 02114 United States

ARN-509-003 United States Massachusetts General Hospital Yawkey 7038, 55 Fruit Street Boston 02114 United States

ARN-509-003 United States University of California San Francisco 1825 Fourth StreetSan Francisco California 94143 United States

ARN-509-003 United States The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 1650 Orleans Street, Clinical Research Building 1, 1M45Baltimore Maryland 21231 United States

ARN-509-003 United States University of Wisconsin Hospital and Clinics 1111 Highland AvenueMadison Wisconsin 53705 United States

ARN-509-003 United States Lancaster Urology 2106 Harrisburg PikeLancaster Pennsylvania 17604 United States

ARN-509-003 United States Chesapeake Urology GBMC/Towson, 6535 North Charles StreetPhysician Pavilion North Towson Maryland 21204 United States

ARN-509-003 United States Urologic Consultants of Southeastern Pennsylvania 1 Presidential BoulevardBala Cynwyd Pennsylvania 19004 United States

ARN-509-003 United States University of Washington 825 Eastlake Avenue East G4-830, Seattle, 98195-0001United States


United States

ARN-509-003 United States City of Hope – Duarte Dept. of Medical Oncology, 1500 East Duarte Road, Building 51 Duarte 91010-3000 United States

ARN-509-003 United States Memorial Sloan-Kettering Cancer Center 353 East 68th Street New York 10065-6094 United States

ARN-509-003 United States Urology of Virginia 225 Clearfield AvenueVirginia Beach, Virginia 23462-1815 United States

ARN-509-003 United States Premier Urology Associates, LLC dba AdvanceMed Research 2 Princess Road Lawrenceville 08648 United States

ARN-509-003 United States University of California Davis Medical Center 4501 X StreetSacramento, California 95817 United States

ARN-509-003 United States Urology Cancer Center and GU Research Network 17607 Gold PlazaOmaha, Nebraska 68130 United States

ARN-509-003 United States Cancer Center of Kansas 818 North Emporia StreetWichita, Kansas 67214 United States

ARN-509-003 United States Oregon Health and Science University 3181 Southwest Sam Jackson Park RoadPortland, Oregon 97239-3079 United States

ARN-509-003 United States University of Cincinnati 200 Albert Sabin WayCincinnati, Ohio 45267-0502 United States

ARN-509-003 United States Five Valleys Urology 2875 Tina Avenue Missoula Missoula, MT 59808 United States

ARN-509-003 United States Seattle Urology Research Center 16259 Sylvester Road Southwest Burien, 98166


United States

ARN-509-003 United States UCLA School of Medicine-Division of Hem/Onc 300 Stein PlazaLos Angeles, California 90095 United States

ARN-509-003 United States Henry Ford Health System 2799 West Grand Boulevard, Pallister Place T-139Detroit, Michigan 48202 United States

ARN-509-003 United States PMG Research of Winston-Salem 1901 South Hawthorne RoadWinston-Salem, North Carolina 27103 United States

ARN-509-003 United States Morristown Medical Center Pharmacy Garden State Urology, 261 James StreetMorristown, New Jersey 07960 United States

ARN-509-003 United States Delaware Valley Urology 15000 Midlantic DriveMount Laurel, New Jersey 08054 United States

ARN-509-003 United States John Theurer Cancer Center 30 Prospect AvenueHackensack, New Jersey 07601 United States

ARN-509-003 United States University of California Irvine Medical Center Dept. of Urology, 333 City Boulevard West Suite 2100- 92868 United States

ARN-509-003 United States Idaho Urologic Institute 2855 East Magic View Drive Meridian 83642 United States

ARN-509-003 United States Fox Chase Cancer Center 333 Cottman AvenuePhiladelphia, Pennsylvania 19111-2434 United States

ARN-509-003 United States The Urology Center of Colorado 2777 Mile High Stadium CircleDenver, Colorado 80211 United States

ARN-509-003 United States Georgis Patsias, MD, PA 3347 State Road 7Wellington, Florida 33449


United States

ARN-509-003 United States Ralph H. Johnson Veterans Affairs Medical Center 96 Jonathan Lucas Street, CSB 644, MSC 620Charleston, South Carolina 29425 United States

ARN-509-003 United States San Antonio Military Medical Center 3551 Roger Brooke Drive Fort Sam, Houston 78234 United States

ARN-509-003 United States Associated Medical Professionals of NY, PLLC (AMP) 1226 East Water StreetSyracuse, New York 13210 United States

ARN-509-003 United States Kansas City Veterans Affairs Medical Center 4801 Linwood Boulevard, Mail Stop 151Kansas City, Missouri 64128 United States

ARN-509-003 United States Urology Centers of Alabama 3485 Independence DriveHomewood, Alabama 35209 United States

ARN-509-003 United States Alaska Clinical Research Center 188 West Northern Lights BoulevardAnchorage, Alaska 99503 United States

ARN-509-003 United States PMG Research of Salisbury 410 Mocksville Avenue Salisbury 28144 United States

ARN-509-003 United States Florida Cancer Affiliates – Trinity 433 Southwest 10th Street Ocala 34474 United States

ARN-509-003 United States Texas Oncology - Baylor Charles A. Sammons Cancer Center 1901 South 2nd Street McAllen 78503-1298 United States

ARN-509-003 United States Texas Oncology - Houston Memorial City 925 Gessner RoadHouston ,Texas 77024 United States

ARN-509-003 United States USOR - Virginia Oncology Associates – Hampton 5900 Lake Wright DriveNorfolk, Virginia 23502


United States

ARN-509-003 United States New York Oncology Hematology - Amsterdam Cancer Center Dept. of Hematology Oncology, 43 New Scotland Avenue Albany 12204 United States

ARN-509-003 United States Comprehensive Cancer Centers of Nevada 3730 South Eastern AvenueLas Vegas, Nevada 89119 United States

ARN-509-003 United States Texas Oncology - Medical City Dallas Building C 7777 Forest LaneDallas 75230 United States

ARN-509-003 United States Morristown Medical Center, Carol G. Simon Cancer 100 Madison Avenue, Box 63 Morristown, NJ, 07962 United States

ARN-509-003 United States Northwest Cancer Specialists, P.C. 19260 Southwest 65th AvenueTualatin, Oregon 97062 United States

ARN-509-003 United States First Urology 101 Hospital BoulevardJeffersonville, Indiana 47130 United States

ARN-509-003 United States South Florida Medical Research 21150 Biscayne BoulevardAventura, Florida 33180 United States

ARN-509-003 United States Advanced Urology Institute 545 Health BoulevardDaytona Beach, Florida 32114 United States

ARN-509-003 United States Texas Oncology Austin Brain Tumor Center 1155 Pressler StreetHouston, Texas 77030 United States

ARN-509-003 United States San Bernardino Urological Associates 489 East 21st StreetSan Bernardino, Carolina 92404 United States

ARN-509-003 United States The Cancer Institute of New Jersey 1 Robert Wood Johnson PlaceNew Brunswick, New Jersey 08901-1928


United States

ARN-509-003 United States Breslin Cancer Center 401 West Greenlawn Avenue Lansing 48910 United States

ARN-509-003 United States Medical Faculty Associates, Inc. 2150 Pennsylvania Avenue NorthwestWashington, District of Columbia 20037 United States

ARN-509-003 United States Arizona Institute of Urology 5670 North Professional Park DriveTucson, Arizona 85704 United States

ARN-509-003 United States Lexington Urology 222 East Medical LaneWest Columbia, South Carolina 29169 United States

ARN-509-003 United States Montefiore-Einstein Center for Cancer Care 111 East 210th StreetBronx, New York 10467 United States

ARN-509-003 United States Houston Metro Urology 7777 Southwest FreewayHouston, Texas 77030 United States

ARN-509-003 United States San Diego Clinical Trials 5555 Reservoir DriveSan Diego, California 92120 United States

ARN-509-003 United States Maryland Oncology Hematology – Columbia 9905 Medical Center DriveRockville, Maryland 20850 United States

ARN-509-003 United States Urology of Indiana, LLC 12188A North Meridian StreetCarmel, Indiana 46032 United States

ARN-509-003 United States Greenville Health System - Main Campus 15 Park Creek Drive Greenville, 29605 United States

ARN-509-003 United States Ochsner Medical Center 1514 Jefferson HighwayNew Orleans, Louisiana 70121


United States

ARN-509-003 United States Eastern Urological Associates 275 Bethesda DriveGreenville, North Carolina 27834 United States

ARN-509-003 United States Skyline Urology 23456 Hawthorne BoulevardTorrance, California 90505 United States

ARN-509-003 United States Barbara Ann Karmanos Cancer Institute 4100 John R. Street, 4HWCRCDetroit, Michigan 48201-2013 United States

ARN-509-003 United States Midwest Urology RmD Clinical Research 675 West North AvenueMelrose Park, Illinois 60160 United States

ARN-509-003 United States VA Greater Los Angeles Healthcare System 11301 Wilshire Boulevard, Building 500Los Angeles, California 90073 United States

ARN-509-003 United States Virginia Mason Medical Center Sacred Heart Doctors Bldg, 105 W 8th Ave Ste 350ESpokane, Washington 99204-2302 United States

ARN-509-003 United States Alliance Urology Specialists 509 North Elam AvenueGreensboro, North Carolina 27403 United States

ARN-509-003 United States Saint Luke's Hospital - Duluth 915 East First Street, WhitesideDuluth, Minnesota 55805 United States

ARN-509-003 United States Sutter Institute for Medical Research 3 Medical Plaza DriveRoseville, California 95661 United States

ARN-509-003 United States Skyline Urology 5522 Sepulveda BoulevardSherman Oaks, California 91411-3437 United States

ARN-509-003 United States Urological Research Network 2140 West 68th Street Hialeah 33016


United States

ARN-509-003 United States Clinical Research Solutions - Corporate Office 6900 Pearl RoadMiddleburg Heights, Ohio 44130 United States

ARN-509-003 United States Urology Health Specialists 245 South Bryn Mawr AvenueBryn Mawr, Pennsylvania 19010 United States

ARN-509-003 United States West Cancer Center 7945 Wolf River BoulevardGermantown, Tennessee 38138 United States

ARN-509-003 United States Pinellas Urology 5747 38th North Avenue Saint Petersburg 33710 United States

ARN-509-003 United States The Iowa Clinic - West Des Moines Campus 5950 University AvenueWest Des Moines, Iowa 50266 United States

ARN-509-003 United States Manatee Medical Research Institute 200 3rd Avenue WestBradenton, Florida 34205 United States

ARN-509-003 United States Comprehensive Urology – Woodward 31157 Woodward AvenueRoyal Oak, Michigan 48073 United States

ARN-509-003 United States New Hampshire Oncology-Hematology PA 200 Technology DriveHooksett, New Hampshire 03106 United States

ARN-509-003 United States Sound Urological Associates 21822 76th Avenue West Edmonds 98026 United States

ARN-509-003 United States Omega Medical Research 400 Bald Hill RoadWarwick, Rhode Island 02886 United States

ARN-509-003 United States Mayo Clinic 4500 San Pablo Road South Jacksonville 32224


ARN-509-003 United States Signal Point Clinical Research Center 235 North Breiel Boulevard Middletown 45042 United States

ARN-509-003 United States Bend Memorial Clinic 1501 Northeast Medical Center DriveBend, Oregon 97701 United States

ARN-509-003 United States Saint Jude Heritage Health Foundation 2151 North Harbor BoulevardFullerton, California 92835 United States

ARN-509-003 United States Urology Associates – Nashville 2801 Charlotte AvenueNashville, Tennessee 37209 United States

ARN-509-003 United States Salisbury Foundation for Research and Education 1601 Brenner Ave (119)Salisbury, North Carolina 28144 United States

ARN-509-003 United States Virginia Urology 9101 Stony Point DriveRichmond, Virginia 23235 United States

ARN-509-003 United States Urology Associates 2525 W. University AvenueMunice, Indiana 47303 United States

ARN-509-003 United States Urology Group of New Mexico (UGNM) 4161 Montgomery Boulevard NortheastAlbuquerque, New Mexico 87109 United States

ARN-509-003 United States Washington University School of Medicine Siteman Cancer Center 660 South Euclid Avenue, Campus Box 8056St. Louis, Missouri 63110 United States

ARN-509-003 United States University of Illinois Chicago 1801 West Taylor StreetChicago, Illinois 60612 United States


Changes in Conduct:

The original protocol, dated 05 November 2012, was amended 8 times on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European Union.

Amendment INT-1, 11 January 2013 was considered as non-substantial amendment Amendment INT-2, 08 May 2013 was considered as substantial amendment Amendment INT-3, 11 March 2014 was considered as substantial amendment Amendment INT-4, 16 June 2014 was considered as substantial amendment Amendment INT-5, 01 July 2014 was considered as substantial amendment Amendment INT-6, 18 May 2015 was considered as substantial amendment Amendment INT-7, 15 March 2017 was considered as non-substantial amendment Amendment INT-8, 03 March 2019 was considered as substantial amendment

General Amendments

The second general Protocol Amendment 2 (Amendment INT-2), dated 08 May 2013 was released to remove ARN-509/placebo storage conditions from the protocol and presented that storage instructions were found on the packaging label. Modified the description of the frequency of tumor assessments with respect to randomization date rather than first dose of study drug. Clarified that subjects should remain on study until they have disease progression confirmed by blinded independent central review (BICR). If the subject discontinues treatment before confirmed disease progression, the schedule of tumor assessment (every 16 weeks from randomization) should continue until disease progression. Modified eligibility criteria. Clarif ication to definition of end of study treatment and end of study with respect to expected length of subject participation. Additional instructions were added regarding missed doses. Revised requirements for collection of concomitant medication information. Clarification regarding reporting of disease progression as serious adverse event (SAE), only disease progression with a fatal outcome should be reported as an SAE.

The third general Protocol Amendment 3 (Amendment INT-3), dated 11 March 2014 was released for the following reasons: to incorporate modifications to the statistical analysis plan for the secondary endpoints; incorporate provision of abiraterone acetate as subsequent therapy for eligible patients; addition of exploratory biomarkers; reduction of population pharmacokinetic sample collection and modification of the population pharmacokinetic (PK) analysis, and modification of the patient-reported outcomes analysis. Additional changes were also implemented based on Health Authority and Investigator feedback. Updated nonclinical and clinical data were also incorporated. Statistical analysis of the secondary endpoints was modified and were incorporate multiple testing method in agreement with the food and drug administration (FDA) proposal. Modification of the interim analysis of overall survival (OS), 2 interim analyses and 1 final analysis were planned. Added ‘other’ objectives and evaluations. Provision of abiraterone acetate as subsequent therapy for those patients who meet the protocol-specified eligibility criteria. Population PK sampling and analysis were modified. The number of sparse samples for population PK analysis were decreased as steady state of ARN-509 and metabolite ARN000308 could be reached within approximately 3 months. PK samples collected up to 24 months should be sufficient to characterize the kinetics of both compounds, and no relevant information would be obtained from later timepoints. Analysis of the metabolite ARN000066 is being removed as this is a minor metabolite in humans with minimal activity. Exploratory biomarker research were added to study the potential mechanisms of resistance to ARN-509. Based on limited published data, approximately 10% of patients with late stage disease might develop resistance over the course of treatment. There was no sufficient data to indicate whether resistance develops at a different frequency in patients with non-metastatic castration-resistant prostate cancer (NM-CRPC). In the original plan proposed to the Committee for Medicinal Products for Human Use (CHMP) and FDA, a sample size of 300 patients was considered sufficient. Based on follow-up advice from the FDA and assuming lower frequencies of mutation emergence in the NM-CRPC, the number of samples were


increased from 300 to 400 in order to have sufficient power for correlative analysis based on calculation on a sliding scale. To capture the F876L mutation status in patients progressing in the later course of treatment, the collection of samples were modified to include Day 1 of Cycle 36, the Day 1 of Cycle 6 assessment were removed. The previous patient-reported outcomes analysis incorporated a 16-point improvement in the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score as the definition for a health-related quality of life improvement. Improvement of the total score was not applicable for this study population. The magnitude of a clinically meaningful change were redefined. The completion of the PRO questionnaires were reduced after Cycle 13 to every other cycle to relieve the burden to the patient and for consistency with other Sponsor protocols. Added second progression-free survival (PFS2) as an evaluation per agreement with health authorities. Inclusion criterion was modified for consistency and based on Investigator feedback. Inclusion of patients with documented Gilbert’s disease were allowed. Bone sparing therapies indicated for the treatment of skeletal events due to bone metastases were not allowed as concurrent therapy. Exclusion criterion was modified to clarify that a history of distant metastases was also exclusionary. Inclusion Criterion was modified to clarify the criteria for eligibility following previous anti-androgen treatment to include the 4 week washout period prior to randomization and documented prostate specific antigen (PSA) progression. Inclusion Criteria to clarify that prior estrogen treatment discontinuation was irrespective of dose used. Clarified that patients with a history of uncontrolled blood pressure were eligible if controlled with anti-hypertensive treatment. Gonadotropin releasing hormone analogs (GnRHa) (or surgical castration) for patients was required as a concomitant therapy and should be continuous throughout treatment. Per Sponsor policy adverse events (AEs) should be collected from the signing of the informed consent form. Analysis of vital signs and concomitant medications should be under safety evaluations and not under other evaluations. Clarification that patients were expected to be treated with local standard of care before enrollment. Rescreening information for screen failures were added. Timing of tumor assessments and collection of blood for thyroid stimulating hormone (TSH), testosterone, and fasting lipid panel was modified from every 16 weeks starting from the date of randomization to starting from Cycle 1 Day 1. Urinalysis were removed as a required laboratory assessment. Incorporated the Danish Health Authority request for inclusion of detailed methods of contraception and required duration of contraceptive methods or donation of sperm after discontinuation of the study drug. Updated nonclinical data and clinical information. The protocol had no information regarding product quality complaint handling. Added a Product Quality Complaint section to the protocol. Patient initials were not be used for any documents in this study. Per request of Danish Health Authority, investigator responsibilities section were updated to include a Declaration of Helsinki statement. Wording consistent with the current Sponsor template were incorporated. Added instruction that subsequent ECG readings should be collected using same position as the baseline reading. Protocol violation forms does not exist. At the time for the final analysis OS, a decision was made regarding whether or not an amendment of the protocol might be needed. Time from screening to randomization were increased from 28 days to 35 days because the required 28 day washout period for eligibility were not allowing enough time to complete screening assessments in some patients. The time from randomization to Cycle 1 Day 1 were also increased by 1 day from 3 days to 4 days to accommodate unforeseen delays due to holidays, weather, etc. Laboratory assessments deemed nonessential for safety or efficacy were removed. PSA was listed under the wrong column. The approximate number of sites had increased from 250 to 330. Additional eligibility criteria for participation in the QT substudy were incorporated. Holter monitoring assessment included at Screening. Informed consent requirement were previously not included in the Schedule of Activities for Screening. Inclusion of all criteria in the synopsis was unnecessary. Clarified that pomegranate was excluded (not just juice). Added that a patient eligibility form must be completed and submitted to the medical monitor before randomization. In order to avoid a protocol amendment in the case where contact information may change, the contact information was removed. The Schedule of Events was confusing to follow and not well organized. Modified wording throughout the document for conciseness or clarity. Minor errors were noted.

The fourth general Protocol Amendment 4 (Amendment INT-4), dated 16 June 2014 was released to incorporate investigator feedback for Inclusion criteria in order to clarify the definitions of prostate specific antigen doubling time (PSADT) and castration-resistance so that the intended homogenous and high-risk patient population was enrolled. The addition of an optional prescreening period is being incorporated to allow investigators time to obtain the required number of PSA values for meeting the study eligibility criteria. The window of requiring PSA values collected within 6 months prior to randomization for


calculation of the PSADT had the unintended consequence of excluding patients who were otherwise eligible, but who might have had one or more of the required PSAs collected outside the 6 month window. Currently, we were asking sites to continue to monitor and collect more recent PSAs from these patients; this delay increased the risk of screen fails as these patients were at high risk for metastasis. This requirement window had been removed from Inclusion criterion and a reference to the protocol, which details the calculation of PSADT for eligibility, have been added. Inclusion criterion required that castration resistant prostate cancer was defined as 3 consecutive rises of PSA. This was not consistent with the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria, and has the unintended consequence of excluding patients who were otherwise eligible, but who have had one or more PSA in a consecutive sequence not rise although there may be 3 rises in total. Currently, we were asking sites to continue to monitor and collect more PSAs until the three consecutive rises are met; this delay increases the risk of screen fails as these patients were at high-risk for metastasis. The requirement for two 50% increases of PSA above the nadir is also considered too stringent and was not consistent with the PCWG2 criteria. The washout period following anti-androgen might be longer than 4 weeks depending on the anti-androgen. Clarif ied that the washout period must be at least 4 weeks. Sampling for PSA might not be frequent enough at some sites. In order to ensure eligible patients were not “missed”, the patient might be asked to participate in the optional Prescreening Phase and sign a prescreening informed consent. The prescreening PSA evaluations would be performed by a local laboratory. As no study medication is being introduced at this point, only collection of serious adverse events related to the PSA blood draw were collected. The description of androgen deprivation therapy as androgen deprivation therapy (ADT)/post -surgery castration was redundant, wording were revised, as applicable. The term radiographic progression-free survival (rPFS) or PFS originated with the ZYTIGA COU-AA-302 study and had specific criteria for the determination of radiographic progression that was not applicable to the patient population in this study. To avoid confusion, the term radiographic PFS or rPFS is being revised to progression free survival or PFS. Aminoglutethimide was erroneously included under Inclusion Criterion and should be under Exclusion Criterion. Update to pregnancy section for consistency with the Janssen Template wording. Clarified timing of submitting the formalin-fixed paraffin-embedded (FFPE) archival tumor samples or slides. The number of sites was planned to increase. Fasting period requirement for the ventricular repolarization study was very long, subjects would be now be allowed to have an approved snack. Minor errors or clarifications were noted. The fifth general Protocol Amendment 5 (Amendment INT-5), dated 1 July 2014 was released to incorporate a time cutoff for the earliest prostate specific antigen (PSA) values used in the calculation of PSA doubling time (PSADT). NOTE: Amendment INT-4 was never implemented and has been superseded by Amendment INT-5. The only change that affects study conduct between Amendments INT-5 and INT-4 was the addition of a 24 month collection time period during which PSA values used to calculate the PSADT could be obtained. This change was made shortly after finalization of the previous amendment. All changes had been incorporated, as appropriate, into the protocol text. The previous amendment did not include information on a timeframe for PSA values that should be used for the calculation of PSADT. A collection period during which PSA values used to calculate the PSADT could be obtained, was now specified. Therefore, this amendment would incorporate a cutoff that allows inclusion of PSA values collected within 24 months prior to the subject’s randomization. Minor revision for consistency with Janssen Research & Development protocol template to numbering of eligibility criteria. Removed the inclusion of the number of sites as this information was not necessary in the protocol and was subject to change. The sixth general Protocol Amendment 6 (Amendment INT-6), dated 18 May 2015 was released to switch softgel capsules to tablets (commercial formulation) for patients currently receiving the softgel capsules and to administer tablets to newly enrolled patients. Added the restriction that did not apply in Japan Switch of softgel capsules to tablets was incorporated. Vitamin E was not included in the tablet formulation. The twice daily dosing was no longer relevant for the tablet formulation. Revised treatment compliance to account for capsules or tablets. The Statistical Analysis Plan would include additional analyses for safety and for the primary endpoint by formulation subgroup. The population PK analysis would include an additional analysis to explore the effect of the formulation switch. To clarify that patients who experience loco-regional tumor progression should continue on study drug until documentation of distant metastatic disease.


Local therapies such as surgery or radiation were allowed with study treatment. This was not clearly stated in the protocol. To incorporate a local restriction in Japan into the global protocol in order to avoid the need for a separate country-specific protocol. The Sponsor would not provide abiraterone acetate as subsequent therapy. It was not necessary to administer study drug within 1 hour onsite after the trough PK sampling. Patients who have a delay of study drug administration for greater than or equal to (>=) 28 days due to toxicity would no longer automatically meet the criteria for discontinuation from the study. Changes were made to improve clarity or correct errors.

The eighth general Protocol Amendment 8 (Amendment INT-8), dated 15 March 2017 was released to revise the statistical sections of the protocol. The current statistical analysis plan for analysis of secondary endpoints lacks power given the projected low event rates; therefore, the Sponsor was revising the multiple testing procedure for the secondary endpoints. In addition, text was added to allow, in the event of a positive study result and unblinding, for subjects receiving placebo to begin receiving active therapy with apalutamide. Added details for placebo subjects to begin receiving active treatment with apalutamide, in the event of a positive study result and the study was unblinded. Changed ‘is’ to ‘was’ to clarify that the text in this section reflects thinking at the time the original protocol was written; deleted text that is no longer applicable. Correction of the median OS time in the study population. Correction was made to note that email can be used for reporting of SAEs in addition to fax. Clarification for criteria of disease progression for administration of subsequent therapy with abiraterone acetate, if the study was unblinded. Minor errors were corrected, minor revisions were made.

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SYNOPSIS - DIMDI

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