Clinical Trials Register

Summary
EudraCT Number:	2012-004322-24
Sponsor's Protocol Code Number:	ARN-509-003
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-09-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2012-004322-24

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Clinical study to assess the safety and effectiveness of ARN-509 in men with Castration-Resistant Prostate Cancer (prostate cancer not responsive to castration treatment)

A.3.2

Name or abbreviated title of the trial where available

SPARTAN

A.4.1

Sponsor's protocol code number

ARN-509-003

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Aragon Pharmaceuticals, Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Janssen Research & Development
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Aragon Pharmaceuticals, Inc
B.5.2	Functional name of contact point	VP, Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	12780 El Camino Real, Suite 301
B.5.3.2	Town/ city	San Diego
B.5.3.3	Post code	CA 92130
B.5.3.4	Country	United States
B.5.4	Telephone number	+1858369 7627
B.5.5	Fax number	+1858639 7662
B.5.6	E-mail	ecmaneval@aragonpharm.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	ARN-509
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Apalutamide
D.3.9.1	CAS number	956104-40-8
D.3.9.3	Other descriptive name	JNJ-56021927-AAA
D.3.9.4	EV Substance Code	SUB127215
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	ARN-509
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Apalutamide
D.3.9.1	CAS number	956104-40-8
D.3.9.3	Other descriptive name	JNJ-56102927-AAA
D.3.9.4	EV Substance Code	SUB127215
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Castration-Resistant Prostate Cancer

E.1.1.1

Medical condition in easily understood language

Prostate cancer with rapidly rising PSA not responsive to hormonal treatment.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10036909
E.1.2	Term	Prostate cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate superiority in the metastasis-free survival (MFS) of men with high risk NM-CRPC treated with Apalutamide versus placebo

E.2.2

Secondary objectives of the trial

To compare the overall survival (OS) of men with high risk NM-CRPC treated with Apalutamide versus placebo and:
 To compare the time to symptomatic progression in men with high risk NM-CRPC treated with Apalutamide versus placebo
 To compare the time to initiation of cytotoxic chemotherapy in men with high risk NM-CRPC treated with Apalutamide versus placebo
 To compare the progression-free survival (PFS) of men with high risk NM-CRPC treated with Apalutamide versus placebo
 To compare the time to metastasis (TTM) in men with high risk NM-CRPC treated with Apalutamide versus placebo
 To evaluate the safety and tolerability of Apalutamide

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

VENTRICULAR REPOLARIZATION SUB-STUDY: (Appendix 8, Protocol Version 3.0 08 May 2013)
To evaluate the effect of Apalutamide on ventricular repolarization in a subset of patients from selected clinical sites. The effect of Apalutamide on ventricular repolarization will be centrally analyzed by a third-party cardiac safety laboratory in a subset of 100 patients enrolled at selected sites that will be participating in the main protocol. Both Apalutamide and placebo patients will be enrolled in a blinded manner as per the main protocol randomization criteria.
-The primary objective of this sub-study is to evaluate whether Apalutamide has a threshold pharmacological effect on cardiac repolarization, as detected by changes in electrocardiogram (ECG) QT intervals corrected for heart rate by Fridericia’s correction method (QTcF)
-The secondary objectives of this study sub-study are as follows:
-To investigate the effect of Apalutamide on the following ECG parameters: PR, RR, QRS, QT, QTcB (Bazett’s correction method), and T-Wave morphology
-To further characterize the pharmacokinetic (PK) profile of Apalutamide and to assess the exposure-effect relationships (if any) between Apalutamide plasma concentrations and ECG interval change

E.3

Principal inclusion criteria

1. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features, with high risk for development of metastases, defined as PSADT ≤ 10 months. PSADT is calculated using at least 3 PSA values obtained during continuous ADT (see Section 5.1).
2. Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 3 PSA rises at least 1 week apart, with the last PSA > 2 ng/mL
3. Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the patient is medically castrated, continuous dosing with GnRHa must have been initiated at least 4 weeks prior to randomization and must be continued throughout the study to maintain castrate levels of testosterone.
4.Patients receiving bone loss prevention treatment with bone-sparing agents indicated for the treatment of osteoporosis at doses and dosing schedule appropriate for the treatment of osteoporosis (e.g., denosumab [Prolia®], zoledronic acid [Reclast®]) must be on stable doses for at least 4 weeks prior to randomization.
5. Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) must have at least a 4-week washout prior to randomization AND must show continuing disease (PSA) progression (an increase in PSA) after washout.
6. At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors (e.g., dutasteride, finasteride), estrogens (irrespective of dose used), and any other anti-cancer therapy prior to randomization, including chemotherapy given in the adjuvant/neoadjuvant setting (e.g., clinical trial)
7. At least 4 weeks must have elapsed from major surgery or radiation therapy prior to randomization
8. Age ≥ 18 years
9. Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1
10. Resolution of all acute toxic effects of prior therapy or surgical procedure to Grade 1 or baseline prior to randomization
11. Adequate organ function as defined by the following criteria:
-Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal (ULN)
-Total serum bilirubin ≤1.5 x ULN. Total serum bilirubin >1.5 x ULN is allowed if Gilbert’s disease is documented prior to end of screening procedures
-Serum creatinine ≤ 2 x ULN
-Absolute neutrophil count (ANC) ≥ 1500/μL
-Platelets ≥ 100,000/μL
-Hemoglobin ≥ 9.0 g/dL
-Administration of growth factors or blood transfusions will not be allowed within 4 weeks of the hematology labs required to confirm eligibility
12. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to randomization
13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory and radiographic assessments, and other study procedures, including ability to swallow study drug tablets, the completion of patient reported outcomes questionnaires and long-term follow-up visits
Eligibility Criteria for Placebo Subjects to Crossover to Open Label Apalutamide:
1a. Subject is willing and able to provide written informed consent to crossover to open-label apalutamide
2a. Subject has adequate organ function as defined by the following criteria:
-Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal (ULN)
-Total serum bilirubin ≤1.5 x ULN
-Total serum bilirubin >1.5 x ULN is allowed if Gilbert's disease has been previously documented
-Serum creatinine ≤ 2 x ULN
-Absolute neutrophil count (ANC) ≥ 1500/L
-Platelets ≥ 100,000/L
-Hemoglobin ≥ 9.0 g/dL
3a. Subject has not received any other systemic therapy for non- metastastic castrate resistant prostate cancer other than blinded study drug and androgen deprivation therapy.
4a. Subjects who have previously had an end of treatment visit and evidence of distant metastasis from the blinded independent central reviewer will not be eligible for open label apalutamide.
5a. Subjects who had study treatment withheld for ≥28 consecutive days at the time of unblinding will need approval from the medical monitor to be eligible for crossover.

E.4

Principal exclusion criteria

1.Presence of distant metastases confirmed by blinded independent central review (BICR), including CNS and vertebral or meningeal involvement, or history of distant metastases. Exception: Pelvic lymph nodes <2 cm in short axis (N1) located below the iliac bifurcation are allowed
2. Symptomatic loco-regional disease requiring medical intervention, such as moderate or severe urinary obstruction or hydronephrosis due to primary tumor (e.g., tumor obstruction of bladder trigone)
3. Prior treatment with second generation anti-androgens (e.g., enzalutamide)
4. Prior treatment with CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galerterone, ketoconazole, aminoglutethimide)
5. Prior treatment with radiopharmaceutical agents (e.g., Strontium-89), immunotherapy (e.g., sipuleucel-T), or any other investigational agent for NM-CRPC
6. Prior chemotherapy for prostate cancer except if administered in the adjuvant/neoadjuvant setting
7. History of seizure or condition that may pre-dispose to seizure (e.g., stroke within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)
8. Concurrent therapy with any of the following (all must have been
discontinued or substituted for at least 4 weeks prior to randomization):
 Medications known to lower the seizure threshold (for a complete list please see Appendix 5)
 Herbal (e.g. saw palmetto) and non-herbal (e.g. pomegranate) products that may decrease PSA levels
 Systemic (oral/IV/IM) corticosteroids. Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated, but it should be tapered off as soon as possible
 Any other experimental treatment on another clinical trial
 Agents indicated for the prevention of skeletal-related events in patients with solid tumors (e.g., denosumab [Xgeva®])
9. History or evidence of any of the following conditions:
 Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization
 Any of the following within 6 months prior to randomization: Severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias
 Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP≥100 mmHg). Patients with a history of uncontrolled hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
 Gastrointestinal disorder affecting absorption
 Active infection, such as human immunodeficiency virus (HIV)
 Any other condition that, in the opinion of the Investigator, would impair the patient’s ability to comply with study procedures.

E.5 End points

E.5.1

Primary end point(s)

Metastasis-Free Survival (MFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

MFS data for patients without metastasis or death will be censored on the date of the last tumor assessment (or, if no tumor assessment was performed after the baseline visit, at the date of randomization + 1 day).
Tumor assessments will be performed at baseline and at 16-week intervals from randomization. Imaging studies will include a CT scan of the chest, abdomen, and pelvis, plus a bone scan.

E.5.2

Secondary end point(s)

For the secondary endpoints, a hierarchical testing will be performed in the following order:
-Time to Metastasis (TTM)
-Progression-Free Survival (PFS)
-Time to symptomatic progression
-Overall Survival (OS)
-Time to initiation of cytotoxic chemotherapy

E.5.2.1

Timepoint(s) of evaluation of this end point

OS (every 4 months via clinic visit or telephone contact)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

185

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Austria

Belgium

Canada

Czech Republic

Denmark

Finland

France

Germany

Hungary

Israel

Italy

Korea, Republic of

Netherlands

New Zealand

Norway

Poland

Russian Federation

Spain

Sweden

Taiwan

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Patients will remain on study until BICR-confirmed disease progression, development of unacceptable toxicity, or withdrawal of consent.
If the study is not terminated beforehand per the recommendation of the DMC, the end of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

360

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

840

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

640

F.4.2.2

In the whole clinical trial

1200

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients will be followed for at least 28 calendar days after the last dose of study drug. All patients discontinuing study treatment will enter the survival FU period and will be followed for the development of symptomatic progression and initiation of subsequent anti-cancer therapies every 4 months until death, loss of follow-up, or withdrawal of consent, whichever comes first. CROSSOVER: Patients randomized to placebo will be offered open-label treatment with apalutamide after unbliding.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-11-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-11-05

P. End of Trial
P.	End of Trial Status	Ongoing

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