Clinical Trials Register

Summary
EudraCT Number:	2015-003741-26
Sponsor's Protocol Code Number:	GS-US-350-1604
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-08-11
Trial results	View 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

Belgium - FPS Health-DGM

A.2

EudraCT number

2015-003741-26

A.3

Full title of the trial

A Phase 1b/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-5829 as a Single Agent and In Combination with Enzalutamide in Subjects with Metastatic Castrate-Resistant Prostate Cancer.

A.3.1

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

A phase 1 study to evaluate GS-5829 alone and in combination with enzalutamide in patients with metastatic castrate-resistant prostate cancer.

A.4.1

Sponsor's protocol code number

GS-US-350-1604

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	Gilead Sciences, 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	Gilead Sciences, Inc.
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	Gilead Sciences International Ltd.
B.5.2	Functional name of contact point	Clinical Trials Mailbox
B.5.3	Address:
B.5.3.1	Street Address	Flowers Building, Granta Park
B.5.3.2	Town/ city	Abington, Cambridge
B.5.3.3	Post code	CB21 6GT
B.5.3.4	Country	United Kingdom
B.5.5	Fax number	+441223897284
B.5.6	E-mail	clinical.trials@gilead.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	GS-5829
D.3.4	Pharmaceutical form	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	GS-5829
D.3.9.2	Current sponsor code	GS-5829
D.3.9.3	Other descriptive name	GS-5829
D.3.9.4	EV Substance Code	SUB182004
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	1
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	GS-5829
D.3.4	Pharmaceutical form	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	GS-5829
D.3.9.2	Current sponsor code	GS-5829
D.3.9.3	Other descriptive name	GS-5829
D.3.9.4	EV Substance Code	SUB182004
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	5
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic castrate-resistant prostate cancer

E.1.1.1

Medical condition in easily understood language

Metastatic castration-resistant prostate cancer

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10076506
E.1.2	Term	Castration-resistant prostate cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Dose Escalation: Characterize the safety/tolerability of GS-5829 as a single agent and in combination with enzalutamide (enz) in subjects with mCRPC; determine the MTD of GS-5829 as a single agent and in combination with enz in subjects with mCRPC
Dose Expansion:
Grp 1: Evaluate the efficacy of GS-5829 as a single agent in subjects with mCRPC who have progressed while receiving enz (may have also received abiraterone (abt)) as measured by Progression Rate (PR) at Wk 24 according to PCWG2;
Grp 2: Evaluate the efficacy of GS-5829 combined with enz in subjects with mCRPC who have progressed while receiving treatment with abt (subjects may not have previously received enz) as measured by PR at Wk 24 according to PCWG2;
Grp 3: Evaluate the efficacy of GS-5829 combined with enz in subjects with mCRPC who have had PSA progression, but not radiographic progression, while receiving treatment with enz (may have also previously received abt), as measured by PR at Wk 24 according to PCWG2.

E.2.2

Secondary objectives of the trial

Dose Escalation: Evaluate the pharmacokinetics (PK) of GS-5829 as a single agent and in combination with enz in subjects with mCRPC
Evaluate the efficacy of GS-5829 as a single agent and in combination with enz in subjects with mCRPC as measured by PCWG2
Dose Expansion:
Evaluate the safety and tolerability of GS-5829 as a single agent and in combination with enz in subjects with mCRPC
Grp 1: Evaluate the efficacy of GS-5829 in subjects with mCRPC who have progressed while receiving enz as measured by PSA at Wk 12, PFS and OS
Grp 2: Evaluate the efficacy of GS-5829 combined with enz in subjects with mCRPC who have progressed while receiving abiraterone as measured by PSA at Week 12, PFS and OS
Grp 3: Evaluate the efficacy of GS-5829 combined with enz in subjects with mCRPC who have had PSA progression, but not radiographic progression, while receiving enz as measured by PSA at Wk12, PFS and OS.l

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be
eligible for participation in this study:
Male aged 18 years and older
Histologically or cytologically confirmed prostate cancer (subjects with primary neuroendocrine carcinoma of prostate are excluded)
Phase 1b Monotherapy Dose Escalation: Subject must have documented progressive disease by meeting at least one of the PCWG2 criteria despite treatment with abiraterone and/or enzalutamide
Phase 1b Combination Therapy Escalation and Phase 2 Dose Expansion (Group 2): Subjects must have documented progressive disease by meeting at least one of the PCWG2 criteria, despite treatment with abiraterone. They may not have received prior enzalutamide or chemotherapy for mCRPC
Phase 2 Monotherapy Dose Expansion (Group 1): Subjects must have documented progressive disease by meeting at least one of the PCWG2 criteria, despite treatment with enzalutamide. They may have received prior abiraterone, but not prior chemotherapy, for mCRPC
Phase 2 Combination Therapy Dose Expansion (Group 3): Subjects must have documented progressive disease by meeting the PCWG2 criteria for PSA progression, but not radiographic progression, despite treatment with enzaluatimide. They may have received prior abiraterone, bit not prior chemotherapy, for mCRPC (similar to Group 1); however they must also have been on continuous enzalutamide therapy for at least 12 weeks prior to Cycle 1, Day 1
Castration-resistant disease defined as ongoing androgen deprivation therapy with GnRH analogue or bilateral orchiectomy and serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) at the screening visit. Subjects who have not had a bilateral orchiectomy must have a plan to maintain effective GnRH-analogue therapy for the duration of the trial
Metastatic disease documented by bone lesions on bone scan or by measurable soft tissue disease by CT/MRI. Subjects whose disease spread is limited to regional pelvic lymph nodes are not eligible
All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of study drug dosing (with the exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity [Grade 1 or 2 permitted])
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
Life expectancy of ≥ 3 months, in the opinion of the Investigator
Adequate organ function defined as follows: a) Hematologic: Platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0 g/dL; ANC ≥ 1.5 x 109/L (without platelet transfusion or any growth factors within previous 7 days of the hematologic laboratory values obtained at screening visit); b) Hepatic: AST / ALT ≤ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN); total or conjugated bilirubin ≤ 1.5 x ULN; c) Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min as calculated by the Cockroft-Gault method
Coagulation: International Normalized Ratio (INR) ≤ 1.2
Male subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception and refrain from sperm donation for at least 90 days
Able and willing to provide written informed consent to participate in the study

E.4

Principal exclusion criteria

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
History or evidence of clinically significant disorder, condition, or disease that, in the opinion of the Investigator or Medical Monitor would pose a risk to subject safety or interfere with the study evaluations, procedures, or completion
Known brain metastasis or leptomeningeal disease
Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, active or chronic bleeding event within 28 days prior to first dose of study drug, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician
A history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident and brain arteriovenous malformation are excluded from combination therapy with enzalutamide
Myocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of Cycle 1 Day 1
Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (ie, larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days of the first dose of study drug
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of GS-5829, including any unresolved nausea, vomiting, or diarrhea that is Common Terminology Criteria for adverse Events (CTCAE) Grade > 1
Minor surgical procedure(s) within 7 days of enrollment or randomization, or not yet recovered from prior surgery (placement of central venous access device, fine needle aspiration, or endoscopic biliary stent ≥ 1 day before enrollment or randomization is acceptable)
Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy) within 21 days or 5 half-lives, whichever is longer, of study drug dosing (6 weeks for nitrosoureas, mitomycin C, or molecular agents with t1/2 > 10 days); concurrent use of an LHRH agonist is permitted for all subjects and ongoing enzalutamide is required in group 3
History of a concurrent or second malignancy, except for: adequately treated local basal cell or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder cancer; breast carcinoma in situ; adequately treated Stage 1 or 2 cancer currently in complete remission; any other cancer that has been in complete remission for ≥ 5 years
History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (> 450 ms). Subjects who screen fail due to this criterion are not eligible to be re-screened
Prior exposure to bromodomain (BET) inhibitors
Clinically significant bleeding within 28 days of Cycle 1 Day 1
Known human immunodeficiency virus (HIV) infection
HBsAg positive
HCV antibody positive
Use of moderate/strong cytochrome P450 (CYP)3A4 inhibitors or moderate/strong CYP3A4 inducers within 2 weeks prior to the first dose of study drug (with the exception of enzalutamide in the combination arms)
Evidence of bleeding diathesis
History of hemoptysis of ≥ 2.5 mL/1 teaspoon within 6 months of Cycle 1 Day 1
History of high grade esophageal or gastric varices
Anticoagulation therapy within 7 days of Cycle 1 Day 1, including acetylsalicylic acid, low molecular weight heparin, or warfarin

E.5 End points

E.5.1

Primary end point(s)

Phase 1b Dose Escalation:
The primary endpoint of this study is incidence of Dose Limiting Toxicity as defined in the protocol.

Phase 2 Dose Expansion:
The primary endpoint is efficacy assessed as non-progression/progression rate at Week 24 according to PCWG2 Criteria.

E.5.1.1

Timepoint(s) of evaluation of this end point

Study visits will occur on Day 1, 8, 15 and 22 of Cycle 1. Visits will occur on Day 1 of Cycle 2 and week 4, followed by a visit every 12 weeks. A cycle is 28 days.

E.5.2

Secondary end point(s)

Phase 1b Dose Escalation:
Dose escalation subjects: PK parameters (Cmax, Ctau, AUClast, AUCtau, and Tmax) for GS-5829

Phase 1b Dose Escalation and Phase 2 Dose Expansion:
PSA response ≥ 30% decline in PSA from baseline at 12 weeks for Groups 1, 2 and 3
Progression free survival (PFS) defined as the interval from first dose date of study drug to the earlier of the first documentation of definitive disease progression (assessed per PCWG2) or death from any cause.

Phase 2 Dose Expansion:
Overall survival (OS) defined as the interval from first dose date of study drug to death from any cause.

E.5.2.1

Timepoint(s) of evaluation of this end point

Study visits will occur on Day 1, 8, 15 and 22 of Cycle 1. Visits will occur on Day 1 of Cycle 2 and week 4, followed by a visit every 12 weeks. A cycle is 28 days.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability.

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose escalation, dose expansion

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised