E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic castrate-resistant prostate cancer |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic castration-resistant prostate cancer |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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. |
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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 |
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E.2.3 | Trial contains a sub-study | No |
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 |
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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 |
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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. |
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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. |
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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. |
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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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Dose escalation, dose expansion |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 | No |
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 |
Belgium |
France |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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End of study for a subject is defined as the date of the last study-related procedure or the date of death for an on-study subject. |
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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 | 35 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 35 |