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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer

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ClinicalTrials.gov Identifier: NCT02607228
Recruitment Status : Active, not recruiting
First Posted : November 17, 2015
Last Update Posted : March 1, 2019
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:

This study consists of two phases: Dose Escalation (Phase 1b) and Dose Expansion (Phase 2)

The Dose Escalation phase will evaluate the safety and tolerability of GS-5829 as a single agent and in combination with enzalutamide, as well as determine the maximum tolerated dose (MTD) of GS-5829 as a single agent and in combination with enzalutamide in participants with metastatic castrate-resistant prostate cancer (mCRPC).

The Dose Expansion phase will evaluate the following:

  • In group 1, the efficacy of GS-5829 as a single agent in participants with mCRPC who have progressed while receiving enzalutamide (may have also received abiraterone)
  • In group 2, the efficacy of GS-5829 combined with enzalutamide in participants with mCRPC who have progressed while receiving treatment with abiraterone (may not have previously received enzalutamide)
  • In group 3, the efficacy of GS-5829 combined with enzalutamide in participants with mCRPC who have had Prostate Specific Antigen (PSA) progression, but not radiographic progression, while receiving treatment with enzalutamide (participants may have also previously received abiraterone)

Condition or disease Intervention/treatment Phase
Metastatic Castrate-Resistant Prostate Cancer Drug: GS-5829 Drug: Enzalutamide Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 8, 2015
Actual Primary Completion Date : October 25, 2017
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: GS-5829 Dose Escalation
Participants who have progressed on either abiraterone and/or enzalutamide will be enrolled to receive increasing doses of GS-5829 to determine the MTD.
Drug: GS-5829
GS-5829 tablet administered orally once daily

Experimental: GS-5829 + Enzalutamide Dose Escalation
Following a two week lead-in with enzalutamide once daily, participants who have progressed on abiraterone will receive GS-5829 in combination with enzalutamide once daily. Based on observed pharmacokinetics (PK) interaction, toxicity, and tolerability observed in the single agent dose escalation, the dose of GS-5829 may be increased.
Drug: GS-5829
GS-5829 tablet administered orally once daily

Drug: Enzalutamide
Enzalutamide capsules administered orally once daily
Other Name: XTANDI®

Experimental: GS-5829 Dose Expansion (Group 1)
Participants will receive ≤ the MTD of GS-5829 (based on safety, pharmacodynamics (PD), and tolerability).
Drug: GS-5829
GS-5829 tablet administered orally once daily

Experimental: GS-5829 + Enzalutamide Dose Expansion (Group 2)
Participants will receive ≤ the MTD of GS-5829 plus enzalutamide (based on safety, PD, and tolerability).
Drug: GS-5829
GS-5829 tablet administered orally once daily

Drug: Enzalutamide
Enzalutamide capsules administered orally once daily
Other Name: XTANDI®

Experimental: GS-5829 + Enzalutamide Dose Expansion (Group 3)
Participants will receive GS-5829 plus enzalutamide (dose will be equivalent to the dose chosen for Group 2).
Drug: GS-5829
GS-5829 tablet administered orally once daily

Drug: Enzalutamide
Enzalutamide capsules administered orally once daily
Other Name: XTANDI®




Primary Outcome Measures :
  1. For dose escalation, incidence of dose limiting toxicities (DLT) [ Time Frame: Up to 29 days ]
    A DLT is a toxicity which occurs during the DLT assessment window (Day 1 through Day 28) in each cohort

  2. For dose expansion, efficacy assessed as non-progression/progression rate at Week 24 according to prostate cancer working group (PCWG2) criteria [ Time Frame: Week 24 ]

Secondary Outcome Measures :
  1. For dose escalation, PK parameter: Cmax of GS-5829 [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose ]
    Cmax is defined as the maximum concentration of drug.

  2. For dose escalation, PK parameter: Ctau of GS-5829 [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

  3. For dose escalation, PK parameter: AUClast of GS-5829 [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose ]
    AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration.

  4. For dose escalation, PK parameter: AUCtau of GS-5829 [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose ]
    AUCtau is defined as concentration of drug over time.

  5. For dose escalation, PK parameter: Tmax of GS-5829 [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose ]
    Tmax is defined as the time (observed time point) of Cmax.

  6. Prostate-specific antigen (PSA) response defined as ≥ 30% decline in PSA from baseline at 12 weeks for Groups 1, 2, and 3 [ Time Frame: Baseline and Week 12 ]
  7. Progression free survival (PFS) [ Time Frame: Up to 3 years ]
    Progression free survival is 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.

  8. Overall survival (OS) [ Time Frame: Up to 3 years ]
    Overall survival is defined as the interval from first dose date of study drug to death from any cause.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Histologically or cytologically confirmed prostate cancer (individuals with primary neuroendocrine carcinoma of prostate are excluded)
  • Must have documented progressive disease by meeting at least one of the Prostate Cancer Working Group 2 Criteria
  • Castration resistant disease defined as ongoing androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) analogue or bilateral orchiectomy and serum testosterone level ≤ 1.73 nmol/l (50 ng/dL) at screening visit. Individuals 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. Patients whose disease spread is limited to regional pelvic lymph nodes are not eligible
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
  • Adequate organ function defined as follows:

    • Hematologic: Platelets ≥ 100 x 10^9/L; Hemoglobin ≥ 9.0 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (without platelet transfusion or any growth factors within previous 7 days of the hematologic laboratory values obtained at screening visit)
    • Hepatic: Aspartate transaminase (AST) / Alanine transaminase (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
    • 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

Key Exclusion Criteria:

  • Known brain metastasis or leptomeningeal disease
  • 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
  • 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
  • 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 luteinizing hormone releasing hormone (LHRH) agonist is permitted for all individuals and ongoing enzalutamide is required in Group 3.
  • History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (> 450 ms).
  • 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
  • Hepatitis C virus (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/antiplatelet therapy within 7 days of Cycle 1 Day 1, including low molecular weight heparin, or warfarin.

NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02607228


Locations
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United States, California
San Francisco, California, United States, 94158
United States, Maryland
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Boston, Massachusetts, United States, 02114
United States, North Carolina
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02607228     History of Changes
Other Study ID Numbers: GS-US-350-1604
2015-003741-26 ( EudraCT Number )
First Posted: November 17, 2015    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases