Clinical trial NCT02607228: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5829 (Alobresib) as a Single Agent and In Combination With Enzalutamide in Participants With Metastatic Castrate-Resistant Prostate Cancer
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Metastatic Castrate-Resistant Prostate Cancer
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2015-11-17
Enrollment: 31
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

The Dose Escalation phase will characterize the safety, tolerability, and determine the maximum tolerated dose (MTD) of alobresib 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 alobresib 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 alobresib 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 alobresib 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)


Eligibility 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 computerized tomography/magnetic resonance imaging (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 alobresib, 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
* Hepatitis B surface antigen (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.

Primary outcomes:
measure: Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs)
timeFrame: Day 1 through Day 28
measure: Phase 2 Dose Expansion: Non-progression Rate at Week 24 According to Prostate Cancer Working Group (PCWG2) Criteria
timeFrame: Week 24
Secondary outcomes:
measure: Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib
timeFrame: Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Days 1 and 15
measure: Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib
timeFrame: Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 15
measure: Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib
timeFrame: Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Days 1 and 15
measure: Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib
timeFrame: Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 15
measure: Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib
timeFrame: Monotherapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Day 8 and Cycle 2 Day 1; Combination therapy: Predose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours postdose on Cycle 1 Days 1 and 15
measure: Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12
timeFrame: Baseline; Week 12
measure: Progression Free Survival (PFS)
timeFrame: Up to approximately 4 years
measure: Overall Survival (OS)
timeFrame: Up to approximately 4 years
Other outcomes:
Locations:
city: San Francisco
country: United States
state: California
city: Baltimore
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Durham
country: United States
state: North Carolina
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References: