Back to resultsSafety, 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
Primary Purpose
Metastatic Castrate-Resistant Prostate Cancer
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Alobresib
Enzalutamide
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Castrate-Resistant Prostate Cancer
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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Alobresib Dose Escalation
Alobresib + Enzalutamide Dose Escalation
Alobresib Dose Expansion (Group 1)
Alobresib + Enzalutamide Dose Expansion (Group 2)
Alobresib + Enzalutamide Dose Expansion (Group 3)
Arm Description
Participants who have progressed on either abiraterone and/or enzalutamide will be enrolled to receive increasing doses of alobresib up to 9 mg to determine the MTD.
Following a two week lead-in with enzalutamide once daily, participants who have progressed on abiraterone will receive less than or equal to MTD of alobresib in combination with enzalutamide 160 mg once daily. Based on observed pharmacokinetics (PK) interaction, toxicity, and tolerability observed in the single agent dose escalation, the dose of alobresib may be increased.
Participants will receive a dose less than or equal to MTD of alobresib (based on safety, pharmacodynamics (PD), and tolerability).
Participants will receive a dose less than or equal to MTD of alobresib plus enzalutamide (based on safety, PD, and tolerability).
Participants will receive alobresib plus enzalutamide (dose will be equivalent to the dose chosen for Group 2).
Outcomes
Primary Outcome Measures
Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs)
A DLT was a toxicity, considered possibly related to alobresib, and which occurred during the DLT assessment window (Days 1 through 28) in each cohort: Grade ≥ 4 neutropenia (absolute neutrophil count (ANC) < 500/mm^3), Grade ≥ 3 neutropenia (ANC< 1000/mm^3) with fever (a single temperature > 38.3°C or a sustained temperature of ≥ 38°C for more than 1 hour (h)), Grade ≥ 3 thrombocytopenia, Grade ≥ 2 bleeding (eg, gastrointestinal, respiratory, epistaxis, purpura), Grade ≥ 3 non hematologic toxicity, except- Grade 3 nausea or emesis with maximum duration of 48 h on adequate medical therapy and Grade 3 diarrhea which persists for < 72 h in the absence of maximal medical therapy, Grade ≥ 2 non hematologic treatment emergent adverse event (TEAE) that in the opinion of the investigator was of potential clinical significance such that further dose escalation would expose participants to unacceptable risk, treatment interruption ≥ 7 days due to unresolved toxicity.
Phase 2 Dose Expansion: Non-progression Rate at Week 24 According to Prostate Cancer Working Group (PCWG2) Criteria
The non-progression rate at Week 24 was defined as the proportion of participants who did not progress by Week 24.
Secondary Outcome Measures
Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib
Cmax is the maximum observed concentration of drug in plasma.
Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib
Ctau is the observed concentration of drug in plasma at the end of dosing.
Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib
AUClast is the concentration of drug over time zero to last concentration (area under the plasma concentration versus time curve).
Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib
AUCtau is defined as the concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib
Tmax is the time observed for the Cmax of alobresib.
Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12
PSA response was defined as percentage of participants with ≥ 30% decline in PSA from baseline by 12 weeks.
Progression Free Survival (PFS)
PFS was 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. PCWG2 criteria for progression was determined as 'Decline from baseline' when record start of therapy to first prostate-specific antigen (PSA) increase that is ≥ 25% and ≥ 2 ng/mL above the nadir and confirmed by a second value 3 or more weeks later; 'No decline from baseline' when PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks.
Overall Survival (OS)
OS is defined as the interval from first dose date of study drug to death from any cause.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02607228
Brief Title
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
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Terminated
Study Start Date
December 8, 2015 (Actual)
Primary Completion Date
October 25, 2017 (Actual)
Study Completion Date
September 3, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Castrate-Resistant Prostate Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
31 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Alobresib Dose Escalation
Arm Type
Experimental
Arm Description
Participants who have progressed on either abiraterone and/or enzalutamide will be enrolled to receive increasing doses of alobresib up to 9 mg to determine the MTD.
Arm Title
Alobresib + Enzalutamide Dose Escalation
Arm Type
Experimental
Arm Description
Following a two week lead-in with enzalutamide once daily, participants who have progressed on abiraterone will receive less than or equal to MTD of alobresib in combination with enzalutamide 160 mg once daily. Based on observed pharmacokinetics (PK) interaction, toxicity, and tolerability observed in the single agent dose escalation, the dose of alobresib may be increased.
Arm Title
Alobresib Dose Expansion (Group 1)
Arm Type
Experimental
Arm Description
Participants will receive a dose less than or equal to MTD of alobresib (based on safety, pharmacodynamics (PD), and tolerability).
Arm Title
Alobresib + Enzalutamide Dose Expansion (Group 2)
Arm Type
Experimental
Arm Description
Participants will receive a dose less than or equal to MTD of alobresib plus enzalutamide (based on safety, PD, and tolerability).
Arm Title
Alobresib + Enzalutamide Dose Expansion (Group 3)
Arm Type
Experimental
Arm Description
Participants will receive alobresib plus enzalutamide (dose will be equivalent to the dose chosen for Group 2).
Intervention Type
Drug
Intervention Name(s)
Alobresib
Other Intervention Name(s)
GS-5829
Intervention Description
Tablet administered orally once daily.
Intervention Type
Drug
Intervention Name(s)
Enzalutamide
Other Intervention Name(s)
XTANDI®
Intervention Description
Capsules administered orally once daily.
Primary Outcome Measure Information:
Title
Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs)
Description
A DLT was a toxicity, considered possibly related to alobresib, and which occurred during the DLT assessment window (Days 1 through 28) in each cohort: Grade ≥ 4 neutropenia (absolute neutrophil count (ANC) < 500/mm^3), Grade ≥ 3 neutropenia (ANC< 1000/mm^3) with fever (a single temperature > 38.3°C or a sustained temperature of ≥ 38°C for more than 1 hour (h)), Grade ≥ 3 thrombocytopenia, Grade ≥ 2 bleeding (eg, gastrointestinal, respiratory, epistaxis, purpura), Grade ≥ 3 non hematologic toxicity, except- Grade 3 nausea or emesis with maximum duration of 48 h on adequate medical therapy and Grade 3 diarrhea which persists for < 72 h in the absence of maximal medical therapy, Grade ≥ 2 non hematologic treatment emergent adverse event (TEAE) that in the opinion of the investigator was of potential clinical significance such that further dose escalation would expose participants to unacceptable risk, treatment interruption ≥ 7 days due to unresolved toxicity.
Time Frame
Day 1 through Day 28
Title
Phase 2 Dose Expansion: Non-progression Rate at Week 24 According to Prostate Cancer Working Group (PCWG2) Criteria
Description
The non-progression rate at Week 24 was defined as the proportion of participants who did not progress by Week 24.
Time Frame
Week 24
Secondary Outcome Measure Information:
Title
Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib
Description
Cmax is the maximum observed concentration of drug in plasma.
Time Frame
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
Title
Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib
Description
Ctau is the observed concentration of drug in plasma at the end of dosing.
Time Frame
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
Title
Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib
Description
AUClast is the concentration of drug over time zero to last concentration (area under the plasma concentration versus time curve).
Time Frame
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
Title
Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib
Description
AUCtau is defined as the concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Time Frame
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
Title
Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib
Description
Tmax is the time observed for the Cmax of alobresib.
Time Frame
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
Title
Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12
Description
PSA response was defined as percentage of participants with ≥ 30% decline in PSA from baseline by 12 weeks.
Time Frame
Baseline; Week 12
Title
Progression Free Survival (PFS)
Description
PFS was 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. PCWG2 criteria for progression was determined as 'Decline from baseline' when record start of therapy to first prostate-specific antigen (PSA) increase that is ≥ 25% and ≥ 2 ng/mL above the nadir and confirmed by a second value 3 or more weeks later; 'No decline from baseline' when PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks.
Time Frame
Up to approximately 4 years
Title
Overall Survival (OS)
Description
OS is defined as the interval from first dose date of study drug to death from any cause.
Time Frame
Up to approximately 4 years
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
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
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