Metastatic Castrate-Resistant Prostate Cancer
Conditions
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)
Interventions
DRUGAlobresib
Tablet administered orally once daily.
DRUGEnzalutamide
Capsules administered orally once daily.
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | Day 1 through Day 28 | 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 | Week 24 | The non-progression rate at Week 24 was defined as the proportion of participants who did not progress by Week 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | 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 | 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 | 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 | 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 | 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 | Tmax is the time observed for the Cmax of alobresib. |
| Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | 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 | Cmax is the maximum observed concentration of drug in plasma. |
| Progression Free Survival (PFS) | Up to approximately 4 years | 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) | Up to approximately 4 years | OS is defined as the interval from first dose date of study drug to death from any cause. |
| Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | Baseline; Week 12 | PSA response was defined as percentage of participants with ≥ 30% decline in PSA from baseline by 12 weeks. |
| Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | 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 | Ctau is the observed concentration of drug in plasma at the end of dosing. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 4 study sites in the United States. The first participant was screened on 08 December 2015. The last study visit occurred on 03 September 2019. Phase 2 Dose Expansion of the study was not conducted. Results are reported for only Dose Escalation Monotherapy and Combination Therapy.
Pre-assignment details
43 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Monotherapy: Alobresib 2 mg Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 2 mg tablets administered orally once daily to determine the maximum tolerated dose (MTD). | 5 |
| Monotherapy: Alobresib 3 mg Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 3 mg tablets administered orally once daily to determine the MTD. | 4 |
| Monotherapy: Alobresib 4 mg Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 4 mg tablets administered orally once daily to determine the MTD. | 3 |
| Monotherapy: Alobresib 6 mg Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 6 mg tablets administered orally once daily to determine the MTD. | 6 |
| Monotherapy: Alobresib 9 mg Participants who had progressed on either abiraterone and/or enzalutamide, received alobresib 9 mg tablets administered orally once daily to determine the MTD. | 5 |
| Combination Therapy: Alobresib 3 mg + Enzalutamide Participants who had progressed on abiraterone, received alobresib 3 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily. | 6 |
| Combination Therapy: Alobresib 6 mg + Enzalutamide Participants who had progressed on abiraterone, received alobresib 6 mg tablets administered orally once daily in combination with enzalutamide 160 mg capsules administered orally once daily. | 2 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 0 | 1 | 1 | 1 |
| Overall Study | Investigator's Discretion | 0 | 0 | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Progressive Disease | 4 | 3 | 1 | 5 | 4 | 3 | 1 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrew Consent | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Monotherapy: Alobresib 2 mg | Monotherapy: Alobresib 3 mg | Monotherapy: Alobresib 4 mg | Monotherapy: Alobresib 6 mg | Monotherapy: Alobresib 9 mg | Combination Therapy: Alobresib 3 mg + Enzalutamide | Combination Therapy: Alobresib 6 mg + Enzalutamide | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 68.2 years STANDARD_DEVIATION 9.28 | 67.3 years STANDARD_DEVIATION 10.69 | 67.7 years STANDARD_DEVIATION 5.69 | 66.8 years STANDARD_DEVIATION 9.39 | 69.2 years STANDARD_DEVIATION 6.61 | 62.5 years STANDARD_DEVIATION 10.23 | 67.0 years STANDARD_DEVIATION 0 | 66.7 years STANDARD_DEVIATION 8.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 3 Participants | 6 Participants | 3 Participants | 5 Participants | 2 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 4 Participants | 4 Participants | 2 Participants | 6 Participants | 4 Participants | 5 Participants | 2 Participants | 27 Participants |
| Region of Enrollment United States | 5 Participants | 4 Participants | 3 Participants | 6 Participants | 5 Participants | 6 Participants | 2 Participants | 31 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 3 Participants | 6 Participants | 5 Participants | 6 Participants | 2 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 1 / 4 | 0 / 3 | 0 / 6 | 0 / 5 | 1 / 6 | 0 / 2 |
| other Total, other adverse events | 5 / 5 | 3 / 4 | 3 / 3 | 6 / 6 | 5 / 5 | 5 / 6 | 2 / 2 |
| serious Total, serious adverse events | 2 / 5 | 0 / 4 | 1 / 3 | 1 / 6 | 2 / 5 | 2 / 6 | 1 / 2 |
Outcome results
Primary
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.
Time frame: Day 1 through Day 28
Population: The DLT Analysis Set included all participants in the Safety Analysis Set who completed all treatment and safety procedures through Day 28, inclusive, or experienced a DLT prior to Day 28, exclusive.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Monotherapy: Alobresib 2 mg | Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
| Monotherapy: Alobresib 4 mg | Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | 1 Participants |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: Number of Participants Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
Primary
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.
Time frame: Week 24
Population: The Phase 2 Dose Expansion of the study was not conducted.
Secondary
Overall Survival (OS)
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
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Monotherapy: Alobresib 2 mg | Overall Survival (OS) | NA months |
| Monotherapy: Alobresib 3 mg | Overall Survival (OS) | NA months |
| Monotherapy: Alobresib 4 mg | Overall Survival (OS) | NA months |
| Monotherapy: Alobresib 6 mg | Overall Survival (OS) | NA months |
| Monotherapy: Alobresib 9 mg | Overall Survival (OS) | NA months |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Overall Survival (OS) | NA months |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Overall Survival (OS) | NA months |
Secondary
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.
Time frame: Baseline; Week 12
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Monotherapy: Alobresib 2 mg | Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | 0.0 percentage of participants |
| Monotherapy: Alobresib 3 mg | Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | 0.0 percentage of participants |
| Monotherapy: Alobresib 4 mg | Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | 33.3 percentage of participants |
| Monotherapy: Alobresib 6 mg | Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | 0.0 percentage of participants |
| Monotherapy: Alobresib 9 mg | Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | 0.0 percentage of participants |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | 0.0 percentage of participants |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Percentage of Participants Who Had ≥ 30% Reduction in Prostate Specific Antigen (PSA) From Baseline at Week 12 | 0.0 percentage of participants |
Secondary
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).
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
Population: Participants in the PK Analysis Set with available data were analyzed.~Monotherapy: Samples were not collected at Cycle 1 Day 1 and Cycle 1 Day 15; samples were only collected for participants who received alobresib 3 mg, 6 mg and 9 mg doses at Cycle 2 Day 1. Combination Therapy: Samples were not collected at Cycle 1 Day 8 and Cycle 2 Day 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monotherapy: Alobresib 2 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 8 | 4207.55 h*ng/mL | Standard Deviation 2319.854 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 2 Day 1 | 3264.79 h*ng/mL | Standard Deviation 2024.141 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 8 | 3742.30 h*ng/mL | Standard Deviation 2106.308 |
| Monotherapy: Alobresib 4 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 8 | 4646.08 h*ng/mL | Standard Deviation 890.441 |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 2 Day 1 | 1709.71 h*ng/mL | Standard Deviation 264.402 |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 8 | 3105.70 h*ng/mL | Standard Deviation 1008.73 |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 2 Day 1 | 10264.74 h*ng/mL | — |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 8 | 4494.79 h*ng/mL | Standard Deviation 4124.948 |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 15 | 652.7 h*ng/mL | Standard Deviation 395.52 |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 1 | 1026.99 h*ng/mL | Standard Deviation 359.22 |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 15 | 701.3 h*ng/mL | Standard Deviation 353.25 |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: AUClast: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Alobresib | Cycle 1 Day 1 | 1741.42 h*ng/mL | Standard Deviation 737.521 |
Secondary
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).
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
Population: Participants in the PK Analysis Set with available data were analyzed.~Monotherapy: Samples were not collected at Cycle 1 Day 15; samples were only collected for participants who received alobresib 3 mg, 6 mg and 9 mg doses at Cycle 2 Day 1. Combination Therapy: Samples were not collected at Cycle 1 Day 8 and Cycle 2 Day 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monotherapy: Alobresib 2 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 1 Day 8 | 4264.51 h*ng/mL | Standard Deviation 2384.628 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 2 Day 1 | 3243.01 h*ng/mL | Standard Deviation 2110.324 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 1 Day 8 | 3758.92 h*ng/mL | Standard Deviation 2076.013 |
| Monotherapy: Alobresib 4 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 1 Day 8 | 4655.48 h*ng/mL | Standard Deviation 949.099 |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 2 Day 1 | 1522.75 h*ng/mL | — |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 1 Day 8 | 3128.58 h*ng/mL | Standard Deviation 998.059 |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 2 Day 1 | 10264.74 h*ng/mL | — |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 1 Day 8 | 7217.02 h*ng/mL | Standard Deviation 4559.957 |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 1 Day 15 | 765.3 h*ng/mL | Standard Deviation 373.39 |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: AUCtau: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval of Alobresib | Cycle 1 Day 15 | 701.3 h*ng/mL | Standard Deviation 353.25 |
Secondary
Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib
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
Population: The PK Analysis Set included participants who took at least 1 dose of study drug and have at least 1 non-missing postdose concentration value. Participants with available data were analyzed.~Monotherapy: Samples were not collected at Cycle 1 Day 1 and Cycle 1 Day 15; samples were only collected for participants who received alobresib 3 mg, 6 mg and 9 mg doses at Cycle 2 Day 1. Combination Therapy: Samples were not collected at Cycle 1 Day 8 and Cycle 2 Day 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monotherapy: Alobresib 2 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 8 | 263.00 ng/mL | Standard Deviation 141.875 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 2 Day 1 | 220.50 ng/mL | Standard Deviation 95.459 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 8 | 263.75 ng/mL | Standard Deviation 132.011 |
| Monotherapy: Alobresib 4 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 8 | 367.33 ng/mL | Standard Deviation 49.359 |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 2 Day 1 | 203.50 ng/mL | Standard Deviation 143.543 |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 8 | 293.33 ng/mL | Standard Deviation 123.362 |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 2 Day 1 | 641.00 ng/mL | — |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 8 | 526.00 ng/mL | Standard Deviation 280.391 |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 15 | 84.4 ng/mL | Standard Deviation 48.58 |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 1 | 111.07 ng/mL | Standard Deviation 37.957 |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 15 | 173.5 ng/mL | Standard Deviation 28.99 |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: Cmax: Maximum Observed Plasma Concentration of Alobresib | Cycle 1 Day 1 | 199.00 ng/mL | Standard Deviation 9.899 |
Secondary
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.
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
Population: Participants in the PK Analysis Set with available data were analyzed.~Monotherapy: Samples were not collected at Cycle 1 Day 15; samples were only collected for participants who received alobresib 3 mg, 6 mg and 9 mg doses at Cycle 2 Day 1. Combination Therapy: Samples were not collected at Cycle 1 Day 8 and Cycle 2 Day 1.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Monotherapy: Alobresib 2 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 1 Day 8 | 180.00 ng/mL | Standard Deviation 77.679 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 2 Day 1 | 127.60 ng/mL | Standard Deviation 59.963 |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 1 Day 8 | 156.78 ng/mL | Standard Deviation 100.307 |
| Monotherapy: Alobresib 4 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 1 Day 8 | 141.67 ng/mL | Standard Deviation 22.811 |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 2 Day 1 | 33.80 ng/mL | — |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 1 Day 8 | 70.93 ng/mL | Standard Deviation 32.905 |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 2 Day 1 | 268.00 ng/mL | — |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 1 Day 8 | 157.20 ng/mL | Standard Deviation 126.996 |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 1 Day 15 | 8.8 ng/mL | Standard Deviation 7.77 |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: Ctau: Observed Drug Concentration at the End of the Dosing Interval of Alobresib | Cycle 1 Day 15 | 3.9 ng/mL | Standard Deviation 3.21 |
Secondary
Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib
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
Population: Participants in the PK Analysis Set with available data were analyzed.~Monotherapy: Samples were not collected at Cycle 1 Day 1 and Cycle 1 Day 15; samples were only collected for participants who received alobresib 3 mg, 6 mg and 9 mg doses at Cycle 2 Day 1. Combination Therapy: Samples were not collected at Cycle 1 Day 8 and Cycle 2 Day 1.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Monotherapy: Alobresib 2 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 8 | 0.50 hours |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 2 Day 1 | 1.76 hours |
| Monotherapy: Alobresib 3 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 8 | 0.66 hours |
| Monotherapy: Alobresib 4 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 8 | 0.58 hours |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 2 Day 1 | 4.93 hours |
| Monotherapy: Alobresib 6 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 8 | 1.42 hours |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 2 Day 1 | 4.08 hours |
| Monotherapy: Alobresib 9 mg | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 8 | 0.72 hours |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 15 | 0.5 hours |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 1 | 1.07 hours |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 15 | 0.5 hours |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Phase 1b Dose Escalation: Tmax: Time (Observed Time Point) of Cmax of Alobresib | Cycle 1 Day 1 | 0.46 hours |
Secondary
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.
Time frame: Up to approximately 4 years
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Monotherapy: Alobresib 2 mg | Progression Free Survival (PFS) | 2.61 months |
| Monotherapy: Alobresib 3 mg | Progression Free Survival (PFS) | 2.10 months |
| Monotherapy: Alobresib 4 mg | Progression Free Survival (PFS) | 4.17 months |
| Monotherapy: Alobresib 6 mg | Progression Free Survival (PFS) | 2.78 months |
| Monotherapy: Alobresib 9 mg | Progression Free Survival (PFS) | 2.69 months |
| Combination Therapy: Alobresib 3 mg + Enzalutamide | Progression Free Survival (PFS) | 3.25 months |
| Combination Therapy: Alobresib 6 mg + Enzalutamide | Progression Free Survival (PFS) | 5.98 months |