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

NCT02607228 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: GS-US-350-16042015-003741-26
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 4

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)

Conditions

Metastatic Castrate-Resistant Prostate Cancer

Outcome Measures

Primary Outcomes (2)

• 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.

  Day 1 through Day 28

• 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.

  Week 24

Secondary Outcomes (8)

• 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

• 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

• 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

• 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

• 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

Study Arms (5)

Alobresib Dose Escalation

EXPERIMENTAL

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.

Drug: Alobresib

Alobresib + Enzalutamide Dose Escalation

EXPERIMENTAL

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.

Drug: Alobresib; Drug: Enzalutamide

Alobresib Dose Expansion (Group 1)

EXPERIMENTAL

Participants will receive a dose less than or equal to MTD of alobresib (based on safety, pharmacodynamics (PD), and tolerability).

Drug: Alobresib

Alobresib + Enzalutamide Dose Expansion (Group 2)

EXPERIMENTAL

Participants will receive a dose less than or equal to MTD of alobresib plus enzalutamide (based on safety, PD, and tolerability).

Drug: Alobresib; Drug: Enzalutamide

Alobresib + Enzalutamide Dose Expansion (Group 3)

EXPERIMENTAL

Participants will receive alobresib plus enzalutamide (dose will be equivalent to the dose chosen for Group 2).

Drug: Alobresib; Drug: Enzalutamide

Interventions

Alobresib DRUG

Tablet administered orally once daily.

Also known as: GS-5829

Alobresib + Enzalutamide Dose Escalation; Alobresib + Enzalutamide Dose Expansion (Group 2); Alobresib + Enzalutamide Dose Expansion (Group 3); Alobresib Dose Escalation; Alobresib Dose Expansion (Group 1)

Enzalutamide DRUG

Capsules administered orally once daily.

Also known as: XTANDI®

Alobresib + Enzalutamide Dose Escalation; Alobresib + Enzalutamide Dose Expansion (Group 2); Alobresib + Enzalutamide Dose Expansion (Group 3)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (4)

Unknown Facility

San Francisco, California, 94158, United States

Location

Unknown Facility

Baltimore, Maryland, 21231, United States

Location

Unknown Facility

Boston, Massachusetts, 02114, United States

Location

Unknown Facility

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Interventions

enzalutamide

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2015
• First Posted: November 17, 2015
• Study Start: December 8, 2015
• Primary Completion: October 25, 2017
• Study Completion: September 3, 2019
• Last Updated: December 8, 2020
• Results First Posted: December 8, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)