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

Gilead Sciences

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Metastatic Castrate-Resistant Prostate Cancer

Treatments: Drug: Enzalutamide; Drug: Alobresib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02607228

GS-US-350-1604

2015-003741-26 (EudraCT Number)

Details and patient eligibility

About

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)

Enrollment: 31 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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31 participants in 5 patient groups

Alobresib Dose Escalation

Experimental group

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.

Treatment:

Drug: Alobresib

Alobresib + Enzalutamide Dose Escalation

Experimental group

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.

Treatment:

Drug: Alobresib

Drug: Enzalutamide

Alobresib Dose Expansion (Group 1)

Experimental group

Description:

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

Treatment:

Drug: Alobresib

Alobresib + Enzalutamide Dose Expansion (Group 2)

Experimental group

Description:

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

Treatment:

Drug: Alobresib

Drug: Enzalutamide

Alobresib + Enzalutamide Dose Expansion (Group 3)

Experimental group

Description:

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

Treatment:

Drug: Alobresib

Drug: Enzalutamide