PATHWAY: A Phase 1b/2a, Multicenter, Open- Label Study of Pocenbrodib as Monotherapy and in Combination With Darolutamide in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Summary
This is a dose-finding study to assess the safety and preliminary antitumor activity of Pocenbrodib alone or with darolutamide in patients with metastatic castration-resistant prostate cancer (mCRPC)
Detailed description
This is a Phase 1b/2a multicenter, open-label study to confirm the safety, pharmacokinetics (PK), preliminary antitumor activity, and pharmacodynamics (PD) of pocenbrodib for the treatment of participants with mCRPC who have progressed following prior therapy and have been treated with at least 1 potent anti-androgen therapy (enzalutamide, apalutamide, abiraterone acetate, or darolutamide). Phase 1b is a dose escalation and optimization study of pocenbrodib monotherapy and in combination with darolutamide in order to determine the maximum tolerated dose (MTD) in participants (n=80) and to determine the recommended Phase 2 dose(s) (RP2D(s)). Phase 1b consists of three arms: Arm 1 (50-250mg QD 5/2), Arm 2 (continuous monotherapy, 125mg-150mg BID), and Arm 3 (continuous combination of pocenbrodib 125-150mg BID + darolutamide 600mg BID), with DRC safety gates governing study progression between arms. Arm 3 is considered the safety run-in for the combination therapy. Phase 2a is a dose expansion portion of the study to further evaluate the combination of pocenbrodib and darolutamide in participants with mCRPC who have progressed following lutetium-Lu-177-vipivotide-tetraxetan (PLUVICTO) and prior to initiation of taxane-based therapy and will consist of 2 cohorts: Cohort 1: pocenbrodib RP2D high + darolutamide Cohort 2: pocenbrodib RP2D low + darolutamide Safety will be monitored by the DRC
Arms & interventions
- DrugPocenbrodib
Pocenbrodib is a selective oral inhibitor of CBP/p300 bromodomain interaction with acetylated lysines on histones.
- DrugPocenbrodib and Darolutamide
Pocenbrodib in combination with darolutamide
Outcome measures
Primary
Phase 1b: Confirm the safety and tolerability of pocenbrodib and in combination with darolutamide
Occurrence and severity of Serious Adverse Events (SAEs) and clinically relevant Adverse Events (AEs), and clinically significant changes in safety laboratory values and electrocardiograms (ECGs)
Time frame: 28 days
Phase 1b: Identify the recommended Phase 2 doses of pocenbrodib and in combination with darolutamide
Frequency and type of DLTs used to determine the maximum tolerated dose (MTD) and RP2Ds
Time frame: 28 days
Phase 2a: Assess the safety and tolerability of the RP2Ds of pocenbrodib in combination with darolutamide
1. Occurrence and severity of SAEs, clinically relevant AEs, and clinically significant changes in safety laboratory values, physical examination (PE) findings, vital signs, and ECGs. 2. Safety and selection of pocenbrodib RP2D for combination with darolutamide for subsequent development
Time frame: Through duration of treatment, estimated 6 months
Phase 2a: Evaluate the efficacy of RP2Ds of pocenbrodib in combination with darolutamide
Post-177Lu-PSMA-617 (Post-PLUVICTO®) pre-taxane mCRPC: Radiographic progression-free survival (rPFS), assessed as time from randomization to first occurrence of Radiographic progression-free survival (rPFS) according to; i) Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and ii) Prostate Cancer Working Group 3 (PCWG3) criteria or death from any cause, whichever comes first.
Time frame: Through duration of treatment, estimated 6 months.
Secondary
Phase 1b: Plasma PK Cmax
Time frame: At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first
Phase 1b: Plasma PK Tmax
Time frame: At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first
Phase 1b: Plasma PK AUC for pocenbrodib
Time frame: At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first.
Phase 1b: Model of cumulative exposure in relation to incidence of adverse events (AEs)
Time frame: Through duration of treatment, estimated 6 months.
Phase 1b: Model of cumulative exposure in relation to incidence of serious adverse events (SAEs)
Time frame: Through duration of treatment, estimated 6 months.
Phase 1b: Model of cumulative exposure in relation to incidence of adverse events of special interest (AESIs)
Time frame: Through duration of treatment, estimated 6 months.
Phase 2a: Characterize the PK of pocenbrodib in combination with darolutamide
Time frame: At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first
Phase 2a: Plasma PK Cmax pocenbrodib/darolutamide
Time frame: At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first
Phase 2a: Plasma PK Tmax pocenbrodib/darolutamide
Time frame: At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first
Phase 2a: Plasma PK AUC0-24 pocenbrodib/darolutamide
Time frame: At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first
Phase 2a: rPFS (radiographic Progression Free Survival)
Time frame: Through duration of treatment, estimated 6 months
Phase 2a: Prostate Specific Antigen (PSA) 50% (PSA50) change from baseline.
Time frame: Through duration of treatment, estimated 6 months
Phase 2a: Prostate Specific Antigen PSA 90% (PSA90) change from baseline.
Time frame: Through duration of treatment, estimated 6 months
Eligibility criteria
Study locations (18)
MemorialCare Orange Coast Medical Center
Fountain Valley, California, 92708
Cancer and Blood Research Center
Los Alamitos, California, 90720
University of Colorado Health
Aurora, Colorado, 80045
Mount Sinai Medical Center
Miami, Florida, 33140
Emory University Hospital
Atlanta, Georgia, 30322
University of Chicago
Chicago, Illinois, 60637
Community Health Network
Indianapolis, Indiana, 46250
Ochsner
Jefferson, Louisiana, 70121
Johns Hopkins Hospital
Baltimore, Maryland, 21287
Karmanos Cancer Institute
Detroit, Michigan, 48201
Siteman Cancer Center
St Louis, Missouri, 63108
Nebraska Cancer Specialists
Omaha, Nebraska, 68130
Duke University medical center
Durham, North Carolina, 27710
The Ohio State University
Columbus, Ohio, 43210
Taylor Cancer Research Center
Maumee, Ohio, 43537
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Oncology Consultants, P.A
Houston, Texas, 77030
NEXT Oncology - Virginia
Fairfax, Virginia, 22031