A Phase 1b/2a Study of Pocenbrodib as Monotherapy and in Combination With Darolutamide in Participants With mCRPC

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

• 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]