mCRPC (Metastatic Castration-resistant Prostate Cancer), Prostate Cancer
Conditions
Keywords
mCRPC, metastatic castrate resistant prostate cancer, prostate cancer,, darolutamide, Pocenbrodib, p300-CBP Transcription Factors
Brief 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
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
Sponsors
Pathos AI, Inc.
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1b/2a open-label dose finding study to assess safety, PK, efficacy, PD in patients with mCRPC.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1b / 2a Inclusion Criteria: 1. ≥18 years of age 2. Histologic documentation of prostate adenocarcinoma 3. Metastatic disease, documented by imaging. Imaging performed within 56 days prior to Screening is acceptable 1b / 2a
Exclusion criteria
1. Current or prior evidence of any small cell or neuroendocrine histology on the most recent prostate biopsy. 2. Any liver metastases confirmed by biopsy or evidence of lesions \>1 cm consistent with liver metastases on imaging. 3. Intervention with any chemotherapy, investigational agent, or other anticancer drug, including enzalutamide, apalutamide, or darolutamide, 14 days prior to Cycle 1 Day 1 or 5 half-lives (whichever is shorter). 4. Any other serious underlying medical, psychiatric, psychological, familial, or geographical condition, which in the judgment of the Investigator may interfere with study participation and compliance or place the participant at high risk from treatment-related complications. 2a only -key inclusion criteria: 1. Must have received at least 2 cycles of PLUVICTO® 2. 1 line of prior any ARPI therapy 3. No prior chemotherapy for mCRPC
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Confirm the safety and tolerability of pocenbrodib and in combination with darolutamide | 28 days | 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) |
| Phase 1b: Identify the recommended Phase 2 doses of pocenbrodib and in combination with darolutamide | 28 days | Frequency and type of DLTs used to determine the maximum tolerated dose (MTD) and RP2Ds |
| Phase 2a: Assess the safety and tolerability of the RP2Ds of pocenbrodib in combination with darolutamide | Through duration of treatment, estimated 6 months | 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 |
| Phase 2a: Evaluate the efficacy of RP2Ds of pocenbrodib in combination with darolutamide | Through duration of treatment, estimated 6 months. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Plasma PK Cmax | At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first | Plasma PK parameter for Cmax |
| Phase 1b: Plasma PK Tmax | At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first | Plasma PK parameter for Tmax, |
| Phase 1b: Plasma PK AUC for pocenbrodib | At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first. | Plasma PK AUC parameter for pocenbrodib. Pocenbrodib parameters compared to monotherapy Arms 1/2. |
| Phase 1b: Model of cumulative exposure in relation to incidence of adverse events (AEs) | Through duration of treatment, estimated 6 months. | — |
| Phase 1b: Model of cumulative exposure in relation to incidence of serious adverse events (SAEs) | Through duration of treatment, estimated 6 months. | — |
| Phase 1b: Model of cumulative exposure in relation to incidence of adverse events of special interest (AESIs) | Through duration of treatment, estimated 6 months. | — |
| Phase 2a: Characterize the PK of pocenbrodib in combination with darolutamide | At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first | Characterize the PK of pocenbrodib in combination with darolutamide in participants with mCRPC after progressing after 177Lu-PSMA-617 (PLUVICTO®) treatment |
| Phase 2a: Plasma PK Cmax pocenbrodib/darolutamide | At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first | Plasma PK parameter for Cmax for pocenbrodib and darolutamide combined |
| Phase 2a: Plasma PK Tmax pocenbrodib/darolutamide | At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first | Plasma PK parameter for Tmax for pocenbrodib and darolutamide combined |
| Phase 2a: Plasma PK AUC0-24 pocenbrodib/darolutamide | At the end of Cycle 1, 2, 3, and 4 (each cycle is 28 days) or until end of treatment, whichever came first | Plasma PK parameter for AUC0-24 for pocenbrodib and darolutamide combined |
| Phase 2a: rPFS (radiographic Progression Free Survival) | Through duration of treatment, estimated 6 months | Evaluate efficacy parameters based on RECIST v1.1 and PCWG3 criteria for rPFS (radiographic Progression Free Survival) |
| Phase 2a: Prostate Specific Antigen (PSA) 50% (PSA50) change from baseline. | Through duration of treatment, estimated 6 months | Evaluate efficacy parameters based on RECIST v1.1 and PCWG3 criteria for Prostate Specific Antigen (PSA) 50% (PSA50) change from baseline |
| Phase 2a: Prostate Specific Antigen PSA 90% (PSA90) change from baseline. | Through duration of treatment, estimated 6 months | Evaluate efficacy parameters based on RECIST v1.1 and PCWG3 criteria for Prostate Specific Antigen PSA 90% (PSA90) change from baseline |
Countries
United States
Contacts
CONTACTSteve Kye, MD, MPH
Outcome results
None listed