PLX2853 in Combination With Abiraterone Acetate and Prednisone and in Combination With Olaparib in Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the investigational drug PLX2853 in subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Official Title
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A Multicenter, Open-Label, Parallel, Phase 1b/2a Study of PLX2853 in Combination With Abiraterone Acetate and Prednisone and Phase 1b/2a Study of PLX2853 in Combination With Olaparib in Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: PLX2853
* Drug: Olaparib
* Drug: Abiraterone acetate
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at the time of signing informed consent. Histologically confirmed adenocarcinoma of the prostate with tumor tissue available for molecular analyses. Eastern Cooperative Oncology Group Performance Status 0 to 1. Adequate organ function as demonstrated following laboratory values. Fertile male subjects with female sexual partners must agree to use a highly effective method of birth control during the study and for 90 days after the last dose of study drug. Except as specified above for organ function, all drug-related toxicity from previous cancer therapy (including ongoing Abiraterone Acetate + Prednisone therapy if applicable) must be resolved (to Grade ≤1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0) prior to study treatment administration (Grade 2: alopecia, hot flashes, decreased libido, or neuropathy is allowed). Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements. Exclusion Criteria: Prior exposure to a bromodomain inhibitor. History of autoimmune hemolytic anemia or autoimmune thrombocytopenia. Clinically significant cardiac disease. Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption. Active known second malignancy with the exception of any of the following: Adequately treated basal cell carcinoma or squamous cell carcinoma of the skin. Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for ≥2 years. Any other cancer from which the subject has been disease-free for ≥3 years. Subject is participating in any other therapeutic clinical study (observational or registry studies are allowed). Presence of any other medical, psychological, familial, sociological, or geographic condition potentially hampering compliance with the study protocol or would interfere with the study endpoints or the subject's ability to participate in the study in the judgment of the Investigator. Receipt of any anti-cancer therapy prior to Cycle 1 Day 1 with less than protocol defined wash-out with the exception of Abiraterone Acetate (for subjects enrolling into Abiraterone Acetate Combination) and GnRH therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLX2853 + Abiraterone Acetate + Prednisone<br>Phase 1b (PLX2853 + Abiraterone Acetate + Prednisone Combination): Up to 15 evaluable subjects with mCRPC will be enrolled. Phase 2a (PLX2853 + Abiraterone Acetate + Prednisone Combination): Up to 19 evaluable subjects with mCRPC will be enrolled. | Drug: PLX2853<br>* PLX2853 tablets<br>Drug: Abiraterone acetate<br>* Abiraterone acetate tablets<br>Drug: Prednisone<br>* Prednisone (or equivalent) tablets<br>|
| Experimental: PLX2853 + Olaparib<br>Phase 1b (PLX2853 + Olaparib Combination): Up to 18 evaluable subjects with homologous recombination repair (HRR) gene-mutated mCRPC will be enrolled. Phase 2a (PLX2853 + Olaparib Combination): Up to 58 evaluable subjects with homologous recombination repair (HRR) gene-mutated mCRPC will be enrolled. | Drug: PLX2853<br>* PLX2853 tablets<br>Drug: Olaparib<br>* Olaparib tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2a (both arms): Disease response as defined by at least one of the following: Objective response by modified RECIST v1.1, PSA response, or circulating tumor cell count (CTC) response. |  | From 6 weeks of treatment (Cycle 3 Day 1; 21 days per cycle) until completion of long term follow-up, an average of 6 months. | 
| Phase 1b (both arms): Incidence of dose-limiting-toxicities (DLTs) |  | From time of first dose of PLX2853 and combination agent(s) through completion of Cycle 1 (21 days). | 
| Phase 1b (both arms): Incidence of TEAEs that are related to treatment |  | From time of first dose of PLX2853 and combination agent(s) until 30 days from end of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic progression-free survival (rPFS) (both arms, both phases) | Radiographic progression-free survival (PFS) will be calculated for each subject as the number of days from the first day of PLX2853 and combination agent(s) treatment (Cycle 1 Day 1) to the date of the first documented disease progression by either RECIST v.1.1 or on bone scan. | From 6 weeks of treatment (Cycle 3 Day 1; 21 days per cycle) until completion of long term follow-up, an average of 6 months. | 
| Time to PSA Progression (both arms, both phases) | PSA progression (defined per PCWG3 as a ≥25% increase and an absolute increase of ≥2 ng/mL above the nadir, which is confirmed by a second consecutive value obtained 3 or more weeks later). | From 3 weeks of treatment (Cycle 2 Day 1; 21 days per cycle) until completion of long term follow-up, an average of 6 months. | 
| Duration of PSA Response (both arms, both phases) | Duration of PSA response will be calculated for each subject with a PSA response as the time from date of first documented, confirmed response (CR or PR) using PCWG3 until date of documented progression confirmed at least 3 weeks later, or death from any cause. | From 3 weeks of treatment (Cycle 3 Day 1; 21 days per cycle) until completion of long term follow-up, an average of 6 months. | 
| Overall Survival (OS) (both arms, both phases) | Overall survival (OS) will be calculated for each subject as the number of days from the first day of PLX2853 treatment and combination agent(s) (Cycle 1 Day 1) to the date of death from any cause. If a subject is lost to follow-up, OS is censored at the date of last contact. | From time of first dose until completion of long term follow-up, approximately 30 months. | 
| Incidence of all TEAEs (both arms, both phases) |  | From time of first dose of PLX2853 and combination agent(s) until 30 days from end of treatment. | 
| Incidence of TEAEs that result in dose interruption, reduction or discontinuation (both arms, both phases) |  | From time of first dose of PLX2853 and combination agent(s) until 30 days from end of treatment. | 
| PLX2853 PK parameter AUC0-24 (both arms, both phases) | AUC from time zero extrapolated to 24 hours (AUC0-24) | From time of first dose until 30 days from end of treatment. | 
| PLX2853 PK parameter Cmax (both arms, both phases) | Maximum observed concentration | From time of first dose until 30 days from end of treatment. | 
| PLX2853 PK parameter T1/2 (both arms, both phases) | terminal elimination half-life (T1/2) | From time of first dose until 30 days from end of treatment. | 
| Best Overall Response (BOR) (both arms, both phases) | Best Overall Response (BOR) per RECIST v1.1 will be calculated for each subject with a minimum interval for confirmation of CR and PR of 4 weeks. | From 6 weeks of treatment (Cycle 3 Day 1; 21 days per cycle) until completion of long term follow-up, an average of 6 months. | 
| Duration of Response (DOR) (both arms, both phases) | Time from date of first documented, confirmed response using RECIST v1.1 and PCWG3 until date of documented progression or death from any cause. | From 6 weeks of treatment (Cycle 3 Day 1; 21 days per cycle) until completion of long term follow-up, an average of 6 months. | 
| Time to first Symptomatic Skeletal-Related Event (SSRE) (both arms, both phases) | Time to first Symptomatic Skeletal-Related Event (SSRE) defined as: Use of radiation therapy to prevent or relieve skeletal symptoms. Occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral). Radiologic documentation is required. Occurrence of spinal cord compression. Radiologic documentation required. Orthopedic surgical intervention for bone metastasis. | From time of first dose until 30 days from end of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PLX2853, Metastatic Castration-resistant Prostate Cancer, Olaparib, Abiraterone Acetate, Adenocarcinoma, Prostate Cancer