PLX2853 in Combination With Abiraterone Acetate and Prednisone and in Combination With Olaparib in Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Study Details
Study Description
Brief Summary
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)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: PLX2853 + Abiraterone Acetate + Prednisone 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
PLX2853 tablets
Drug: Abiraterone acetate
Abiraterone acetate tablets
Drug: Prednisone
Prednisone (or equivalent) tablets
|
| Experimental: PLX2853 + Olaparib 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
PLX2853 tablets
Drug: Olaparib
Olaparib tablets
|
Outcome Measures
Primary Outcome Measures
- 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
- Radiographic progression-free survival (rPFS) (both arms, both phases) [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.]
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.
- Time to PSA Progression (both arms, both phases) [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.]
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).
- Duration of PSA Response (both arms, both phases) [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.]
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.
- Overall Survival (OS) (both arms, both phases) [From time of first dose until completion of long term follow-up, approximately 30 months.]
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.
- 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) [From time of first dose until 30 days from end of treatment.]
AUC from time zero extrapolated to 24 hours (AUC0-24)
- PLX2853 PK parameter Cmax (both arms, both phases) [From time of first dose until 30 days from end of treatment.]
Maximum observed concentration
- PLX2853 PK parameter T1/2 (both arms, both phases) [From time of first dose until 30 days from end of treatment.]
terminal elimination half-life (T1/2)
- Best Overall Response (BOR) (both arms, both phases) [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.]
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.
- Duration of Response (DOR) (both arms, both phases) [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 from date of first documented, confirmed response using RECIST v1.1 and PCWG3 until date of documented progression or death from any cause.
- Time to first Symptomatic Skeletal-Related Event (SSRE) (both arms, both phases) [From time of first dose until 30 days from end of treatment.]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥18 years at the time of signing informed consent.
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Histologically confirmed adenocarcinoma of the prostate with tumor tissue available for molecular analyses.
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Eastern Cooperative Oncology Group Performance Status 0 to 1.
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Adequate organ function as demonstrated following laboratory values.
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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.
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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).
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Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.
Exclusion Criteria:
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Prior exposure to a bromodomain inhibitor.
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History of autoimmune hemolytic anemia or autoimmune thrombocytopenia.
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Clinically significant cardiac disease.
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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.
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Active known second malignancy with the exception of any of the following:
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Adequately treated basal cell carcinoma or squamous cell carcinoma of the skin.
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Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for ≥2 years.
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Any other cancer from which the subject has been disease-free for ≥3 years.
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Subject is participating in any other therapeutic clinical study (observational or registry studies are allowed).
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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.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 2 | Karmanos Cancer Institute | Detroit | Michigan | United States | 48201 |
| 3 | Columbia University Medical Center | New York | New York | United States | 10032 |
| 4 | Carolina Urologic Research Center | Myrtle Beach | South Carolina | United States | 29572 |
| 5 | Tennessee Oncology/ Sarah Cannon | Nashville | Tennessee | United States | 37203 |
| 6 | Virginia Cancer Specialist | Fairfax | Virginia | United States | 22031 |
| 7 | University of Wisconsin | Madison | Wisconsin | United States | 53792 |
| 8 | Sarah Cannon Research Institute | London | United Kingdom | W1G 6AD |
Sponsors and Collaborators
- Opna-IO LLC
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PLX124-04