Adenosine Receptor Antagonist Combination Therapy for Metastatic Castrate Resistant Prostate Cancer

Study Overview
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Brief Summary
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This is a Phase 1b/2, open-label, multicenter platform trial to evaluate the antitumor activity and safety of etrumadenant (AB928)-based combination therapy in participants with metastatic castrate resistant prostate cancer (mCRPC).

Detailed Description
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This study has several treatment arms and each treatment arm has 2 stages. During Stage 1 - Etrumadenant plus zimberelimab (AB122) alone, etrumadenant plus zimberelimab with or without a standard of care treatment (enzalutamide or docetaxel), or etrumadenant plus AB680 with or without zimberelimab, or etrumadenant plus Sacituzumab govitecan (SG) alone or etrumadenant plus zimberelimab plus SG will be administered to participants with mCRPC. During Stage 2 - Additional participants with mCRPC may receive an etrumadenant-based combination therapy evaluated in Stage 1 or, a standard of care treatment. A pharmacokinetic (PK) Sub-Study (etrumadenant plus zimberelimab) will be conducted separately. Treatment may continue until unacceptable toxicity or progressive disease, or other reasons specified in the protocol.

Official Title
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A Phase 1b/2, Open-Label, Randomized Platform Study Evaluating the Efficacy and Safety of AB928-Based Treatment Combinations in Patients With Metastatic Castrate Resistant Prostate Cancer

Conditions
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Prostatic Neoplasms, Castration-Resistant, Androgen-Resistant Prostatic Neoplasms, Castration Resistant Prostatic Neoplasms, Prostatic Cancer, Castration-Resistant

Intervention / Treatment
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* Drug: Etrumadenant
* Drug: Zimberelimab
* Drug: Quemliclustat
* Drug: Enzalutamide
* Drug: Docetaxel
* Drug: SG


Participation Criteria
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Eligibility Criteria
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General Inclusion Criteria: Male participants; age ≥ 18 years Metastatic castrate-resistant prostate cancer while on anti-androgen treatment with castrate levels of testosterone (≤1.7 nanomoles per liter [nmol/L] or 50 nanograms per deciliter [ng/dL]) Measurable or non-measurable disease as per radiographic evaluation Participants with measurable disease may require a fresh tumor biopsy at study entry Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1 Life expectancy of at least 3 months Adequate hematologic and end-organ function Human immunodeficiency virus (HIV), Hepatitis B, and C test results negative prior to first study treatment Inclusion Criteria for Participants receiving an enzalutamide-containing treatment Disease progression after prior treatment with abiraterone Inclusion Criteria for Participants receiving a docetaxel-containing treatment Disease progression after prior androgen synthesis inhibitor therapy Inclusion Criteria for all other Participants Disease progression after prior androgen synthesis inhibitor treatment and up to 2 prior lines of taxane chemotherapy General Exclusion Criteria: Prior treatment with immune checkpoint blockade therapy Prior anticancer treatment including approved agents, systemic radiotherapy, or investigational therapy, within 2-4 weeks prior first study treatment Corrected QT interval (QTc) ≥480 msec using Fredericia's QT correction formula (based on an average of triplicate recordings) Prior allogeneic stem cell or solid organ transplantation Prior treatment with drugs that stimulate the immune system within 4 weeks prior to first study treatment Prior treatment with drugs that suppress the immune system within 2 weeks prior to first study treatment Received a live, attenuated vaccine within 4 weeks prior to first study treatment, or may need to receive a vaccine during study treatment Presence of metastases in the brain or cancer spreading into the cerebrospinal fluid - CSF (leptomeningeal disease) Prior pulmonary fibrosis, pneumonia, or pneumonitis Cancer other than prostate within 2 years prior to study entry, except for some cancers with a low risk of spreading like non-melanoma skin Prior treatment with an agent targeting the adenosine pathway No oral or IV antibiotics within 2 weeks prior to first study treatment No severe infection within 4 weeks prior to first study treatment No clinically significant cardiac disease Inability to swallow medications Exclusion Criteria for Participants receiving an enzalutamide-containing treatment Prior treatment with docetaxel, cabazitaxel, or other taxane chemotherapy (prior docetaxel [up to 6 cycles] for hormone-sensitive prostate cancer is allowed if the last dose was at least 6 months prior to study treatment initiation) Prior treatment with enzalutamide or similar therapy other than abiraterone Active or history of autoimmune disease or immune deficiency History of severe allergic reactions to antibody therapy Concomitant use of a medication prohibited by the protocol (including certain transporter substrates as well as known strong CYP3A4 inducers and CYP3A4 inhibitors) within 4 weeks prior to and throughout study treatment Exclusion Criteria for Participants receiving a docetaxel-containing treatment Prior treatment with docetaxel, cabazitaxel, or other taxane chemotherapy Active or history of autoimmune disease or immune deficiency History of severe allergic reactions to antibody therapy Concomitant use of a medication prohibited by the protocol (including certain transporter substrates as well as known strong CYP3A4 inducers and CYP3A4 inhibitors) within 4 weeks prior to and throughout study treatment Exclusion Criteria for all other Participants Prior treatment with docetaxel, cabazitaxel, topoisomerase 1 inhibitors, or other taxane chemotherapy Active or history of autoimmune disease or immune deficiency History of severe allergic reactions to antibody therapy Concomitant use of a medication prohibited by the protocol (including certain transporter substrates as well as known strong CYP3A4 inducers and CYP3A4 inhibitors) within 4 weeks prior to and throughout study treatment

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 and 2: Etrumadenant + zimberelimab + enzalutamide<br>Participants will receive oral etrumadenant in combination with intravenous (IV) zimberelimab and standard oral enzalutamide | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is an anti-PD-1 antibody<br>* Other names: AB122;Drug: Enzalutamide<br>* Enzalutamide is an androgen receptor inhibitor<br>* Other names: Xtandi;|
| Active Comparator: Stage 2: enzalutamide<br>Participants will receive standard oral enzalutamide | Drug: Enzalutamide<br>* Enzalutamide is an androgen receptor inhibitor<br>* Other names: Xtandi;|
| Experimental: Stage 1 and 2: Etrumadenant + zimberelimab + docetaxel<br>Participants will receive oral etrumadenant in combination with IV zimberelimab and standard IV docetaxel | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is an anti-PD-1 antibody<br>* Other names: AB122;Drug: Docetaxel<br>* Docetaxel is type of chemotherapy<br>* Other names: Taxotere;|
| Active Comparator: Stage 2: docetaxel<br>Participants will receive standard dose of IV docetaxel | Drug: Docetaxel<br>* Docetaxel is type of chemotherapy<br>* Other names: Taxotere;|
| Experimental: Stage 1 and 2: Etrumadenant + zimberelimab<br>Oral etrumadenant in combination IV zimberelimab | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is an anti-PD-1 antibody<br>* Other names: AB122;|
| Experimental: Stage 2: Etrumadenant + zimberelimab + quemliclustat<br>Participants will receive oral etrumadenant in combination with IV zimberelimab and IV quemliclustat | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is an anti-PD-1 antibody<br>* Other names: AB122;Drug: Quemliclustat<br>* Quemliclustat is a Cluster of Differentiation (CD)73 Inhibitor.<br>* Other names: AB680;|
| Experimental: Stage 2: Etrumadenant + quemliclustat<br>Participants will receive oral etrumadenant in combination with IV quemliclustat | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Quemliclustat<br>* Quemliclustat is a Cluster of Differentiation (CD)73 Inhibitor.<br>* Other names: AB680;|
| Experimental: Stage 1: Etrumadenant + zimberelimab PK Sub-Study<br>Participants will receive oral etrumadenant in combination with IV zimberelimab | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is an anti-PD-1 antibody<br>* Other names: AB122;|
| Experimental: Stage 1 and 2: Etrumadenant + SG<br>Participants will receive oral etrumadenant in combination with IV SG. | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: SG<br>* Sacituzumab govitecan is an antibody-drug conjugate<br>* Other names: Trodelvy;|
| Experimental: Stage 1 and 2: Etrumadenant + Zimberelimab + SG<br>Participants will receive oral etrumadenant in combination with IV zimberelimab and SG. | Drug: Etrumadenant<br>* Etrumadenant is an A2aR and A2bR antagonist<br>* Other names: AB928;Drug: Zimberelimab<br>* Zimberelimab is an anti-PD-1 antibody<br>* Other names: AB122;Drug: SG<br>* Sacituzumab govitecan is an antibody-drug conjugate<br>* Other names: Trodelvy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) in Stage 1 and 2 | ORR defined as the composite proportion of participants with a Prostate Specific Antigen (PSA) and/or radiographic complete response (CR) and partial response (PR) determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria | From study enrolment until participant discontinuation, or first occurrence of progressive disease, or death from any cause, whichever occurs first (approximately 3-5 years) | 
| Incidence and Severity of AEs and Serious Adverse Events (SAEs) in Stage 1 |  | From first dose date to 90 days after the last dose (approximately 1.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with a PSA response in Stage 1 and 2 | PSA response defined as the proportion of participants with a confirmed PSA decrease from baseline of 50% or more based on two consecutive assessments measured 3 to 4 weeks apart | From study enrollment until disease progression or loss of clinical benefit (approximately 3-5 years) | 
| Percentage of participants with Radiographic Response in Stage 1 and 2 | Radiographic Response is measurable disease at baseline who achieved a best overall response of CR or PR according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | From study enrollment until disease progression or loss of clinical benefit (approximately 3-5 years) | 
| Percentage of Participants with Disease Control Rate in Stage 1 and 2 | Disease Control Rate is defined as the percentage of participants with measurable disease at baseline who achieved a best overall RECIST response of CR, PR, or Stable Disease (SD). | From study enrollment until disease progression or loss of clinical benefit (approximately 3-5 years) | 
| Serum/Plasma Concentration for etrumadenant, zimberelimab, and enzalutamide when administered as part of a combination regimen in Stage 1 and 2. |  | Recorded at baseline (enrollment), during the first 5 months of treatment and 3 additional timepoints in the first year of treatment. (approximately 1.5 years) | 
| Serum/Plasma Concentration for etrumadenant and zimberelimab when administered as part of a combination regimen with docetaxel in Stage 1 and 2 |  | Recorded at baseline (enrollment), during the first 5 months of treatment and 3 additional timepoints in the first year of treatment. (approximately 1.5 years) | 
| Serum/Plasma Concentration for etrumadenant and zimberelimab when administered as part of a combination regimen in Stage 1 and 2 |  | Recorded at baseline (enrollment), during the first 5 months of treatment and 3 additional timepoints in the first year of treatment. (approximately 1.5 years) | 
| Serum/Plasma Concentration for etrumadenant, zimberelimab, and AB680 when administered as part of a combination regimen in Stage 1 and 2 |  | Recorded at baseline (enrollment), during the first 5 months of treatment and 3 additional timepoints in the first year of treatment. (approximately 1.5 years) | 
| Serum/Plasma Concentration for etrumadenant and AB680 when administered as part of a combination regimen in Stage 1 and 2. |  | Recorded at baseline (enrollment), during the first 5 months of treatment and 3 additional timepoints in the first year of treatment. (approximately 1.5 years) | 
| Percentage of participants with anti-drug antibodies to zimberelimab in Stage 1 and 2 |  | Recorded at baseline (enrollment), during the first 4 months of treatment, 4 additional timepoints in the first year of treatment, and at end of treatment. (approximately 1.5 years) | 
| Incidence and severity of AEs and serious adverse events (SAEs) in Stage 2 |  | From first dose date to 90 days after the last dose (approximately 3-5 years) |