A Phase 2 Trial of Nivolumab Plus Ipilimumab, Ipilimumab Alone, or Cabazitaxel in Men with Metastatic Castration-Resistant Prostate Cancer

The primary objective of this study is to evaluate the **objective response rate (ORR)** in subjects with metastatic castration-resistant prostate cancer (mCRPC) and measurable disease at baseline, using the Response Evaluation Criteria in Solid Tumors (RECIST) V1.1, as assessed by Blinded Independent Central Review (BICR). Additionally, the study aims to assess **radiographic progression-free survival (rPFS)** in all treated subjects with mCRPC, utilizing RECIST V1.1 for soft tissue disease progression and PCWG2 for bone disease progression. These objectives are clinically relevant as they provide critical insights into the efficacy of the treatment regimens in controlling disease progression and improving patient outcomes.

Secondary objectives include:

• Assessing **radiographic/clinical progression-free survival (rcPFS)**.
• Evaluating **overall survival (OS)**.
• Determining the **PSA response rate (PSA-RR)**.
• Assessing the **safety and tolerability** in all treated subjects.
• Estimating changes in pain using the Brief Pain Inventory-Short Form (BPI-SF).
• Estimating changes in cancer-related symptoms and quality of life (QoL) using the FACT-P questionnaire.
• Estimating changes in health status and health utility using the 3-level EQ-5D-3L questionnaire.

The clinical trial involves a total of **237 participants** diagnosed with **Metastatic Castration-Resistant Prostate Cancer**. The study population is exclusively male, with an age range that includes adults and the elderly. Participants were selected based on specific criteria, including an **ECOG performance status** of 0-1 and current evidence of metastatic disease, as documented by bone or soft tissue lesions. All participants are undergoing ongoing androgen deprivation therapy with a Gonadotropin-releasing hormone analogue or have undergone surgical/medical castration. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. The selection process ensures that participants have measurable disease at baseline, as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. The trial aims to evaluate the objective response rate and assess radiographic progression-free survival in the study population.

The clinical trial is designed to evaluate the efficacy and safety of **nivolumab** in combination with **ipilimumab**, **ipilimumab** alone, or **cabazitaxel** in men with metastatic castration-resistant prostate cancer. This is a Phase 2, randomized, double-blind, controlled trial. The trial aims to assess the objective response rate (ORR) and radiographic progression-free survival (rPFS) using the Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 and Prostate Cancer Working Group 2 (PCWG2) criteria. The trial is expected to conclude by October 8, 2026, with recruitment having started on June 28, 2017.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as an ECOG performance status of 0-1 and evidence of metastatic disease. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment. The expected length of participant involvement is up to 24 months, depending on the treatment arm and individual response.

Participants may be withdrawn from the study early if they experience unacceptable adverse events, disease progression, or if they withdraw consent. The trial will also monitor secondary endpoints, including overall survival, incidence of adverse events, and changes in quality of life. The study will ensure rigorous data collection and analysis to provide comprehensive insights into the treatment's impact on metastatic castration-resistant prostate cancer.

The clinical trial involves the administration of several experimental medications, primarily focusing on **nivolumab** and **ipilimumab**. **Nivolumab** is provided as a concentrate for solution for infusion, marketed under the name OPDIVO, with a concentration of 10 mg/mL. It is administered intravenously with a maximum daily dose of 480 mg and a total dose limit of 9999 mg over a treatment period of up to 24 months. The pharmaceutical form is a solution for infusion, and the product is manufactured by Bristol-Myers Squibb Pharma EEIG. Another formulation of **nivolumab**, known as MDX1106 ONO-4538, is also used in the study, provided as a solution for injection with similar dosing parameters and intravenous administration.

**Ipilimumab** is another key experimental medication in this trial, available as a concentrate for solution for infusion. It is administered intravenously with a dosing regimen of 3 mg/kg, not exceeding a total dose of 12 mg/kg over a 12-month period. The product is manufactured by Bristol-Myers Squibb International Corporation and is also known by the sponsor product code BMS734016. The pharmaceutical form is a concentrate for solution for infusion.

Additionally, the trial includes the use of **cabazitaxel**, marketed as JEVTANA, which is provided as a concentrate and solvent for solution for infusion. This medication is administered intravenously with a maximum daily dose of 25 mg/m² and a total dose limit of 250 mg/m² over a 30-month period. The product is manufactured by Sanofi Winthrop Industrie and is classified as a chemical substance.

As a non-experimental treatment, **prednisone** is utilized in the study. It is administered orally in tablet form with a maximum daily dose of 10 mg and a total dose limit of 2100 mg over a 30-month period. Prednisone serves as a standard-of-care therapy in this clinical trial.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these medications in men with metastatic castration-resistant prostate cancer.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** in Cohorts B, C, and D, and **Radiographic Progression-Free Survival (rPFS)**. These endpoints will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) V1.1, assessed by Blinded Independent Central Review (BICR) for subjects with metastatic castration-resistant prostate cancer (mCRPC) and measurable disease at baseline. The secondary endpoints encompass a range of measures, including Radiographic/Clinical Progression-Free Survival (rcPFS) in Cohorts B, C, and D, Overall Survival (OS) in these cohorts, and various safety and quality of life assessments. These include the incidence of Adverse Events (AEs), Serious Adverse Events (SAEs), and Immune-mediated Adverse Events (IMAEs), as well as changes in pain, health status, and quality of life as measured by validated instruments such as the Brief Pain Inventory-Short Form (BPI-SF), the 3-level EuroQol Five Dimensions (EQ-5D-3L), and the Functional Assessment Of Cancer Therapy - Prostate (FACT-P) questionnaire. Additionally, the Prostate Specific Antigen (PSA) Response Rate will be monitored. The trial is designed to provide comprehensive data on the efficacy and safety of the treatments under investigation, with assessments scheduled at various timepoints throughout the study duration.