A Study of Nivolumab Plus Ipilimumab, Ipilimumab Alone, or Cabazitaxel in Men With Metastatic Castration-Resistant Prostate Cancer (CheckMate 650)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness, safety and tolerability of nivolumab followed by ipilimumab, in subjects with metastatic castration resistant prostate cancer (mCRPC).

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

Conditions
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Prostate Cancer

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab
* Drug: Cabazitaxel
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Current evidence of metastatic disease documented by either bone lesions on radionuclide bone scan and/or soft tissue lesions on computerized tomography/magnetic resonance imaging (CT/MRI). Ongoing androgen deprivation therapy (ADT) with a Gonadotropin-releasing hormone (GnRH) analogue or a surgical/medical castration with testosterone level of ≤1.73nmol/L (50ng/dL) For crossover phase for participants originally randomized to Arm D3 or Arm D4 only: Previously randomized to Arm D3 or D4; had histologic confirmation of adenocarcinoma of the prostate and evidence of Stage IV disease (as defined by American Joint Committee of Cancer criteria (AJCC criteria) prior to randomization Exclusion Criteria: Presence of visceral metastases in the liver Active brain metastases or leptomeningeal metastases Active, known, or suspected autoimmune disease or infection Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways For crossover phase for participants originally randomized to Arm D3 or Arm D4 only: Prior radiation therapy within 14 days prior to first dose of nivolumab combined with ipilimumab Have received systemic anti-cancer therapy after the last dose of study treatment (ipilimumab or cabazitaxel) Other protocol-defined inclusion/exclusion criteria apply

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: Cohort A (Arm A)<br> | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Cohort B (Arm B)<br> | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Cohort C (Arm C)<br> | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Cohort D (Arm D1)<br> | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Cohort D (Arm D2)<br> | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Biological: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Cohort D (Arm D3)<br> | Biological: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy;|
| Experimental: Cohort D (Arm D4)<br> | Drug: Cabazitaxel<br>* Specified dose on specified days<br>Drug: Prednisone<br>* Specified dose on specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Cohorts B and C Per BICR | Objective response rate (ORR) is defined as the percent of participants who had confirmed complete or partial best overall response (BOR) per retrospective Blinded Independent Central Review (BICR) among treated participants with measurable disease at baseline. For participants without documented progression by RECIST v1.1 or subsequent therapy, all available response assessments contributed to the BOR assessment. Partial Response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor assessments were performed every 8 weeks (± 7 days) for 6 months since treatment initiation and thereafter every 12 weeks (± 7 days). Confidence-interval based on Clopper Pearson method. | From first dose to the date of objectively documented progression or the date of subsequent systemic anti-cancer therapy, whichever occurred first (assessed up to approximately 61 months) | 
| Objective Response Rate (ORR) Cohort D | In Cohort D, ORR is defined as the percentage of participants who had confirmed complete or partial BOR by BICR among randomized subjects with measurable disease at baseline as entered in Interactive Response Technologies web-based system (IWRS). For participants without documented progression or subsequent therapy, all available response assessments will contribute to the BOR assessment. Partial Response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor assessments were performed every 8 weeks (± 7 days) for 6 months since treatment initiation and thereafter every 12 weeks (± 7 days). Confidence-interval based on Clopper Pearson method. | From randomization to the date of objectively documented progression or the date of subsequent systemic anti-cancer therapy, whichever occurred first (assessed up to approximately 61 months) | 
| Radiographic Progression Free Survival (rPFS) for Cohorts B and C Per BICR | Radiographic progression-free survival (rPFS) is defined as the time between the date of first treatment and the first date of documented radiographic progression or death due to any cause, whichever occurs first. The following progressive diseases were collected, documented and assessed as below: Radiographic progression per retrospective Blinded Independent Central Review (BICR) assessment Bone disease progression by Prostate Cancer Working Group (PCWG2) Non-bone soft tissue disease progression by RECIST v1.1 Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates. | From first dose to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 61 months) | 
| Radiographic Progression-Free Survival (rPFS) for Cohort D | Radiographic progression-free survival (rPFS) is defined as the time between the date of randomization and the first date of documented progression per BICR or death due to any cause, whichever occurs first. The following progressive diseases were collected, documented and assessed as below: Radiographic progression per BICR assessment Bone disease progression by (Prostate Cancer Working Group) PCWG2 Non-bone soft tissue disease progression by RECIST v1.1 Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates. | From randomization and the first date of documented progression or death due to any cause, whichever occurs first (assessed up to approximately 61 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate-Specific Antigen Response Rate (PSA-RR) Cohorts B and C | The percent of participants with a 50% or greater decrease in prostate-specific antigen (PSA) from baseline to the lowest post-baseline PSA result. BBaseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. Confidence-interval based on Clopper Pearson method. | From baseline to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 61 months) | 
| Prostate-Specific Antigen Response Rate (PSA-RR) Cohort D | The percent of participants with a 50% or greater decrease in prostate-specific antigen (PSA) from baseline to the lowest post-baseline PSA result. Baseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. Confidence-interval based on Clopper Pearson method. | From baseline to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 61 months) | 
| The Number of Participants Experiencing Adverse Events (AEs) in Cohorts A, B and C | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation in a participant administered study treatment and that does not necessarily have a causal relationship with this treatment. | From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months) | 
| The Number of Participants Experiencing Adverse Events (AEs) in Cohort D | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation in a participant administered study treatment and that does not necessarily have a causal relationship with this treatment. | From first dose to 30 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 26.5 months) | 
| The Number of Participants Experiencing Serious Adverse Events (SAEs) in Cohorts A, B and C | A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months) | 
| The Number of Participants Experiencing Serious Adverse Events (SAEs) in Cohort D | A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | From first dose to 30 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 26.5 months) | 
| The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation in Cohorts A, B and C | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. | From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months) | 
| The Number of Participants Experiencing Adverse Events (AEs) Leading to Discontinuation in Cohort D | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. | From first dose to 30 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 26.5 months) | 
| The Number of Participants Experiencing Immune Mediated Adverse Events in Cohorts A, B and C | Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity. | From first dose to 100 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 20.7 months) | 
| The Number of Participants Experiencing Immune Mediated Adverse Events in Cohort D | Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity. | From first dose to 100 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 29.5 months). | 
| The Number of Participants Who Died in Cohorts A, B and C | Death due to any cause. | From first dose to 100 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 20.7 months). | 
| The Number of Participants Who Died in Cohort D | Death due to any cause. | From first dose to 100 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 29.5 months). | 
| The Number of Participants With Changes in Laboratory Values From Baseline in Cohorts A, B and C | The number of participants with a change in laboratory values from baseline Grade in Cohorts A, B and C. | From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months) | 
| The Number of Participants With Changes in Laboratory Values From Baseline in Cohort D | The number of participants with an change in laboratory values from baseline Grade in Cohort D. | From first dose to 30 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 26.5 months) | 
| The Number of Participants With Liver Function Laboratory Abnormalities in Cohorts A, B and C | The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal | From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months) | 
| The Number of Participants With Liver Function Laboratory Abnormalities in Cohort D | The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal | From first dose to 30 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 26.5 months) | 
| The Number of Participants With Thyroid Function Laboratory Abnormalities in Cohort A, B and C | The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal | From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months) | 
| The Number of Participants With Thyroid Function Laboratory Abnormalities in Cohort D | The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal | From first dose to 30 days after last dose of study therapy (an average of 4.83 months assessed up to approximately 26.5 months) | 
| Overall Survival (OS) Cohort D | Overall survival (OS) is defined as the time from randomization to the date of death from any cause. For participants who were alive, their survival time was censored at the last known alive date. Overall survival was censored for participants at the date of first treatment if they had no follow-up. Based on Kaplan-Meier estimates. | From randomization to the date of death due to any cause (assessed up to approximately 61 months) | 
| Radiographic/Clinical Progression Free Survival (rcPFS) for Cohorts B and C | Radiographic/clinical progression-free survival (rcPFS) is the time between first dose and first documented progression or death due to any cause, whichever occurred first. Radiographic progression per Investigator assessment: Bone disease progression by Prostate Cancer Working Group (PCWG2) Non-bone soft tissue disease progression by RECIST v1.1 Clinical progression per investigator assessment: Need for palliative radiation therapy involving more than one site, OR Surgery of kyphoplasty to any neoplastic lesion, OR Cancer-associated clinical deterioration determined by treating physician. Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates. | From first dose to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 61 months) | 
| Radiographic/Clinical Progression Free Survival (rcPFS) for Cohort D | Radiographic/clinical progression-free survival (rcPFS) is the time between first dose and first documented progression or death due to any cause, whichever occurred first. Radiographic progression per Investigator assessment: Bone disease progression by Prostate Cancer Working Group (PCWG2) Non-bone soft tissue disease progression by RECIST v1.1 Clinical progression per investigator assessment: Need for palliative radiation therapy involving more than one site, OR Surgery of kyphoplasty to any neoplastic lesion, OR Cancer-associated clinical deterioration determined by treating physician. Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates. | From randomization and the first date of documented progression or death due to any cause, whichever occurs first (assessed up to approximately 61 months) | 
| Overall Survival (OS) Cohorts B and C | Overall survival (OS) is defined as the time from first treatment to the date of death from any cause. For participants who were alive, their survival time was censored at the last known alive date. Overall survival was censored for participants at the date of first treatment if they had no follow-up. Based on Kaplan-Meier estimates. | From first dose to the date of death due to any cause (assessed up to approximately 61 months) | 
| Changes in Pain Severity as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Scores Cohorts B and C | Change between Mean BPI-SF scores at baseline and week 4 (cycle 2). The BPI-SF measures pain severity through the use of a numerical rating scale. Participants rate the severity of their pain at its ''worst,'' ''least,'' and ''average'' in the last 24 hours using an 11-point numerical rating scale with anchors of ''0 = no pain'' and ''10 = pain as bad as you can imagine.'' A higher score = a worse outcome. Pain Severity Score = Mean of items 3-6 (pain at its worst, pain at its least). Baseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. | At baseline and Week 4 (Cycle 2) | 
| Changes in Pain Severity as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Scores Cohort D | Change between Mean BPI-SF scores at baseline and week 4 (cycle 2). The BPI-SF measures pain severity through the use of a numerical rating scale. Participants rate the severity of their pain at its ''worst,'' ''least,'' and ''average'' in the last 24 hours using an 11-point numerical rating scale with anchors of ''0 = no pain'' and ''10 = pain as bad as you can imagine.'' A higher score = a worse outcome. Pain Severity Score = Mean of items 3-6 (pain at its worst, pain at its least). Baseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. | At baseline and 4 weeks after first dose. | 
| Change in Cancer-Related Symptoms and Quality of Life (QoL) by Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire Cohort D | The Functional Assessment of Cancer Therapy - Prostate (FACT-P) is a multidimensional, self-report Quality of Life (QoL) instrument designed for use with prostate cancer patients. It consists of 27 core items. The Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being. This is further supplemented by the Prostate Cancer Subscale (PCS), 12 disease-specific items to assess for prostate-related symptoms. Each item is rated from 0 (Not at all) to 4 (Very much) and combined to produce subscale scores for each domain, a Trial Outcome Index which is based on the Physical and Functional well-being scales and the PCS as well as a total score which ranges from 0 to 156. Higher scores represent better QoL. Baseline evaluations or events were defined as those that occur before or on the date and time of the first dose of study treatment. | At baseline and 4 weeks after first dose. | 
| Change From Baseline in Health Status and Health Utility by 3-level EuroQol Five Dimensions (EQ-5D-3L) Questionnaire Cohorts B and C | The European Quality of Life 5D-3L Scale (EQ-5D-3L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. Responses are: '1' = no problem, and '3' = the most serious problem. The responses are combined in a 5-digit number. These health states are converted to a single index value using the crosswalk method to the EQ-5D-3L value set from the United Kingdom (UK). The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility. Baseline evaluations or events are defined as occurring before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. | At baseline and at Week 4 of Cycle 2. | 
| Change From Baseline in Health Status and Health Utility by 3-level EuroQol Five Dimensions (EQ-5D-3L) Questionnaire Cohort D | The European Quality of Life 5D-3L Scale (EQ-5D-3L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. Responses are: '1' = no problem, and '3' = the most serious problem. The responses are combined in a 5-digit number. These health states are converted to a single index value using the crosswalk method to the EQ-5D-3L value set from the United Kingdom (UK). The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility. Baseline evaluations or events are defined as occurring before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. | At baseline and 4 weeks after first dose. |