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Randomized, Open-label, Phase 3 Trial of Nivolumab Plus Brentuximab Vedotin Versus Brentuximab Vedotin Alone in Participants With Relapsed Refractory or Ineligible for Autologous Stem Cell Transplant (ASCT) Advanced Stage Classical Hodgkin Lymphoma (CheckMate 812: CHECKpoint Pathway and nivolumab Clinical Trial Evaluation 812)

Primary Objective: To compare progression free survival of nivolumab + BV vs BV based on BICR assessments Primary Endpoint: Progression Free Survival (PFS): defined as time from date of randomization to death, or disease progression. Secondary Objectives: To compare the complete response rate of nivolumab + BV vs BV based on BICR assessments To assess objective response rate and duration of response based on BICR To assess duration of complete response based on BICR To assess overall survival of participants treated with nivolumab + BV vs BV To assess PFS based on investigator assessments Secondary Endpoints: Complete Response Rate (CRR): defined as proportion of participants who have achieved complete response (Lugano 2014 classification) Objective Response Rate (ORR): defined as the proportion of participants who have achieved complete response or partial response (Lugano 2014 classification) Duration of response or duration of complete response (DOR or DOCR): defined as the time from first response or complete response to the date of initial objectively documented progression as determined using the 2014 Lugano classification or death due to any cause Overall Survival (OS): defined as the time between the date of randomization and the date of death. PFS defined as the above but assessed by investigator. Tertiary/Exploratory Objectives: To assess the overall safety and tolerability of nivolumab in combination with chemotherapy, as measured by incidence and severity of adverse events (AEs), serious adverse events (SAEs), and specific laboratory abnormalities To assess CRR, BOR, ORR, DOR and DOCR based on investigator assessments To investigate the association between biomarkers in the peripheral blood and tumor tissue, such as PD-L1 expression, with safety and efficacy measures To characterize pharmacokinetics of nivolumab + BV and explore exposure-response relationships To characterize the immunogenicity of nivolumab and BV To evaluate both generic health related quality of life as assessed by the EQ-5D and cancer specific quality of life as assessed by the QLQC30, FACT-Lymphoma and WPAI-GH. To evaluate the pharmacodynamic activity of nivolumab + BV combination therapy in the peripheral blood and tumor tissue as measured by flow cytometry, immunohistochemistry, soluble factor analysis, and gene expression (microarray technology, quantitative RT-PCR). To assess the indeterminate response (IR) as defined by LYRIC Tertiary/Exploratory Endpoints: AEs, study treatment-related AEs, SAEs, and study treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v.4.0 criteria by system organ class and preferred term. Onstudy lab parameters will be summarized using worst grade per NCI CTCAE v.4.0 criteria. CRR, BOR, ORR, DOR and DOCR defined as the above but assessed by investigator PD-L1 expression variable of archived tumor (evaluable, indeterminate, or not evaluable stained tumor cells) will be assessed in available tumor specimens obtained at baseline. In addition, 9p24,1 genomic status (polysomy, gain, amplified, and residual % disomy) may be tested in available archived tumor samples. Pharmacokinetic parameters, influence of intrinsic and extrinsic covariates and potential exposure response relationship will be characterized using integrated analyses. Immunogenicity assessed by ADA positivity QLQ-C30, FACT-Lymphoma, EuroQol (EQ)-5D- 3L scoring function, and WPAI-GH scoring algorithm. Pharmacodynamic activity will be investigated by ctDNA analysis in the serum and other serum assessments such as, but not limited to, cytokines, soluble factors, circulating antibodies, and proteome analysis. Peripheral blood immune cell subsets may also be tested. LYRIC (Lymphoma Response to Immunomodulatory therapy Criteria) will be used to assess indeterminate response.

Primary Objective: To compare progression free survival of nivolumab + BV vs BV based on BICR assessments Primary Endpoint: Progression Free Survival (PFS): defined as time from date of randomization to death, or disease progression. Secondary Objectives: To compare the complete response rate of nivolumab + BV vs BV based on BICR assessments To assess objective response rate and duration of response based on BICR To assess duration of complete response based on BICR To assess overall survival of participants treated with nivolumab + BV vs BV To assess PFS based on investigator assessments Secondary Endpoints: Complete Response Rate (CRR): defined as proportion of participants who have achieved complete response (Lugano 2014 classification) Objective Response Rate (ORR): defined as the proportion of participants who have achieved complete response or partial response (Lugano 2014 classification) Duration of response or duration of complete response (DOR or DOCR): defined as the time from first response or complete response to the date of initial objectively documented progression as determined using the 2014 Lugano classification or death due to any cause Overall Survival (OS): defined as the time between the date of randomization and the date of death. PFS defined as the above but assessed by investigator. Tertiary/Exploratory Objectives: To assess the overall safety and tolerability of nivolumab in combination with chemotherapy, as measured by incidence and severity of adverse events (AEs), serious adverse events (SAEs), and specific laboratory abnormalities To assess CRR, BOR, ORR, DOR and DOCR based on investigator assessments To investigate the association between biomarkers in the peripheral blood and tumor tissue, such as PD-L1 expression, with safety and efficacy measures To characterize pharmacokinetics of nivolumab + BV and explore exposure-response relationships To characterize the immunogenicity of nivolumab and BV To evaluate both generic health related quality of life as assessed by the EQ-5D and cancer specific quality of life as assessed by the QLQC30, FACT-Lymphoma and WPAI-GH. To evaluate the pharmacodynamic activity of nivolumab + BV combination therapy in the peripheral blood and tumor tissue as measured by flow cytometry, immunohistochemistry, soluble factor analysis, and gene expression (microarray technology, quantitative RT-PCR). To assess the indeterminate response (IR) as defined by LYRIC Tertiary/Exploratory Endpoints: AEs, study treatment-related AEs, SAEs, and study treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v.4.0 criteria by system organ class and preferred term. Onstudy lab parameters will be summarized using worst grade per NCI CTCAE v.4.0 criteria. CRR, BOR, ORR, DOR and DOCR defined as the above but assessed by investigator PD-L1 expression variable of archived tumor (evaluable, indeterminate, or not evaluable stained tumor cells) will be assessed in available tumor specimens obtained at baseline. In addition, 9p24,1 genomic status (polysomy, gain, amplified, and residual % disomy) may be tested in available archived tumor samples. Pharmacokinetic parameters, influence of intrinsic and extrinsic covariates and potential exposure response relationship will be characterized using integrated analyses. Immunogenicity assessed by ADA positivity QLQ-C30, FACT-Lymphoma, EuroQol (EQ)-5D- 3L scoring function, and WPAI-GH scoring algorithm. Pharmacodynamic activity will be investigated by ctDNA analysis in the serum and other serum assessments such as, but not limited to, cytokines, soluble factors, circulating antibodies, and proteome analysis. Peripheral blood immune cell subsets may also be tested. LYRIC (Lymphoma Response to Immunomodulatory therapy Criteria) will be used to assess indeterminate response.