MDX-1106

Length of time participants are alive

Length of time participants are free of disease progression

PFS (as assessed by the IRRC) will be calculated using the following formula : PFS (days) = "date when overall response is assessed as progressive disease (PD) or date of death (for any reason), whichever comes first" - "date of randomization" + 1. Please refer to the protocol, in this study, tumor response will be evaluated by CT, etc. according to the RECIST 1.1 criteria.

Blood samples were collected to assess serum concentration.

Blood samples were collected to assess serum concentration.

Blood samples were collected to assess serum concentration.

Blood samples were collected to assess serum concentration.

An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.

A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: * Results in death. * Is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe). * Requires inpatient hospitalization or causes prolongation of existing hospitalization.

An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom or disease.

A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: * Results in death. * Is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe). * Requires inpatient hospitalization or causes prolongation of existing hospitalization.

Plasma samples were collected to assess the serum concentration.

Plasma samples were collected to assess the serum concentration.

To determine the effect of RegoNivo on overall survival (OS) (death from any cause) in the overall study population and in the Asian sub-population. Overall survival is defined as the interval from the date of randomisation to date of death from any cause, or the date last known alive.

Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose that results in death, Is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe) or requires inpatient hospitalization or causes prolongation of existing hospitalization, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect or is an important medical event.

Number of participants who died due to any cause are summarized.

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.

Laboratory results were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Grade 3 =Severe, Grade 4 = Life-threatening). Highest grade measured for hemoglobin and albumin was Grade 3.

Blood samples were collected for specific thyroid test.

Blood samples were collected for specific liver tests.

rPFS for randomized participants is the time between randomization and the first date of documented progression or death due to any cause, whichever occurs first. The rPFS was censored at the last radiographic tumor assessment up to the start of subsequent cancer therapy for those without progression or death. It was also censored at the date of last radiographic tumor assessment prior to the missed tumor assessments for participants who had progressive disease (PD) or death immediately after more than one consecutive missed tumor assessments. Radiographic progression is defined as 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 millimeter (mm). The appearance of one or more new lesions is also considered progression.

OS for all randomized participants is the time between randomization and the date of death from any cause. For participants who are alive, their survival time was censored at the last date that they were known to be alive. OS was censored for participants at the date of randomization if they had no follow-up.

Pathologic Complete Response (pCR) is defined as the percentage of randomized participants with absence of any cancer in pathology specimens after radical cystectomy, based on blinded independent pathology review (BIPR). Participants who do not undertake surgery will be counted as non-pCR.

Event Free Survival (EFS) is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence based on blinded independent committee review (BICR) assessments, or death due to any cause. Participants who did not have an EFS event will be censored on the date of their last evaluable tumor assessment (imaging or biopsy) or at the date of radical surgery whichever occur last. Participants who did not have any baseline tumor assessments (imaging or biopsy) and did not undergo radical cystectomy for other reason than worsening/progression of disease will be censored on their date of randomization. Participants who did not have any on study tumor assessments (imaging or biopsy) and did not die will be censored on their date of radical cystectomy (or randomization date if no radical cystectomy performed).

pCR rate is defined as the percentage of participants who achieved pCR. pCR is defined as no invasive residual disease in breast and lymph nodes performed by a local pathologist. Criteria for evaluation of pCR includes the following: pCR in breast, axillary lymph nodes and non-axillary sentinel node; no histologic evidence of invasive tumor cells; and pCR in the breast.

The length of time from randomization to any of the following events: progression of disease or worsening of disease precluding surgery, if surgery is attempted but gross resection is abandoned due to unresectable tumor or worsening of disease, progression or recurrence of disease after surgery, progression or recurrence of disease without surgery, or death due to any cause. Progression/recurrence will be assessed by BICR per RECIST 1.1. Participants who do not undergo surgery for reason other than progression will be considered to have an event at RECIST 1.1 progression or death

Recurrence Free Survival (RFS) is defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (whatever the cause), whichever occurs first. For participants who remain alive and whose disease has not recurred or did not die, RFS will be censored on the date of last evaluable disease assessment. For those participants who remained alive and had no recorded post-randomization tumor assessment, RFS will be censored on the day of randomization.

Progression-Free Survival then (PFS) is defined as the time between the date of randomization and the date of first documented disease progression, based on BICR assessments (per RECIST v1.1), or death due to any cause, whichever occurs first based on Kaplan-Meier estimates. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the 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.

Arm B vs. Arm A

Arm B vs. Arm A

PFS by investigator was defined as the time from randomization to disease progression, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. Progressive disease was defined as a 20% increase in the sum of the longest diameter of measurable lesions, an unequivocal increase in existing non-measurable lesion(s), or the appearance of unequivocal new lesion(s).

PFS by investigator was defined as the time from randomization to disease progression, according to RECIST v1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. Progressive disease was defined as a 20% increase in the sum of the longest diameter of measurable lesions, an unequivocal increase in existing non-measurable lesion(s), or the appearance of unequivocal new lesion(s).

PFS by investigator was defined as the time from randomization to disease progression, according to RECIST v1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. Progressive disease was defined as a 20% increase in the sum of the longest diameter of measurable lesions, an unequivocal increase in existing non-measurable lesion(s), or the appearance of unequivocal new lesion(s).

Number of non-HBV participants experiencing high grade (combined CTCAE v4 Grade 3-4 and Grade 5) treatment-related select adverse events in non-HBV infected participants. To evaluate safety and tolerability in non-HBV infected participants with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed during or after one prior systemic therapy and are treated with nivolumab monotherapy with an infusion duration of 30 minutes. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.

Number of Participants with an Adverse Event

Number of Participants with an Serious Adverse Event (SAE)

Number of Participants with an Adverse Event Leading to Discontinuation

Number of Participants with an Adverse Event Leading to dose modification

Number of Participants with select adverse events. Select Adverse events include: gastrointestinal, hepatic, hypersensitivity/infusion reaction, pulmonary, renal, or skin.

Number of Participants with an immune-mediated adverse event (IMAE)

Time to onset and time to resolution of immune-related adverse events

Number of Participants who experienced death

Number of participants with an abnormality in specific thyroid tests

Number of participants with an abnormality in specific liver tests

PFS is defined as the time from date of randomization to the first documented tumor progression date or death due to any cause, whichever occurs first based on BICR assessment using RECIST v1.1. Participants who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment on or prior to initiation of subsequent anti-cancer therapy. Progressive disease (PD); 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study

Disease-Free Survival (DFS) is defined as the time from randomization to development of local disease recurrence (ie, recurrence of primary tumor in situ or occurrence of a secondary renal cell carcinoma (RCC) primary cancer), distance metastasis, or death, whichever came first per Blinded Independent Central Review (BICR) based on Kaplan-Meier estimates.

Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.

Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.

RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median values based on Kaplan-Meier Estimates.

RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.

This measure looks at how long participants who cannot receive cisplatin (a type of chemotherapy) live after being placed into a treatment group in the primary study. Overall Survival (OS) is defined as the time between the date a participant is randomized (assigned to a treatment group) and the date of death from any cause. For participants without documentation of death, OS will be measured up to the last date the participant was known to be alive. If a participant was randomized but had no follow-up information, OS will be counted from the date of randomization. This helps to understand if the treatment can help people who are unable to receive cisplatin chemotherapy live longer.

This measure looks at how long participants with PD-L1 positive tumors (meaning their tumor cells have at least 1% PD-L1, as determined by a laboratory test called immunohistochemistry or IHC) live after being placed into a treatment group in the primary study. Overall Survival (OS) is defined as the time between the date a participant is randomized (assigned to a treatment group) and the date of death from any cause. For participants without documentation of death, OS will be measured up to the last date the participant was known to be alive. If a participant was randomized but had no follow-up information, OS will be counted from the date of randomization. This helps to understand whether the treatment can help people with PD-L1 positive tumors live longer.

This measure looks at how long people who can receive cisplatin chemotherapy live without their cancer getting worse after being assigned to a treatment group in the sub-study. Progression-Free Survival (PFS) is the time from when a participant is assigned to a group (randomization) until their cancer is first shown to get worse (progress), based on reviews by independent experts who do not know which treatment was given. These experts use standard rules (RECIST 1.1) to decide if the cancer has progressed. If a participant dies before their cancer is shown to get worse, the date of death will be used as the time their disease progressed. If a participant's cancer does not get worse and they do not die during the study, their PFS will be measured up to the date of their last tumor check. This helps to understand if the treatment helps people eligible for cisplatin live longer without their cancer progressing.

This measure looks at how long people who are able to receive cisplatin (a type of chemotherapy) live after being placed into a treatment group in the sub-study. Overall Survival (OS) is defined as the time between the date a participant is randomized (assigned to a treatment group) and the date of death from any cause. For participants without documentation of death, OS will be measured up to the last date the participant was known to be alive. If a participant was randomized but had no follow-up information, OS will be counted from the date of randomization. This helps to understand if the treatment can help people who are eligible for cisplatin chemotherapy live longer.

PFS is defined as the time between the date of randomization and the date of first documented tumor progression, as determined by BICR (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Participants who died without reported progression will be considered to have progressed on the date of their death. Subsequent therapy was accounted for by censoring at the last evaluable tumor assessment on or prior to the date of subsequent therapy. Progression is the appearance of one or more new lesions. RECIST - "response evaluation criteria in solid tumors" is a standard system to measure tumor response to treatment. Based on Kaplan-Meier estimates

Event-free survival (EFS) is defined as the length of time from randomization to any of the following events: any progression of disease precluding surgery, progression or recurrence disease based on blinded independent central review (BICR) assessment per response evaluation criteria in solid tumors (RECIST) 1.1 after surgery, or death due to any cause. Participants who don't undergo surgery for reason other than progression will be considered to have an event at progression or death. Progression is defined as 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. (Note: the appearance of one or more new lesions is also considered progression).

Pathologic complete response (pCR) rate is defined as the number of randomized participants with absence of residual tumor in lung and lymph nodes as evaluated by blinded independent pathological review (BIPR).

This outcome describes the percentage of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction broad scope SMQ. Such AEs include any acute systemic reaction characterized by a large list of terms, including (but not limited to) pruritus, urticaria, flushing, hypotension, respiratory distress, and vascular insufficiency. It also includes other signs and symptoms such as asthma, choking sensation, coughing, sneezing, and difficulty breathing due to laryngeal spasm and/or bronchospasm. Less frequent clinical presentations are also captured and include hyperventilation, sensation of foreign body, and ocular edema.

Overall survival (OS), defined as the time from randomization to the time of death, in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS (combined positive score) ≥ 5. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.

Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented PD or death due to any cause. PD is determined by blinded independent committee review (BICR) per RECIST1.1 criteria in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS ≥ 5. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking in reference the smallest sum on study that also demonstrated an absolute increase of at least 5 mm. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.

Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)

Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)

Disease-free survival is defined as the time between randomization date and first date of recurrence or death, whichever occurs first. Recurrence is defined as the appearance of one or more new lesions, which can be local, regional, or distant in location from the primary resected site ( assessed by imaging or pathology). All deaths without prior recurrence are considered as DFS events. For participants who remained alive and without recurrence, DFS was censured on the date of last evaluable disease assessment

The proportion of participants remaining progression free and surviving at 6 months. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Progression is defined as 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. Note: the appearance of one or more new lesions is also considered progression.

The proportion of participants remaining progression free and surviving at 6 months. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Progression is defined as 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. Note: the appearance of one or more new lesions is also considered progression.

The time from randomization to the date of the first documented tumor progression or death by any cause. PFS will be determined by a Blinded Independent Central Review (BICR) assessed based on Radiologic Assessment in Neuro-Oncology (RANO) criteria. Specifically, RANO response criteria indicates that within the first 12 weeks of completion of radiotherapy, progression can only be assessed if the majority of the new enhancement is outside of the radiation field or if there is pathologic confirmation of progressive disease.

The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria.

The time between the date of randomization and the date of first documented recurrence (local urothelial tract, local non-urothelial tract or distant), or death due to any cause, whichever occurs first.

The time between the date of randomization and the date of first documented recurrence (local urothelial tract, local non-urothelial tract or distant), or death due to any cause, whichever occurs first.

Incidence of participants with high-grade (CTCAE v4.0 grade 3-5) treatment-related, select adverse events of potentially immune-mediated etiology including pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity

OS was defined as the time between the date of randomization and the date of death. For subjects without documentation of death, OS was censored on the last date the subject was known to be alive

OS was defined as the time between the date of randomization and the date of death. For subjects without documentation of death, OS was censored on the last date the subject was known to be alive. Rates provided are Kaplan-Meier estimates.

OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug

Progression-Free Survival then (PFS) is defined as the time between the date of randomization and the date of first documented disease progression, based on BICR assessments (per RECIST v1.1), or death due to any cause, whichever occurs first based on Kaplan-Meier estimates. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the 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.

ORR was defined as the proportion of randomized subjects who achieved a best response of complete response (CR) or partial response (PR) using the RECIST v1.1 criteria based on Independent Radiology Review Committee (IRRC) assessment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

OS was defined as the time from randomization to the date of death from any cause. Survival time was censored at the date of last contact ("last known alive date") for subjects who were alive.

PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the IRRC (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first. Subsequent therapy included anticancer therapy, tumor directed radiotherapy, or tumor directed surgery. Subjects who died without a reported progression were considered to have progressed on the date of their death.

A treatment related adverse event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered an investigational (medicinal) product and that has a causal relationship with this treatment. The select AEs categories are those that are expected to be most commonly used to describe pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, rash, and endocrinopathies and hypersensitivity/infusion reactions. AEs are graded according to NCI CTCAE (Version 4.0) guidelines where Grade 3= Severe, Grade 4 = Life-threatening, Grade 5 = Death.

Progression-Free Survival (PFS) was defined as the time between the date of randomization and the first date of documented tumor progression, as determined by the Independent Radiology Review Committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause, whichever occurs first. Participants who die without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the day they were randomized. Participants who received subsequent anti-cancer therapy prior to documented progression were censored at the last evaluable tumor assessment prior to the initiation of new therapy.

The percentage of participants who experienced a drug-related adverse event leading to drug discontinuation by worst grade (grade 5 being the worst) prior to complete four-dose treatment. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1

The percentage of participants who experienced an adverse event by worst grade in each treatment arm. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1

The percentage of participants who experienced a serious adverse event by worst grade in each treatment arm. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1

The percentage of participants who experienced a laboratory abnormality of the liver in each treatment arm. MedDRA Version: 24.1 Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Denominator corresponds to participants with at least on one treatment measurement of the corresponding laboratory parameter. Includes laboratory results reported after the first dose and within 30 days of last dose of study therapy.

The percentage of participants who experienced a laboratory abnormality of the thyroid in each treatment arm. MedDRA Version: 24.1 Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN) (A) Within a 2-week window after the abnormal TSH test date. (B) Includes participants with TSH abnormality and with no FT3/FT4 test values in the 2-week window or with non-abnormal value(s) from only one of the two tests and no value from the other test.

OS was measured in months from the time of randomization to the event date (death) due to any cause. A participant who has not died will be censored at the last known alive date. Based on Kaplan-Meier Estimates. Hazard ratio from Cox proportional hazard model stratified by presence of measurable lesions at baseline per IVRS. P-value from log-rank test stratified by presence of measurable lesions at baseline per IVRS.

OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive. The overall survival rate at time T (6, 12, or 24 months) was defined as the probability that a participant was alive at time T following randomization.

PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants treated beyond progression were considered to have progressive disease at the time of the initial progression event regardless of subsequent tumor response. Participants who started anti-cancer therapy without a prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.

OS rate is calculated as the percentage of participants alive at the indicated timepoints

Objective response rate (ORR) per Independent Review Committee (IRC) is defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of randomized participants using RECIST 1.1

Overall survival was defined as the time from randomization to the date of death. A participant who has not died will be censored at last known date alive. OS will be followed continuously while participants are on the study drug and every 3 months via in-person or phone contact after participants discontinue the study drug. Median and hazard ratio computed using Kaplan-Meier method.

The overall survival rate is the probability that a participant will be alive at 6, 12, and 18 months following randomization. Overall survival was defined as the time between the date of randomization and the date of death as a result of any cause. Survival rates were determined via Kaplan-Meier estimates.

The number of participants who died from any cause was reported for each arm. Interim analysis (Primary Endpoint) was planned to occur after at least 196 deaths, with the actual analysis occurring at 199 deaths.

Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred after 398 deaths (70% of the total OS events needed for final analysis). At that time the data monitoring committee noted that the pre-specified boundary for OS (nominal significance level p \< 0.0148) was crossed while no new safety signals that would affect continuation of the study were found. The study was stopped early by the Sponsor, Bristol-Myers Squibb (BMS) and the interim analysis became the final analysis. As a result, participants in the everolimus groups could be assessed for a crossover to nivolumab treatment if they met all inclusion criteria.

ORR is defined as best response of complete response (CR) or partial response (PR) as measured by RECIST v1.1. RECIST 1.1 = Response Evaluation Criteria in Solid Tumors. CR= Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis. PR= At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

CBR is defined as the percentage of participants who show clinical benefit, defined as obtaining a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; ≥ 30% decrease in the sum of the longest diameter of target lesions), or stable disease (SD) for ≥ 6 months, as determined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Percentage of participants in the nivolumab plus ipilimumab ("CD8 low") arm whose tumors convert from CD8 low (\<15%) to CD8 high (\>=15%) as measured by the percentage of tumoral CD8 cells. Participants in the CD8 high arms are not evaluated for this outcome. On-treatment biopsies for the advanced metastatic cancer cohort were scheduled for as early as possible after the 2nd and 4th doses of ipilimumab (Day 2 - 10 of Cycle 2 and Cycle 6, respectively). On-treatment biopsies for the advanced prostate cancer cohort were scheduled for within 3 days (+/-) of the 2nd and 4th doses of nivolumab (Day 22 of Cycle 1 and Cycle 2, respectively).

Adverse events will be graded according to National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE version 4.03).

OS is defined as the time between the date of randomization and the date of death. For subjects without documentation of death, OS will be censored on the last date the subject was known to be alive.

Evaluation of response by ORR by irRECIST criteria. Response classification will follow the irRECIST criteria and will be defined as PR or CR. Patients who are lost to follow-up without a valid response assessment will be classified as NR (non-responder, progression). The ORR will be computed for all patients with at least one cycle of the study drug.

As determined by CTCAE v5.0 and Grade 3 or 4 adverse event rate was determined by counting the number of subjects that had at least one Grade 3 or Grade 4 adverse while on treatment of nivolumab.

Treatment-emergent AEs will be graded according to NCI CTCAE v4.0, vital signs and clinical laboratory

We defined a novel primary endpoint, combining pathological complete response (pCR) rate among operated patients and long-term (≥12 months) clinical complete response (cCR) rate for those electing watchful waiting, into a composite endpoint of modified pCR (mpCR) rate.

Efficacy measure by objective response rate

Durability or response per RECIST v1.1

Number of participants who are relapse-free at 48 months after initiating treatment in the study.

PFS distribution will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for PFS will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (12-month PFS rate, median PFS, etc.) will be calculated from the K-M life table, each one with its respective 90% confidence interval (CI).

The number of patients that have CR or PR plus the number of patients with stable disease as a percentage of the total number of patients in the study.

The percentage of patients who were alive and disease free at one year past salvage surgery. Patients who were alive at last contact prior to the one year mark are censored. Data analysis conducted through Kaplan Meier methods.

MPR is defined as \<10% viable tumor within resection, at time of surgery.

STN is defined as necrosis of \>70% of tumor base on pathologic analysis of gross tumor resection at time of surgery.

The primary endpoint is the efficacy of treatment via assessment of 6 month rPFS defined by RECIST version 1.1 for soft tissue and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases. rPFS is defined as the duration of time from the first day of the start of study treatment to time of radiographic progression or death due to any cause, whichever occurs first.

Pathologic response rate is defined as the proportion of patients demonstrating a complete pathologic or partial pathologic response, according to central revision (pathology of NKI)

Subjects will be evaluated at each visit by a review of systems based on the most recent version of the NCI common toxicity criteria. Safety and Tolerability of this intervention is defined as following: a toxicity rate p0 of at most 15% of Grade ≥ 3 toxicity events (CTCAE v.4.0) will be considered as acceptable while a toxicity rate p1=35% or more will be considered as unacceptably high. See Adverse Events Section for full summary of data.

A PSA CR will be defined as the percentage of participants with a serum PSA \<0.2 ng/mL and confirmatory PSA \<0.2 ng/mL at least 4 weeks later, as per Prostate Cancer Working Group 2 (PCWG2) recommendations. To qualify as a PSA CR, there must be no evidence of radiographic progression.

Progression-free survival will be determined by immune modified or Prostate Cancer Working Group 3 (PCWG3)-defined RECIST 1.1 radiographic criteria.

Response will be defined by a complete response (CR) or partial response (PR), confirmed or unconfirmed. Response will be defined for patients with measurable disease and who receive at least one dose of combination treatment. Exact binomial 95% confidence intervals for the true PR+CR response rate will be calculated.

RECIST 1.1 and immune mediated RECIST. Confirmatory scans are required. Patients may remain on study post initial progression, but are required to be removed from treatment if they progress an additional 10%.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. 1-year Progression-Free Survival (PFS) Rate refers to the percentage of patients who have not experienced disease progression or death from any cause within one year of starting treatment. The 1-year PFS rate of nivolumab in treatment-naïve patients with clear cell renal cell carcinoma (ccRCC) was assessed according to tumor PD-L1 expression levels.

Proportion of patients with a pathological complete response, as determined on the week 6 surgical specimen using the guidelines published by the International Neoadjuvant Melanoma Consortium: Complete pathological response (pCR) = 0% viable tumour cells in the surgical specimen

The primary efficacy endpoint of the trial is the progression-free survival rate after 6 months (PFSR6), assessed by applying RECIST 1.1.

The primary safety endpoint is to assess the feasibility of combined treatment with trabectedin and nivolumab in patients with metastatic or inoperable soft tissue sarcomas as determined by the safety and tolerability of the combination treatment.

Clinical complete response rate will be defined as the percentage of patients who achieved cT0 or cTa disease after gemcitabine, cisplatin, plus nivolumab.

Determine the ability of clinical complete response (cT0 or cTa) to predict benefit from treatment.Benefit will be defined as a pathologic complete response (\<pT1) in patients undergoing cystectomy and 2 year metastasis-free in patients pursuing surveillance. The positive predictive value of CCR with 95% confidence interval are presented in Outcome Measure Data Table. Positive predictive value is the ratio of patients truly diagnosed as positive to all those who had positive test results.

The primary endpoint of this study is the incidence for high-grade (CTCAE v4.0 Grade 3-4 and Grade 5) adverse reactions of interest (i.e. adverse event related to study treatment). The adverse reactions of interest are: skin, endocrinopathy, gastrointestinal, hepatic, renal, pulmonary, and hypersensitivity adverse events.

Depth of response will be determined for each participant post ide-cel with adjuvant nivolumab indicating if their best overall response is a Complete Response (CR) or stringent Complete Response (sCR). The post-ide-cel disease response assessments will be calculated relative to the participant's pre-ide-cel disease assessment parameters. Responses will be determined per IMWG 2016 response criteria.

Number of participants experiencing adverse events greater than grade 3 related to treatment with nivolumab in combination with relatlimab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Number of participants experiencing adverse events greater than grade 3 related to treatment with nivolumab in combination with ipilimumab per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Clinical complete response rate, per World Health Organization (WHO) Clinical Response Criteria for externally visible tumor(s) which can only be assessed clinically with bidimensional measurements.

Pathological complete response defined as pT0N0 or pTisN0 in all evaluable patients

PFS is defined for all randomized participants as the date from randomization to the date of the documentation of disease progression by BICR or death due to any cause, whichever is earlier. Progressive Disease (PD): 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.

subgroup analysis of PFS. Same definition of PFS as Outcome 1 applies.

Patients achieving a complete (CR) or partial response (PR), assessed by PET/CT (using Lugano)

Percentage of participants with treatment related adverse events (TRAEs) leading to discontinuation within 12 weeks of first dose. AE is defined as any new untoward medical occurrence or worsenig of a preexising medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Grading will be determined for severity according to the NCI CTCAE v5.0.

Objective Response Rate (ORR) per RECIST v1.1 by BICR is defined as the number of participants in the randomized population who achieve a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on BICR assessments (using RECIST v1.1) divided by the number of participants in the population. BOR is defined as the best response, as determined by the BICR, recorded between the date of randomization and the date of first objectively documented progression per RECIST v1.1 or the date of subsequent therapy, whichever occurs first.

will be defined according to RECIST 1.1.

Objective Response Rate (ORR) (as per Recists v1.1) is defined as the percentage of participants whose best overall response (BOR) is either confirmed complete response (CR) or confirmed partial response (PR) based on BICR assessments among all participants in the respective analysis set. BOR is defined as the best response, as determined by the BICR, recorded between the date of randomization and the date of first objectively documented progression or death due to any cause or the date of subsequent therapy, whichever occurs first. For participants without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination. Confirmation of response is required at least 4 weeks after the initial response.

Estimate the overall response rate (ORR) for unirradiated lesions for nivolumab/ipilimumab/radiation in metastatic, microsatellite stable colorectal cancer by RECIST 1.1. ORR is the number of patients that achieve either a CR or PR. * Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Assessed by disease-specific guidelines: multiple myeloma - International Myeloma Working Group response criteria, non-Hodgkin lymphoma - Response assessment will be based on the Lugano Criteria, and chronic lymphocytic leukemia - Response assessment based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria. ORR will be estimated, and its corresponding 95% exact binomial confidence interval (CI) will be provided.

The probability of response to therapy in patients who have progressed on prior immunotherapy. Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) Complete Response (CR) is disappearance of all target and non-target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Summarized as percentage with 80% two-sided exact binominal confidence interval (CI) for each cohort

Each center will assess the pathologic response with a centralized center review in case of cPRR and the analysis will be in intention-to-treat (ITT). cPRR will be defined as complete tumor disappearance of tumor in the low esophagus or the stomach (from 1/3 inferior of the esophagus to pylorus) after surgery anatomopathologic examination according to mandard scale. Surgery will be performed within 5 weeks +\\- 1 week after the last cycle (cycle 6) of neoadjuvant therapy

The number of participants with dose limiting toxicities (DLTs) during the safety run-in phase. DLTS are defined as treatment emergent adverse events (TEAE) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 that occurs during the first 4 weeks (1 cycle) after treatment. Participants who withdraw from the study during the DLT evaluation period or have received less than 1 dose of nivolumab and 75% of accumulative doses of palbociclib of the cycle for reasons other than a DLT will not be considered as DLT-evaluable participants.

RCB 0-I rate is defined as the percentage of randomized participants who achieve RCB 0: no residual disease or RCB-I: minimal residual disease. RCB is a continuous index combining pathological measurements of primary tumor (size and cellularity) and nodal metastases (number and size) defined by a point system at surgery. No participants continued to the randomized phase; trial was closed after completion of the Safety Run-in.

number of patients with no residual invasively growing tumor cells detected by microscopic examination in breast and axilla

patient will be defined as experiencing DCB if they remain free of disease progression at their third trial specific CT scan since treatment start date (i.e. at approximately 27 weeks) or at any CT scan after 27 weeks that shows the patient remains free of disease progression

As the primary outcome in part 1. MPR rate, defined as the number of participants with \<10% residual tumor in lung and lymph nodes, divided by the number of treated participants for each arm. Viable tumors in situ carcinoma should not be included in the MPR calculation.

Primary Outcome for Part 2. Outcome Measure Definition: Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death.

Primary Outcome for Part 3. Outcome Measure Definition: 18months Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death.

The primary endpoint of Part 3 is the surgical conversion rate, defined as the proportion of patients who successfully undergo definitive surgery following neoadjuvant chemoimmunotherapy, relative to the total enrolled population (Intent-to-Treat \[ITT\] analysis set). Statistical Analysis: The surgical conversion rate will be summarized descriptively using frequencies and percentages. The two-sided 95% exact confidence interval (CI) for the proportion will be calculated using the Clopper-Pearson method.

LFS defined as time from study registration to earlier of surgical removal of larynx and/or hypopharynx, or death due to any cause. Participants alive with intact larynx and hypopharynx are censored at date of last disease evaluation. Given limited sample size and zero events, the Kaplan-Meier method was not used for estimate of LFS.

Will be assessed by computed tomography (CT) or magnetic resonance imaging (MRI) scans. The proportions of the primary endpoint in the two treatment groups will be compared at 25% significance level using a two-sided test in proportions. Will re-analyze the primary endpoints using a combined patients collection. Historical controls of patients who received nivolumab alone for 4 weeks in previous window of opportunity trial (CA209-9A7) will be included in the control group. Patients' demographic as well as pre-treatment clinical measurements will be compared between the combined control group versus the treatment group to ensure the homogeneity of the two groups. A multi-variable logistic regression model will be used in the statistical analysis, if any difference in the demographic and clinical predictors between treatment groups is detected. Otherwise, the proportions of the primary endpoint in the two treatment groups will be compared at 5% significance level using a two-sided test.

To assess the 24-week clinical benefit rate of nivolumab combined with bicalutamide and ipilimumab in advanced HER2-negative breast cancers assessed by radiographic criteria (computed tomography (CT) scan or magnetic resonance imaging (MRI) according to iRECIST criteria.

Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

The primary endpoint is the dichotomous endpoint of whether a subject responds to PD-1 immune checkpoint inhibition using nivolumab. Response will be based on the 6-month change (difference between 6-month score and baseline score) in worst (i.e., maximum) histologic classification score, using the 2004 World Health Organization (WHO) classification scale for pre-invasive squamous lesions of the bronchus. The histologic classification consists of: normal (grade 1.0), reserve cell hyperplasia (grade 2.0), squamous metaplasia (grade 3.0), mild dysplasia (grade 4.0), moderate dysplasia (grade 5.0), severe dysplasia (grade 6.0), carcinoma in situ (grade 7.0) and invasive cancer (grade 8.0).

BORR on treatment is the percentage of participants who achieved CR or PR. Best overall response is the best response recorded from study registration until the first disease progression/diagnosis of invasive OSCC (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Best overall response was determined by using composite scores based on both measurement and histology, matching to the response grid as following, (1)CR, a decrease of \>80% or more; (2)PR, a decrease of 40-80%; (3)SD, neither PR or PD, (4)PD, an increase of 10% or more.

The probability of PFS measured from of beginning of study treatment, without local, regional or distant disease recurrence (appearance of new metastatic lesions). Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.

The probability of PFS measured from of beginning of study treatment, without local, regional or distant disease recurrence (appearance of new metastatic lesions). Measurement/determination of disease progression (recurrence) by CT and MRI, Chest X-Ray (Lesions acceptable as measurable when clearly defined and surrounded by an aerated lung), Tumor Markers, Clinical Examination (Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, including a ruler to estimate size of the lesion, Cytology and Histology (Cytologic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the measurable tumor has met response or stable disease criteria, Ultrasound (Ultrasound may be used only as an alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.

Presence /absence of enteral feeding tube.

ORR was defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR) based on Blinded Independent Central Review (BICR) assessment. RECIST Criteria: CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. RANO Criteria: CR= Disappearance of all enhancing measurable and nonmeasurable disease; stable or improved nonenhancing T2/FLAIR lesions; off corticosteroids; and stable or improved clinically PR= ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasureable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; and stable or improved clinically.

The overall response rate is defined as the percentage of patients with a reduction in tumor size while on treatment.

PIS were developed using methods previously described (Farsaci, B. et al. Cancer Immunol. Res. 2016), based on tertile distribution of frequencies and ratios of peripheral immune cell subsets in patients prior to therapy. Immune subsets were calculated as a % of PBMC and sorted by frequency. Points were assigned to each subset in a given patient based on tertile distribution. For subsets with an expected positive effect on anti-tumor immunity zero (0) points were assigned to the low bin, one (1) point for the middle bin, and two (2) points if in the high bin. For subsets with an expected negative effect on anti-tumor immunity zero (0) points were assigned to the high bin, one (1) point for the middle bin, and two (2) points if in the low bin. The peripheral immunoscore for a given patient was the sum of points assigned to the individual PBMC subsets that were included within the immunoscore. Positive change means enhanced and negative change means reduced immune function.

MTD is defined as the dose in which 1 or more dose limiting toxicities (DLT) is reported by study participants in Part 1 within the first cycle of treatment. Participants in Part 1 must receive at least 2 doses of nivolumab and at least 75% of sorafenib doses within 28 days (1 cycle), or experience a qualifying DLT event to be evaluable.

All adverse event (AE) will be summarized based on proportion of total participants in Part 2 to evaluate the safety of the treatment combination in participants with Child-Pugh B7-9 liver function as measured by proportion of participants with an AE of toxicity grade \>=3 as graded by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and assessed as at least possibly related to sorafenib, nivolumab, or the combination of therapies.

Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented progression, as determined by BICR (per RECIST 1.1), or death due to any cause, whichever occurs first. Baseline tumor assessment is defined as tumor scans prior to or on randomization date. Participants who did not have documented progression per BICR and who did not die or participants who started any subsequent anti-cancer therapy without a prior reported progression per BICR will be censored at the date of the last tumor assessment on or prior to initiation of the subsequent anticancer therapy, if any. Participants who die without a reported prior progression per BICR will be considered to have progressed on the date of death. Participants who did not have any baseline or post baseline tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date.

The rate of completion of all adjuvant therapy by patients treated at the maximum tolerated dose (MTD) schedule will be determined and compared to a historical control rate of 52%, the rate of completion of a standard adjuvant cisplatin-based platform to determine feasibility of study treatment

Defined as the time from randomization to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation

Objective response rate per prostate cancer clinical trials working group 3 (ORR-PCWG3) for target lesions and assessed by MRI is the percentage of participants who have a confirmed complete or partial best overall response (BOR) per PCWG3 among treated participants who have measurable disease

Prostate-specific antigen response rate (RR-PSA) is the percentage of treated participants with a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result

Objective Response Rate (ORR) is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. CR = disappearance of all target lesions, PR is =\>30% decrease in sum of diameters of target lesions. Participants who discontinue due to toxicity or clinical progression prior to post-baseline tumor assessments will be considered as non-responders. Participants who discontinue for other reasons prior to their first dose of study drug will not included in the analysis.

Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 confirmed by repeat assessment ≥4 weeks after initial documentation. The categories are: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).

The rate (and its 95%CI) of patients who report at least one high-grade (Grade 3-4 and Grade 5) adverse events of interest will be provided.

ORR will be assessed per cohort by an IRC according to RECIST v1.1.

A dose-limiting toxicity (DLT) is defined as a drug-related AE occurring in the first 6 weeks of study treatment. A participant was considered evaluable for a DLT if study treatment was delayed \> 2 weeks or was discontinued due to a related Adverse Event (AE), or if planned study treatment (3 doses of nivolumab in Module A, 2 doses of nivolumab plus ipilimumab in Module B) was administered and safety evaluation after 6 weeks on study is available to the study steering committee (SSC).

The number of Safety Lead-In Participants who experienced a Serious Adverse Event (SAE) during the course of the study.

The number of Safety Lead-In Participants who experienced an Adverse Event (AE) during the course of the study that lead to discontinuation of study therapy.

Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1.

Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.

Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.

The number of participants who experienced at least 1 select AE of Grade 3-5, judged to be related to study drug per investigator with onset on or after first dose of study treatment and within 30 days of last dose of study treatment, divided by number of treated participants. AE grade is defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 criteria. The select AEs consist of pulmonary events, gastrointestinal events, hepatic events, renal events, skin events, endocrine events categories, thyroid disorders, diabetes, pituitary, adrenal disorder subcategories. Grade 3 is defined as severe or medically significant but not immediately life-threatening. Grade 4 is defined as life-threatening consequences and urgent intervention indicated. Grade 5 is defined as death related to AE.

Objective response rate: the sum of patients with either a pCR defined as no invasive and no in situ residuals present in the surgical specimen or partial pathologic response defined at least a 30% reduction in the size of the lesion in the surgical specimen. The reduction in size will be determined by comparing the pretreatment clinical measurements (the sum of the greatest axial measurement obtained with calipers at the time of initial evaluation) with the final pathologic measurements.

ORR is defined as proportion of patients with reduction in tumor burden as assessed by RECIST 1.1 criteria (investigator-assessed).

ORR is defined as proportion of patients with reduction in tumor burden as assessed by RECIST 1.1 criteria (investigator-assessed).

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to \<10 mm. Blood tumor mutational burden (bTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in serum. CR+PR, confidence interval based on the Clopper and Pearson method.

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to \<10 mm. Blood tumor mutational burden (bTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in serum. CR+PR, confidence interval based on the Clopper and Pearson method.

Objective response rate (ORR) is defined as the percent of treated participants with a best overall response of a complete response (CR) or partial response (PR) assessed by investigator per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR is disappearance of all target lesions and a reduction in pathological lymph node (whether target or non-target) short axis to \<10 mm. Tissue tumor mutational burden (tTMB) is the total number of nonsynonymous somatic mutations produced by a tumor that are detected in tumor tissue samples. CR+PR, confidence interval based on the Clopper and Pearson method.

Adverse events will be assessed (according to CTCAE v4.0) during treatment and follow-up.

To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival

To assess efficacy of neoadjuvant nivolumab monotherapy and neoadjuvant nivolumab plus relatlimab in terms of major pathologic response

The complete metabolic response (CMR) rate is defined as the percent of all response-evaluable participants who, assessed by the BICR, achieved best response of CMR. Complete metabolic response (CMR): * Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale * New lesions: No * Bone marrow: No FDG-avid disease Participants who stopped study treatment early for toxicity without a CMR were evaluable. Confidence interval is based on the Clopper and Pearson method

Event Free Survival (EFS) is the time from the first treatment to the earliest occurrence of composite events including: Disease progression (PD), Failure to achieve complete metabolic response (CMR) after 4 cycles of N+Bv and 2 cycles of Bv+B, Secondary malignancy, Death . PD : Lymph Nodes and Lesions: new growth or increase of \>= 50% in size from nadir. New or growing lesions outside the lymph nodes. Spleen: Significant increase in spleen size, either from a previously enlarged state or from normal size. New Lesions: Yes Bone Marrow: New or returning FDG-avid disease CMR: Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale New lesions: No Bone marrow: No FDG-avid disease Participants without an "event" were censored at the last tumor assessment. Those who started subsequent anticancer therapy without a prior "event" were censored at the last tumor assessment prior to or upon starting subsequent therapy. Based on Kaplan-Meier Estimates.

The complete metabolic response (CMR) rate is defined as the percent of all response-evaluable participants who, assessed by the BICR, achieved best response of CMR. Complete metabolic response (CMR): * Lymph nodes/extralymphatic sites: Score 1, 2, 3 with/without residual mass on 5-point scale * New lesions: No * Bone marrow: No FDG-avid disease Participants who came off study treatment early for toxicity without a CMR were evaluable. Confidence interval is based on the Clopper and Pearson method

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.

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.

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 1. Bone disease progression by Prostate Cancer Working Group (PCWG2) 2. 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.

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 1. Bone disease progression by (Prostate Cancer Working Group) PCWG2 2. 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.

The percentage of participants who experienced at least 1 adverse event in the MedDRA Anaphylactic Reaction broad scope SMQ with onset on the day of or within 2 days after any study therapy infusion during the combination period (Part 1).

ORR is percent of participants whose best overall response (BOR) is complete response (CR) or partial response (PR). BOR is the best response from the start of the study treatment until objectively documented progression per RECIST v1.1 or subsequent anticancer therapy, whichever occurs first. For participants who received re-treatment or were re-randomized, the re-treatment and re-randomized therapies were considered subsequent anticancer therapy. CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The Response Evaluation Criteria in Solid Tumors (RECIST) is a standard way to measure the response of a tumor to treatment. CR+PR, confidence interval based on Clopper and Pearson method.

Duration of Response is defined as the time between the date of first response and the date of first documented disease progression as determined by RECIST 1.1 or death due to any cause (death occurring after re-treatment or randomization to new combination treatment was not considered), whichever occurred first. Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Median computed using Kaplan -Meier method

The PFSR at 24 weeks is defined as the proportion of treated participants remaining progression free and surviving at 24 weeks since the first dosing date. Progressive Disease (PD) 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. (Note: the appearance of one or more new lesions is also considered progression). Point estimates are derived from Kaplan-Meier analyses, the 95% CIs are derived from Greenwood formula

Number of patients with a best overall response of CR or PR, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

ORR is the percent of participants whose best overall response (BOR) is complete response (CR) or partial response (PR). BOR is the best response from the start of the study treatment until objectively documented progression per RECIST v1.1 or subsequent anticancer therapy, whichever occurs first. CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The Response Evaluation Criteria in Solid Tumors (RECIST) is a standard way to measure the response of a tumor to treatment. CR+PR, confidence interval based on Clopper and Pearson method.

Duration of Response (DOR) is the time between the date of first response and the date of first documented disease progression as determined by RECIST 1.1 or death due to any cause, whichever occurred first. Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Median computed using Kaplan -Meier method.

The PFSR at 24 weeks is defined as the proportion of treated participants remaining progression free and surviving at 24 weeks since the first dosing date. Progressive Disease (PD) 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. Point estimates are derived from Kaplan-Meier analyses, the 95% CIs are derived from Greenwood formula.

ORR is defined as best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each treatment group. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

The time between the date of first confirmed response to the date of the first documented tumor progression, or death due to any cause, whichever occurs first.

Time to Response (TTR) for participants demonstrating a response (either CR or PR) was defined as the time from the date of randomization to the date of the first confirmed response. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Percentage of participants with a confirmed objective response rate (ORR) by blinded independent central review (BICR) assessment was analyzed and reported for both PCNSL and PTL patient populations. This endpoint is further defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR), based on the IPCG Criteria for PCNSL and Lugano 2014 response evaluation for PTL, divided by the number of treated participants within each cohort.

The primary endpoint will be the 2-year progression-free percent and will be reported with corresponding 90% confidence interval. All patients who have received one dose of study treatment will be included for the analysis, including those who die or are lost to follow-up before 2 years. Progression is defined as ≥ 25% increase and an absolute increase of ≥ 0.5g/dL from their nadir in their serum or urine m-spike or FLC with no CRAB features attributable to MM progression.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete response (CR) rate as defined by CT scan using RECIST 1.1 criteria - disappearance of all target lesions and no new sites or disease-related symptoms confirmed at least 4 weeks after initial documentation and CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) down to normal limits; Partial Response (PR), at least a 30% decrease in the sum of the diameters of target lesions; Overall Response (OR) = CR + PR. When a complete response is documented, a Positron emission tomography (PET) scan will be obtained to confirm.

To evaluate the anti-tumor activity for single-agent nivolumab (cohort 1) or nivolumab plus ipilimumab following radiation therapy (cohort 2) among patients with recurrent/progressive grade I, II or III meningioma.

Objective response rate (ORR) in PD-L1 positive (PD-L1 ≥1%) and PD-L1 negative (PD-L1 \<1%) participants was defined as the percentage of treated participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 based on Blinded Independent Central Review (BICR) assessment.

Dose limiting toxicities (DLTs) were defined as any of the items listed below. 1. Any Grade 2 drug-related uveitis or eye pain that does not respond to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires systemic treatment. 2. Any Grade 2 drug-related pneumonitis or interstitial lung disease that does not resolve to dose delay and systemic steroids in 14 days. 3. Any Grade 3 non-skin drug-related adverse event with the exception of laboratory abnormalities that cannot be alleviated or controlled by appropriate care within 14 days. 4. Any Grade 4 drug-related adverse event including laboratory abnormalities except Grade 4 leukopenia or neutropenia lasting \< 14 days and asymptomatic amylase/lipase elevation. 5. Drug-related hepatic function laboratory abnormalities.

Number of participants with adverse events (AEs) including serious adverse events (SAEs) and deaths graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy.

Number of participant with specific liver laboratory abnormalities graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy.

Number of participants with specific thyroid laboratory abnormalities graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Ipilimumab combined with chemotherapy.

It is defined as the number of patients reaching up to 6 months post-radiotherapy without any episode of CTCAE v4.0 grade ≥3 pneumonitis. It will be used as the primary endpoint for all patients followed for at least 6 months beyond radiotherapy.

The number of patients that have CR or PR plus the number of patients that have SD, as a percentage of the total number of patients in the study.

The total number of participants with high grade treatment related select adverse events.

Objective Response Rate (ORR) was defined as the number of participants with a best overall response of confirmed Complete Response (CR) or Partial Response (PR) (per RECIST 1.1 criteria) divided by the number of all treated participants. RECIST 1.1 = Response Evaluation Criteria in Solid Tumors. CR= Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. BIRC= blinded independent review committee

Objective Response Rate (ORR) was defined as the number of participants with a best overall response of confirmed Complete Response (CR) or Partial Response (PR) (per RECIST 1.1 criteria) divided by the number of all treated participants. RECIST 1.1 = Response Evaluation Criteria in Solid Tumors. CR= Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. BIRC= blinded independent review committee PD-L1 expression level= membranous staining in greater than or equal to 5% and greater than or equal to 1% tumor cells. n = Number of participants in each category

TTR is defined as the time from first dosing date to the date of the first confirmed complete response (CR) or partial response (PR), as assessed by the Blinded Independent Review Committee (BIRC). Complete response is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

DOR is defined as the time from first confirmed response, complete response (CR) or partial response (PR) to the date of the first documented tumor progression as determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first. Participants who start subsequent therapy without a prior reported progression will be censored at the last evaluable tumor assessments prior to initiation of the subsequent anticancer therapy. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who neither progress nor die will be censored on the date of their last evaluable tumor assessment.

Proportion of patients with a complete or partial response in intracranial metastases as measured using RECIST 1.1 criteria (modified for brain metastases - bm RECIST), from week 12.

The number of participants who reported high-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, select AEs (pulmonary,gastrointestinal, skin, renal, hepatic, endocrine) were summarized using the all treated analysis set by system organ class and Medical Dictionary for Regulatory (MedDRA) preferred term.

ORR is the percent of participants achieving either a complete remission (CR) or partial remission (PR) according to the 2007 IWG criteria. Analyses of efficacy endpoints were performed separately for each cohort, according to IWG 2007. For cohort A and B, if the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. For cohort C, no evidence of FDG-avid disease in bone marrow was required in all participants in lieu of bone marrow aspirate/ biopsy. CR is the percent of participants with a best overall response (BOR) of CR (disappearance of all evidence of disease) according to the 2007 IWG criteria, based on IRRC assessment. PR is the percent of participants with a best overall response (BOR) of PR (regression of measurable disease and no new sites) according to the 2007 IWG criteria, based on IRRC assessment. Confidence interval based on Clopper-Pearson method.

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.

The number of patients alive and free of disease at 12 months after randomization in arm A compared to DFS in arm B.

The number of patients alive and free of disease at 24 months after randomization

The number of patients alive and free of disease at 48 months after randomization

ORR is determined by an independent radiologic review committee (IRRC) according to the revised International Working Group Criteria for non-Hodgkin Lymphoma. ORR is defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) and expressed as a percentage of all treated participants. CR=Disappearance of all clinical/radiographic evidence of disease, regression of lymph nodes to normal size, absence of spleen, liver, and bone marrow involvement. PR=Regression of measurable disease and no new sites; no increase in size of liver or spleen. \>=50% decrease in SPD of up to 6 largest dominant masses (index lesions); no increase in size of other nodes (non-index lesions)

ORR is defined as the percentage of participants with a Best Overall Response (BOR) of Complete Remission (CR) or Partial Remission (PR), according to the 2007 revised International Working Group (IWG) Criteria for Malignant Lymphoma, , based on IRRC assessment. CR= Disappearance of all evidence of disease, confirmed by PET scan; PR= Regression of measurable disease and no emergence of new sites

Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (\<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

The percentage of participants with treatment-related grade 3-5 adverse events (AEs) is defined as the number of participants who experienced at least 1 treatment related grade 3 - 5 adverse event (AE) per national cancer institute common terminology criteria for adverse events (NCI CTCAE v4.0, any preferred term) with an onset date after or on first day of Induction Period #1 and not later than discontinuation date from Induction Period #2, divided by the total number of treated participants. Adverse Event (AE) = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may or may not have a causal relationship with treatment. Treatment-related = having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 3=Severe Gr 4=Potentially Life-threatening or disabling Gr 5=Death

ORR is defined as the percentage of participants with best overall response (OR) of confirmed complete response (CR) or partial response (PR) divided by the number of participants who received treatment. The IRC-assessed ORR (using RECIST v1.1, to confirm response and based on the IRC global radiology review after incorporation of on-study clinical data) was estimated using a binomial response rate and its corresponding 2-sided 95% exact confidence intervals using the Clopper-Pearson method.

DOR is defined as the time from first confirmed response (CR or PR) per IRC assessment to the date of the first documented tumor progression as determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first. Participants who start subsequent therapy without a prior reported progression will be censored at the last evaluable tumor assessments prior to initiation of the subsequent anticancer therapy. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who neither progress nor die will be censored on the date of their last evaluable tumor assessment. Median values of DOR, along with two-sided 95% CI in each treatment group will be computed based on a log-log transformation method.

The primary endpoint for the Stage 1 phase of the study is dose-limiting toxicity which will be assessed for each Stage 1 subject using the DLT criteria

The primary endpoint for the Stage 1 phase of the study is the 2-year progression-free endpoint which will be determined for each subject as a binary variable indicating if they are alive and progression-free at 2 years (PFS2)

Safety will be evaluated for all treated subjects using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

DLT

Review of adverse events including serious adverse events (SAEs), adverse events meeting protocol defined DLT criteria, adverse events leading to study treatment or study discontinuation, and adverse events resulting in death

Maximum tolerated dose (MTD) / maximum feasible dose (MFD) of enadenotucirev administered IV in combination with nivolumab.

TIL density will be assessed and compared between the three arms using the Two-sample t-Test.

Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Safety will be assessed by quantifying the toxicities and grades experienced by participants who have received at least one dose of study treatment.

The percentage of patients who experience unacceptable toxicity during combination treatment by arm is tabulated. Unacceptable toxicity is defined as any grade 3, 4, or 5 adverse event that is possibly, probably, or definitely related to either nivolumab or DC vaccination treatment during concurrent treatment, or any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires systemic treatment. In addition, any complication following resection (ex. excessive intracranial bleeding, delays in wound healing) that are prolonged longer than 4-6 weeks post-surgery will be considered an unacceptable toxicity.

* Protocol defined hematologic DLTs that occur during the first cycle that are attributed as possibly, probably, or definitely related to study treatment * Protocol defined non-hematologic DLTs possibly, probably, or definitely related grade 3 or 4 non-hematologic toxicity that occurs during the first cycle of treatment.

An unacceptable toxicity will be defined as any life-threatening toxicity ≥ Grade 3 that is possibly, probably, or definitely related to the PEP CMV vaccine. There are exceptions listed in the protocol

The rate of Dose Limiting Toxicities (DLT) that are determined to be definitely, probably or possibly attributed to SBRT or one or both of the immunotherapies. Patients receiving one of more fractions of SBRT are evaluable for DLT. Toxicities include grade 3 or higher adverse events, by organ system, by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Maximum tolerable dose is defined by less than or equal to 30% dose limiting toxicity (DLT) event rate within a given dose combination,

-Stromal TIL score is defined as the percentage of tumor stroma area that was occupied by mononuclear inflammatory cells.

Safety lead-in consists of the first 12 patients treated on the study (Arm A and Arm B).

To determine the MTD and preliminary safety of HCQ when administered in conjunction with one of the following treatments in patients with advanced melanoma: * HCQ administered in combination with nivolumab; or * HCQ administered in combination with nivolumab and ipilimumab followed by maintenance nivolumab

To assess the ORR as measured by RECIST v1.1. in subjects with advanced melanoma

An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

The maximum tolerated dose (MTD) is commonly estimated to be the maximum dose that can be determined through DLT of two among 6 subjects administered with TST001 Q2W in 28 days cycles.

The RP2D will be determined during the dose expansion stage of the study. RP2D will be determined using available safety and efficacy data.

DLT is short for Dose Limiting Toxicity. dose-limiting describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.

DLT is short for Dose Limiting Toxicity. dose-limiting describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.

Characterization of TST001 + CAPOX safety profile including frequency and severity of adverse events that are related to treatment.

Number of participants experiencing study drug-related adverse events Grade 3 or higher as defined by CTCAE v5.0

Evaluated by the fold change in interferon-producing mutant-KRAS-specific CD8 and CD4 T cells after vaccination at 16 weeks compare to pre-vaccination baseline.

Characterization of TST001 safety profile including frequency and severity of adverse events that are related to treatment.

As measured by number of participants experiencing dose related toxicity (DLT) in each escalating cohort

Characterization of TST001 + Nivolumab safety profile including frequency and severity of adverse events that are related to treatment.

Characterization of TST001 + Nivolumab + mFOLFOX6 safety profile including frequency and severity of adverse events that are related to treatment.

Characterization of TST001 + Gemcitabine + albumin-bound paclitaxel safety profile including frequency and severity of adverse events that are related to treatment.

Safety and tolerability of VE800 in combination with nivolumab: Number of Participants with Adverse Events

Patients who experience a greater than 30 day toxicity induced delay of surgery will be counted as a failure for the primary feasibility endpoint.

If one or fewer dose limiting toxicities (DLT's) occur in 6 participants the study will advance to the next dose level. If 2 or more DLT's occur at a dose level, the prior dose level will be identified as the RP2D.

Continued complete remission by computed tomography (CT) scan 1 year after surgery.

Number of participants experiencing a Dose Limiting Toxicity (DLT) in each dose level. DLT is defined as any of the following study drug-related toxicities occurring during the first cycle of study drug on study: * Grade 4 anemia * Grade ≥ 3 neutropenia lasting ≥ 14 days * Grade ≥ 3 febrile neutropenia * Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically significant bleeding * Treatment-related ≥ grade 4 AEs, except transient hyperglycemia * Grade ≥ 3 Pneumonitis or recurrent Grade 2 pneumonitis * Grade ≥ 3 Nephritis * Grade ≥ 3 elevated AST or ALT * Grade ≥ 2 eye pain or reduction of visual acuity that does not respond to topical therapy, improve to ≤ grade 1 within 2 weeks of topical therapy, or requires systemic therapy * Any other Grade ≥ 3 toxicities (with certain exceptions for transient AEs or asymptomatic labs)

The proportion of subjects with partial response (PR) or complete response (CR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Per RECIST 1.1, complete response is defined as disappearance of all target lesions, and partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Lesions are assessed by CT or MRI.

Measured by the incidence of adverse events (AEs), serious adverse events (SAEs), deaths

Biochemistry - Na (mmol/l), K (mmol/l), Cl (mmol/l), Ca (mmol/l), Ca ionized (mmol/l), Mg (mmol/l), P (mmol/l), urea (mmol/l), creatinine (µmol/l), LDH (µkat/l), AST(µkat/l), ALT(µkat/l), ALP(µkat/l), GMT(µkat/l), total bilirubin (µmol/l), conjuged bilirubin (µmol/l), total protein (g/l), albumin (g/l), fasting glucose (mmol/l), amylase (µkat/l), C-reactive protein (mg/l), endocrine panel - TSH (mU/l), Free T3 (pmol/l), Free T4 (pmol/l), hematology - complete blood count (CBC): hemoglobin (g/l), hematocrit (ratio), white blood cells (WBC) (10E9/l), red blood cells (10E12/l), platelets (10E9/l) including differential (all 10E9/l), coagulation - APTT (ratio), PT (ratio)

Maximum tolerable dose will be defined as the highest dose level where at most 1 of 6 patients experience dose limiting toxicity (DLT).

Complete response rate will be determined by dividing the number of CRs (per Lugano criteria) by the total number of evaluable patients.

Cmax is the maximum observed serum nivolumab concentration. Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.

Tmax is the time taken to reach the maximum observed serum nivolumab concentration (Cmax). Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.

AUC (TAU) is the area measured under the concentration-time curve taken over the dosing interval. Collected for Arm A, B, and D on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 1 Day 21. Collected for Arm E on Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 4, Cycle 1 Day 8, Cycle 1 Day 15.

Ctau is the observed serum nivolumab concentration at the end of the dosing interval. Collected for Arma A, B, and D.

Ctrough assessed during Part C. Ctrough is the lowest observed serum nivolumab concentration.

Defined as a PSA \>0.2ng/ml for radical prostatectomy patients or PSA \>2.0ng/ml for patients who received primary radiation therapy at a time point of 10 months after start of therapy.

All participants receiving at least one dose of the study drug will be evaluated for safety and toxicity. Adverse events will be classified and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

An initial set of 6 participants will be enrolled at Dose Level 1. If 0 or 1 dose limiting toxicity (DLT) is observed during Cycle 1, enrollment in the phase II at Dose Level 1 will be initiated. If DLT is observed in 2 patients during Cycle 1, an additional 3 participants will be enrolled at Dose Level 1 (total 9 patients). If DLT is observed in ≤ 2 of 9 patients, enrollment in the phase II as Dose Level 1 will be initiated. If DLT is observed in 3 or more of 9 patients at Dose Level 1, the maximum tolerated dose (MTD) will have been exceeded, this combination will be determined to be unsafe to conduct the phase II portion of the trial, and the trial will be discontinued. CTCAE

PSA failure is defined for first line Radiotherapy (RT) treatment in accordance with NCCN guidelines: PSA failure for treatment with RT is defined as PSA increase by 2 ng/mL or more above the nadir PSA.

-Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

-MHC tetramers made against the identified neoantigens will be used to evaluate PBMC for neoantigen-reactive T cells

-Laser capture microdissection will be performed to perform genomic studies on specific areas of tissue

-Multiparametric flow cytometry or CyTOF will be performed in parallel to evaluate for any shifts (in quality and quantity) in peripheral leukocyte subsets.

-DLT is defined as any unexpected, treatment-related grade 4 or 5 adverse event that occurs with increased severity or incidence outside of known, expected toxicities, that occur in the first 6 patients enrolled (safety lead-in cohort)

An adequate quality tumor biopsy providing sufficient information prior to choosing a combination immunotherapy/Stereotactic Body Radiation Therapy (SBRT)

Dose Limiting Toxicities are defined as adverse events have to be at least possibly related to study treatment, and not to disease progression, be clinically relevant and a clinically relevant shift from baseline.

Safety-related events in clinical trials include Adverse Events (AEs), Serious Adverse Events (SAEs), and deaths. An AE is any new or worsening medical issue in a participant receiving the study drug, regardless of its relation to the drug. This includes abnormal lab results, symptoms, or diseases. An SAE is a more severe AE that results in death, is life-threatening, requires or prolongs hospitalization, causes significant disability, involves a birth defect, or is deemed medically important-potentially jeopardizing the participant or requiring intervention, even if not immediately life-threatening. These definitions help ensure consistent reporting and evaluation of safety during clinical studies.

Number of participants with clinical laboratory abnormalities in specific thyroid tests

Number of participants with clinical laboratory abnormalities in specific liver tests.

ORR is defined as the proportion of all treated participants whose BOR is either confirmed complete response (CR) or confirmed partial response (PR).

Maximum tolerated dose of 177Lu-DOTA0-Tyr3-Octreotate as determined during the phase I portion.

Time between start of treatment and tumor progression or death

As determined by rate of toxicity grade 3 or higher per CTCAE v4.0

Number of participants with Adverse events

Number of participants with Adverse events

Number of participants with Adverse events

Number of participants with Adverse Events leading to death.

Number of participants with clinical laboratory abnormalities.

ORR is defined as the number of subjects with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by BICR, according to RECIST v1.1 criteria, divided by the number of treated subjects. The BOR is defined as the best response designation recorded between the date of first dose and the date of initial objectively documented progression per RECIST v1.1 or the date of subsequent therapy, whichever occurs first. For participants without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination. For purposes of analysis, if a subject receives one dose and discontinues the study without assessment or receives subsequent therapy prior to assessment, this participant will be counted in the denominator (as nonrespondent).

Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)

The primary endpoint was the 1-year OS rate of each treatment arm, compared to the historical rate of 35% for gemcitabine and nab-Paclitaxel. OS was defined as the time from treatment initiation until death from any cause. Patients who were not reported as having died at the time of analysis were censored at the most recent contact date. OS and the 1-year OS rate were estimated by the Kaplan-Meier method for each treatment arm. The 1-year OS rate and corresponding one-sided, 95% CI were calculated to determine whether the lower bound of the CI excluded the assumed historical value of 35%. P values were calculated using a one-sided, one-sample z-test of the Kaplan-Meier estimate of the 1-year OS rate (and its standard error) against the historical rate of 35%. This study was not powered for statistical comparison between arms.

To assess the safety and tolerability of lirilumab in combination with nivolumab

To assess the safety and tolerability of lirilumab in combination with nivolumab

Number of participants with any grade of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine the safety and tolerability of Nivolumab and Daratumumab

Number of participants with laboratory abnormalities in specific liver tests based on US conventional units to determine the safety and tolerability of Nivolumab and Daratumumab. The number of participants with the following laboratory abnormalities from on-treatment evaluations will be summarized: * ALT or AST \> 3 x ULN, \> 5 x ULN, \> 10 x ULN and \> 20 x ULN * Total bilirubin \> 2 x ULN * ALP \> 1.5 x ULN * Concurrent (within 1 day) ALT or AST \> 3 x ULN and total bilirubin \> 1.5 x ULN * Concurrent (within 30 days) ALT or AST \> 3 x ULN and total bilirubin \> 1.5 x ULN * Concurrent (within 1 day) ALT or AST \> 3 x ULN and total bilirubin \> 2 x ULN * Concurrent (within 30 days) ALT or AST \> 3 x ULN and total bilirubin \> 2 x ULN

Number of participants with laboratory test results of worst (CTC v4.0) grades 0-4 to determine the safety and tolerability of Nivolumab and Daratumumab

A traditional escalation rule, also known as "3 + 3" rule, will be used for this study. Subjects are treated in groups of 3 with each receiving the same dose. If none of the 3 subjects experience a DLT within Cycle 1, the next group of 3 subjects receives the next higher dose, otherwise, the group will expand to 6 subjects treated at the same dose level. If ≤ 1 of the 6 subjects treated at that dose level experience a DLT within Cycle 1, the trial will continue to the next higher dose level. If ≥ 2 of the 6 experience a DLT at the dose level within Cycle 1, then escalation stops at that level and the prior dose level will be considered the MTD. If MTD is not identified and both dose levels are tolerated, 1.5 mg will be considered the recommended Phase II dose (RP2D) for the expansion.

Includes body temperature, respiratory rate, blood pressure and heart rate. Blood pressure and heart rate should be measured after the participant has been resting quietly for at least 5 minutes.

Participants peak nivolumab serum concentration

Participant trough nivolumab serum concentration

Participant average nivolumab serum concentration

Participant observed time of maximum concentration

Area under the serum concentration-time curve from time zero to time of last quantifiable concentration

Total clearance of serum concentration of nivolumab

Vlume of distribution of nivolumab serum concentration

Half-Life of nivolumab derived from serum concentration

Safety of the vaccine (Strata A and B) or vaccine in combination with nivolumab (Stratum C) will be assessed for participants who received the vaccination. The severity of toxicities will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE)version 5.0. and include any clinically-significant lab abnormalities meeting Grade 3, 4, or 5 criteria according to CTCAE. Grade 1 \& 2 AEs will be summarized if probably, possible, or definitely related to study therapy. Descriptive statistics will be utilized to display the data on toxicity reported by participants.

OS12 is defined as the percentage of participants still alive at 12 months, and is the clinical efficacy, primary endpoint for Stratum A. Any eligible participant that received at least one dose of the K27M/TT vaccine will be considered evaluable for clinical efficacy. OS12 will be censored at the last contact date and estimated using the Kaplan-Meier method.

To identify maximum tolerated dose (MTD) of nivolumab for combination treatment of nivolumab following Y-90 in patients with advanced hepatocellular carcinoma. The MTD will be defined as the highest dose of nivolumab that causes dose limiting toxicities (DLTs) in \<2 of 6 patients. The Phase I portion of the study follows a 3+3 dose escalation design. Nivolumab has two dose levels: Level 1: 80mg IV every 2 weeks, Level 2: 240mg IV every 2 weeks. Toxicity will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03. A DLT is defined as an Adverse Event (AE) or abnormal laboratory value assessed as at least possibly related to the study medication, occurs ≤ 28 days (1 cycle) following the first dose of nivolumab and meets any of the criteria listed in the Protocol (Section 4.3.1).

Evaluate tumor response by assessing the proportion of patients with Objective response rate (ORR) (according to RECIST v. 1.1 criteria) to the combination treatment of nivolumab with Y-90 by examining imaging scans. Per RECIST v. 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

DLTs are defined as any study drug-related toxicity (brentuximab vedotin or nivolumab) that requires either a dose reduction or delay of more than 7 days of either study drug in Cycle 2 or delays the Cycle 3 Day 1 administration of combined treatment by more than 7 days.

Number of participant Deaths

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 drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.

A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: * results in death * is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe) * requires inpatient hospitalization or causes prolongation of existing hospitalization. * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * is an important medical event

Number of participants with adverse events leading to discontinuation

Number of participants with adverse events leading to dose delay or reduction

Number of participants with Drug Related Adverse Events

Percentage of participants with specific thyroid test abnormalities

Percentage of participants with specific Liver test abnormalities

A drug related 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 drug that has a causal relationship with the treatment. AEs are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03) (NCI CTCAE) guidelines where Grade 3= Severe and Grade 4= Life-threatening.

A drug related serious adverse event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event that has a casual relationship with the treatment. SAEs are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.03) (NCI CTCAE) guidelines where Grade 3= Severe and Grade 4= Life-threatening.

The number of participants with the following laboratory abnormalities from the following on-treatment evaluations: * ALT or AST \> 3 x ULN, \> 5 x ULN, \> 10 x ULN and \> 20 x ULN * Total bilirubin \> 2 x ULN * Concurrent (within 1 day) ALT or AST \> 3 x ULN and total bilirubin \> 2 x ULN * Concurrent (within 30 days) ALT or AST \> 3 x ULN and total bilirubin \> 2 x ULN

The number of participants with Grade 3-4 laboratory results according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. Note: Grade 4 Toxicities not included in the below table if there were no participants that experienced Grade 4 in that category. Grade 3: prolonged recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae \[e.g., renal impairment, pulmonary infiltrates\]. Grade 4: Life-threatening; pressor or ventilatory support indicated.

Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented tumor progression, as determined by investigators (per RECIST v1.1), or death due to any cause, whichever occurs first.

Overall survival (OS) is defined as the time from randomization to the date of death.

Percentage of participants who experienced a treatment-related AE during the course of the study that lead to discontinuation of both study drugs.

Number of participants with any grade of drug-related select adverse events (AEs) including endocrine, gastrointestinal, hepatic, pulmonary, renal, skin, and hypersensitivity AEs in Neoadjuvant cohort

Number of participants with any grade of drug-related serious adverse events (SAEs) in Neoadjuvant cohort

Rate of surgery delay is defined as the percentage of participants in the neoadjuvant cohort with surgery delayed \> 4 weeks from the planned surgery date or planned start date for chemoradiation due to a drug-related adverse event. Participants with the following diseases will be assessed: 1. HPV positive squamous cell carcinoma of the Head and Neck (SCCHN); 2. HPV negative SCCHN; 3. Cervical Carcinoma; 4. Vaginal/Vulvar Carcinoma; 5. Merkel Cell Carcinoma

Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) using RECIST 1.1 criteria. An ORR in excess of 10% will be considered of clinical interest, and an ORR of 25% or greater will be considered of strong clinical interest. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with the following diseases will be assessed: 1. EBV positive related gastric cancer; 2. HPV positive SCCHN; 3. Other anogenital HPV associated cancers; 4. GYN (Cervical, Vaginal, Vulvar) carcinoma; 5. Merkel cell carcinoma (MCC); 6. Nasopharyngeal carcinoma (NPC)

MTD is highest dose level in which \<2 patients of 6 develop first cycle dose-limiting toxicity (DLT).

The number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants.

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. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.

Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by BICR per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the 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 5mm (Note: The appearance of 1or more new lesions is also considered progression).

Objective response rate (ORR) is defined as the percent of all treated participants whose best overall response (BOR) is either complete response (CR) or partial response (PR) by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the 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 5mm (Note: The appearance of 1or more new lesions is also considered progression).

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment.

A Serious Adverse Event (SAE) is 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.

Number of participants that experienced an AE leading to discontinuation. An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment.

The number of participants who died.

Number of participants that experienced a clinical laboratory test abnormality, including hematology and serum chemistry, and thyroid panel abnormalities. Abnormalities considered are those Grade 3-4 events with a \>= 1 grade increase from baseline. Laboratory tests are graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 3 is severe, and Grade 4 is life threatening. Baseline is defined as the last non-missing measurement prior to the first dosing date and time.

Baseline and post-treatment modulation of serum levels of chemokines, cytokines and other immune mediators were assessed by techniques that included ELISA or other multiplex-based assay methods. Primary analysis included IFN-gamma and IFN-gamma inducible factors, including chemokine \[C-X-C motif\] ligand 9 (CXCL9) and CXCL10

Biomarkers examined were percent positive CD8 and percent positive CD4, both using the Mosaic Singleplex IHC assay. Analyses are presented with the medians at baseline and on-treatment, rather than the median change because the baseline values differed across groups. Baseline was defined as the last non-missing value on or prior to the first dose of study therapy. Biopsies were also collected on treatment.

Number and percent of participants that experienced drug related Grade 3-4 AEs occurring up to 100 days after the last dose of study drug.

Number and percent of participants that experienced drug related Grade 3-4 SAEs occurring up to 100 days after the last dose of study drug.

Number and percent of participants that experienced drug related Grade 3-4 AEs occurring up to 100 days after the last dose of study drug.

Safety assessments by treatment arm and dose level were based on incidence of AEs, and the incidence of serious adverse events (SAEs). AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling.

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling.

The number of participants who experienced an AE of interest due to any cause is presented. Endocrine, Gastrointestinal, Hepatic, Pulmonary, Renal, Skin, and Hypersensitivity/Infusion select AEs were identified that are potentially associated with the use of nivolumab, based on the following 4 guiding principles: * AEs that may differ in type, frequency, or severity from AEs caused by non-immunotherapies * AEs that may require immunosuppression (eg, corticosteroids) as part of their management * AEs whose early recognition and management may mitigate severe toxicity * AEs for which multiple event terms may be used to describe a single type of AE, thereby necessitating the pooling of terms for full characterization.

The number of subjects with selected hepatic laboratory abnormalities is reported. AST= aspartate aminotransferase; ALT= alanine aminotransferase; ULN= upper limit of normal.

The number of subjects with selected thyroid laboratory abnormalities is reported. FT3 and FT4 test abnormalities were considered for a 2-week window after the abnormal TSH test date. TSH= thyroid-stimulating hormone; FT3= Free T3; FT4= Free T4; LLN= lower limit of normal; ULN= upper limit of normal

The objective of the study was to investigate the pharmacodynamic immunomodulatory activity of anti-PD-1 antibody in activated and memory T cells with metastatic clear-cell Renal Cell Carcinoma (RCC)

Objective is to investigate the pharmacodynamic immunomodulatory activity of serum chemokines (CXCL9, CXCL10)

Objective is to investigate the pharmacodynamic immunomodulatory activity of serum chemokines (CXCL9, CXCL10)

The objective of the study was to investigate the pharmacodynamic immunomodulatory activity of anti-PD-1 antibody on circulating CD4 infiltrations in tumors in participants with metastatic clear-cell Renal Cell Carcinoma (RCC).

The objective of the study was to investigate the pharmacodynamic immunomodulatory activity of anti-PD-1 antibody on circulating CD8 infiltrations in tumors in participants with metastatic clear-cell Renal Cell Carcinoma (RCC).

incidence of all cause and treatment related serious adverse events

incidence of all cause and treatment related adverse events which lead to discontinuation

incidence of all cause and treatment related deaths

incidence of all cause and treatment related Adverse events in certain organ systems

Number of Participants with On-Treatment Laboratory Abnormalities in Specific Liver Tests Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN)

Number of Participants with On-Treatment Laboratory Abnormalities in Specific Thyroid Tests Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)

AE=any new unfavorable symptom, sign or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity or drug dependency/abuse; is life-threatening, an important medical event or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible or missing relationship to study drug. Death=during the study and up to 28 days past study discontinuation. The select AEs were determined using the Medical Dictionary for Regulatory Activities (MedDRA, v15.1) and graded using the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0.

Alkaline phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatinine and Total Bilirubin. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Abnormal values for ALP, ALT and AST were based on grades; Gr 1: \> 1.0 - 2.5 \* upper limits of normal (ULN); Gr 2: \> 2.5 - 5.0 \* ULN; Gr 3: \> 5.0 - 20.0 \* ULN; Gr 4: \> 20.0 \* ULN. Abnormal values for Creatinine were based on Gr 1: \> 1.0 - 1.5\*ULN; Gr 2: \> 1.5 - 3.0\*ULN; Gr 3: \> 3.0 - 6.0\*ULN; Gr 4: \> 6.0\*ULN. Abnormal values for Total Bilirubin were based on Gr 1: \> 1.0 - 1.5 \* upper limits of normal (ULN); Gr 2: \> 1.5 - 3.0 \* ULN; Gr 3: \> 3.0 - 10.0 \* ULN; Gr 4: \> 10.0 \* ULN.

Hemoglobin, Lymphocytes, Neutrophils, Platelets and Leukocytes. National Cancer Institute Common Terminology Criteria (CTC) version (v) 3.0 was used to determine Grade (Gr). Abnormal values for Hemoglobin were based on Gr 1: 10.0 - less than (\<) lower limit of normal (LLN); Gr 2: 8.0 - \< 10.0; Gr 3: 6.5 - \< 8.0; Gr 4: \< 6.5. Abnormal values for Lymphocytes were based on Gr 1: 0.8 - \< 1.5; Gr 2: 0.5 - \< 0.8; Gr 3): 0.2 - \< 0.5; Gr 4: \< 0.2. Abnormal values for Neutrophils were based on Gr 1: 1.5 - \< 2.0; Gr 2: 1.0 - \< 1.5; Gr 3: 0.5 - \< 1.0; Gr 4: \< 0.5. Abnormal values for Platelets were based on Gr 1: 75.0 - \< lower limits of normal (LLN); Gr 2: 50.0 - \< 75.0; Gr 3: 25.0 - \< 50.0; Gr 4: \< 25.0. Abnormal values for Leukocytes were based on Gr 1: 3.0 - \< LLN; Gr 2: 2.0 - \< 3.0; Gr 3: 1.0 - \< 2.0; Gr4: \< 1.0.

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Severe=All Grade 3 or 4 events. Death=during the study and up to 28 days past study discontinuation. AEs graded using the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. irAEs=unknown etiology, associated with study drug and consistent with an immune phenomenon. DLT: ≥Gr 3 AE(s) or lab abnormality without alternative explanation other than drug.

Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated enzyme-linked immunosorbent assay (ELISA) method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The pharmacokinetic (PK) parameter of Cmax was measured in micrograms per milliliter (µg/mL).

Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated ELISA method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The PK parameter of Tmax was measured in hours (h).

AUC(0-T): Area under the concentration-time curve from the time of dosing to the time of the last observation. AUC(INF): Area under the curve from the time of dosing extrapolated to infinity. Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated ELISA method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The PK parameters of AUC(0-T) and AUC (INF) were measured in micrograms\*hours per milliliter (µg\*h/mL).

Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated ELISA method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The PK parameter of T-HALF was measured in days.

Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated ELISA method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The PK parameter of CLT was measured in milliliters per hour per kilogram body weight (mL/h/kg).

Nivolumab in human serum was assayed during the period of known analyte stability and reported as final data for this study by PPD® (Richmond, Virginia) using a cross-validated ELISA method. For the single dose (Day 1), serum concentrations of nivolumab were assessed: prior to dosing, at 30 minutes (during dosing), immediately post-dose, and 30 minutes post-infusion end time; at 1, 2, 4, 6, 8, 24, 48, and 72 hours post-infusion end time; and on Days 8, 15, 22, 29, 43, 57, 71, and 85. The PK parameter of Vz was measured in milliliters per kilogram of body weight (mL/kg).

The Best Overall Response Rate (BORR) was defined as the number of participants who had a confirmed complete response (CR) or partial response (PR) during the study divided by the total number of participants evaluated. Response was based on tumor assessment for both target and non-target lesions using: Clinical examination; Chest X-ray; Computed Tomography and Magnetic Resonance Imaging; Bone scan; Ultrasound. Per National Cancer Institute Response Evaluation Criteria in Solid Tumors (RECIST) v1.0, best overall response (BOR) for tumors was confirmed CR or PR. CR=disappearance of all target and non-target lesions; PR=at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter. Confidence intervals (CIs) were computed using the Clopper and Pearson method.

The PSA response rate was defined as the number of participants who had at least a 50% decrease of the PSA value from the PSA reference value divided by the total number of participants evaluated (percent of participants). PSA reference value was the PSA concentration measured immediately prior to dosing on Day 1. PSA response was assessed using the Recommendations from the National Cancer Institute Prostate-Specific Antigen Working Group. A PSA response had to be confirmed at least 4 weeks after first response. 95% exact CIs were computed using the Clopper and Pearson method.

The number of participants with DLTs will defined as treatment-related, grade 3-5 adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

The MTD is defined as the dose at which no more than 1/6 patients experience a DLT