The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. T-HALF was measured from first dose to end of the induction period (4 doses) in day(s). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. CLT was measured from first dose to end of the induction period (4 doses) in milliliters per hour (mL/h). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. Vss was measured from first dose to end of the induction period (4 doses) in liter(s) (L). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

Overall Response (OR) was determined as the combination of assessments of index and non-index lesions using mWHO criteria which were: Complete Response=complete disappearance of all lesions; Partial Response=decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index lesions, in the absence of Complete Response; Stable Disease=does not meet criteria for complete or partial response, in the absence of progressive disease, or a decrease or tumor stabilization of one or more non-index lesions; Progressive Disease (Progression)=at least 25% increase in the sum of the products of all index lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesion(s), or progression of non-index lesion(s). OR was measured across the entire study from Day 1 to the last patient, last visit (2009 to 2012)

ir RC=modifications of mWHO criteria reflecting clinical experience with ipilimumab in over 20 completed and/or ongoing clinical studies. irRC were designed to capture clinical activity of ipilimumab immunotherapy that may not be adequately addressed by the mWHO criteria. irComplete Response (irCR): Complete disappearance of all index and non-index lesions. irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index and all new measurable lesions in the absence of irCR, non-index lesions not considered. irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease (irPD). irProgressive Disease (irPD): At least 25% increase in Tumor Burden when compared to sum of the products of diameters of lesions at nadir.

Overall survival (OS) was defined as the time between the first dose of study treatment and death and was analyzed using Kaplan-Meier methods, with participants who had not died censored at the last date known to be alive. Overall survival was measured in months.

Absolute lymphocyte counts (ALC) were obtained throughout the study as part of the hematology panel. Results collected from 28 days prior to the first infusion of ipilimumab through the end of the Induction-Dosing Period were included in the analyses of ALC. Mean ALC was estimated via an extended linear model, with linear splines and a spatial exponential within-patient correlation structure. Lymphocytes were measured as 1000 cells per micro liter (c/µL).

Adverse events (AEs) and Serious AEs (SAEs) were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events version 3.0. Medical Dictionary for Regulatory Activities (MedDRA) version 15.1 was used. Note there is a difference in number of participants with an SAE in this outcome measure and the number listed in the Adverse Events Section of this document. This is because the SAEs reported in the xml upload of the Adverse Events section includes additional participants who reported SAEs after the clinical study report database was closed.

Electrochemiluminescent (ECL) Immunoassay was used to detect human anti-human ipilimumab antibodies (HAHA) in serum. Blood samples were collected prior to the start of each ipilimumab infusion at Weeks 1, 4, 7, 10, 24, and at end of treatment. Those participants who were positive HAHA on treatment were then tested for presence of neutralizing antibodies.

Systolic and Diastolic blood pressure were measured in millimeters of mercury (mmHg) and were obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below.

Pulse Rate was measured in beats per minute (bpm) and was obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below.

Common Terminology Criteria (CTC), Version 3 used to assess parameters. Lower limit of normal (LLN); grams per deciliter (g/dL); Grade (GR); cells per microliter (c/µL). Hemoglobin Gr 1:\

Alanine transaminase (ALT); Aspartate aminotransferase (AST); Alkaline phosphatase (ALP); upper limits of normal (ULN). ALT Gr 1:>1.0 to 2.5*ULN; Gr 2: >2.5 to 5.0*ULN; Gr 3: >5.0 to 20.0*ULN; Gr 4: >20.0*ULN. AST Gr 1: >1.0 to 2.5*ULN; Gr 2: >2.5 to 5.0*ULN; Gr 3: >5.0 to 20.0*ULN; Gr 4: >20.0*ULN. Total bilirubin Gr 1: >1.0 to 1.5*ULN; Gr 2: >1.5 to 3.0*ULN; Gr 3: >3.0 to 10..0*ULN; Gr 4: >10.0.0*ULN. ALP (U/L) Gr1:>1.0 to 2.5*ULN, Gr2:>2.5 to 5.0*ULN, Gr3:>5.0 to 20.0*ULN, Gr4:>20.0*ULN. Albumin (low) Gr 1:<LLN to 3 g/dL; Gr 2: <3.0 - 2.0 g/L; Gr 3: < 2 g/dL. Creatinine Gr 1: >1 - 1.5*ULN; Gr 2: >1.5 - 3.0*ULN; Gr 3: >3.0- 6.0*ULN; Gr 4: >6.0*ULN. Lipase (U/L) Gr 1: 1.0 to 1.5*ULN; Gr 2: >1.5 to 2.0*ULN; Gr 3: 2.0 to 5; Gr 4: >5*ULN. Amylase (U/L) Gr 1: >ULN to 1.5*ULN; Grade 2 >1.5 to 2.0*ULN, Grade 3 >2.0 to 5.0*ULN, Grade 4 >5.0*ULN. Baseline was screening or Day 1, prior to first dose of drug.

Sodium high (H) Gr 1:>ULN - 150; Gr 2: >150 - 155; Gr 3: >155 - 160; Gr 4: >160 mmol/L; Sodium low(L) Gr 1:<LLN - 130; Gr 3: <130 - 120; Gr 4: <120 mmol/L. Potassium (H) Gr 1: >ULN - 5.5; Gr 2: >5.5 - 6.0; Gr 3: > 6.0 - 7.0; Gr 4: >7.0 mmol/L; Potassium (L) Gr 1: <LLN - 3.0; Gr 2: <LLN - 3.0; Gr 3: < 3.0 - 2.5; Gr 4: <2.5 mmol/L. Bicarbonate Gr1: 16-<LLN, Gr2: 11-16, Gr3, 8-11, Gr4: <8 milliequivalents per liter (mEq/L). Phosphorus Gr 1: 2.5 - <LLN, Gr2 2.0-<2.5, Gr3: 1.0-<2.0, Gr4: <1.0. Calcium (L) Gr 1: <LLN to 8.0; Gr2: 7.0 - 8.0; Gr3: 6.0-7.0; Gr 4: <6.0 mg/dL; calcium (H) Gr1:>ULN - 11.5, Gr2:>11.5 - 12.5, Gr3: 12.5 - 13.5, Gr4: >13.5. Baseline is screening or Day 1, prior to first dose of drug.

Total of all reporting groups

Body weight measured in kilograms (kg).

ECOG performance: 0= Fully active, able to carry on all pre-disease performance without restriction;1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2=Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or Chair; 5=Dead

The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. Tmax was measured from first dose to end of the induction period (4 doses) in hours (h). Samples were obtained at 0 h (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.

The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. T-HALF was measured from first dose to end of the induction period (4 doses) in day(s). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.

The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. CLT was measured from first dose to end of the induction period (4 doses) in milliliters per hour (mL/h). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.

The single-dose pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. AUC(0-21d) was measured from first dose to end of the induction period as micrograms*hours per milliliter (μg*h/mL). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.

The single-dose Pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. Vss was measured from first dose to end of the induction period (4 doses) in liter(s) (L). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox [version 2.6.1]).

PK evaluable Population: All participants who received at least one dose of drug and had adequate PK profiles.

Overall Response (OR) was determined as the combination of assessments of index and non-index lesions using mWHO criteria which were: Complete Response=complete disappearance of all lesions; Partial Response=decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index lesions, in the absence of Complete Response; Stable Disease=does not meet criteria for complete or partial response, in the absence of progressive disease, or a decrease or tumor stabilization of one or more non-index lesions; Progressive Disease (Progression)=at least 25% increase in the sum of the products of all index lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesion(s), or progression of non-index lesion(s). OR was measured across the entire study from Day 1 to the last patient, last visit (2009 to 2012)

All participants randomized to a treatment arm who received at least 1 dose of ipilimumab as randomized with measurable disease at baseline, at least one baseline assessment and one on-treatment tumor assessment, no resection of index lesions.

ir RC=modifications of mWHO criteria reflecting clinical experience with ipilimumab in over 20 completed and/or ongoing clinical studies. irRC were designed to capture clinical activity of ipilimumab immunotherapy that may not be adequately addressed by the mWHO criteria. irComplete Response (irCR): Complete disappearance of all index and non-index lesions. irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all index and all new measurable lesions in the absence of irCR, non-index lesions not considered. irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease (irPD). irProgressive Disease (irPD): At least 25% increase in Tumor Burden when compared to sum of the products of diameters of lesions at nadir.

All participants randomized to a treatment arm who received at least 1 dose of ipilimumab as randomized with measurable disease at baseline, at least one baseline assessment and one on-treatment tumor assessment, no resection of index lesions, and for irRC, no resection of new lesions.

Overall survival (OS) was defined as the time between the first dose of study treatment and death and was analyzed using Kaplan-Meier methods, with participants who had not died censored at the last date known to be alive. Overall survival was measured in months.

All participants who received at least one dose of ipilimumab.

Absolute lymphocyte counts (ALC) were obtained throughout the study as part of the hematology panel. Results collected from 28 days prior to the first infusion of ipilimumab through the end of the Induction-Dosing Period were included in the analyses of ALC. Mean ALC was estimated via an extended linear model, with linear splines and a spatial exponential within-patient correlation structure. Lymphocytes were measured as 1000 cells per micro liter (c/µL).

All participants in the Pharmacodynamic data set with: (1) a baseline ALC evaluation; and (2) at least 1 post-baseline ALC evaluation (after the date of first dose).

Adverse events (AEs) and Serious AEs (SAEs) were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events version 3.0. Medical Dictionary for Regulatory Activities (MedDRA) version 15.1 was used. Note there is a difference in number of participants with an SAE in this outcome measure and the number listed in the Adverse Events Section of this document. This is because the SAEs reported in the xml upload of the Adverse Events section includes additional participants who reported SAEs after the clinical study report database was closed.

All participants who received at least 1 dose of ipilimumab.

Electrochemiluminescent (ECL) Immunoassay was used to detect human anti-human ipilimumab antibodies (HAHA) in serum. Blood samples were collected prior to the start of each ipilimumab infusion at Weeks 1, 4, 7, 10, 24, and at end of treatment. Those participants who were positive HAHA on treatment were then tested for presence of neutralizing antibodies.

Participants who received study drug and had HAHA data prior to infusion in Week 1 and while on treatment.

Systolic and Diastolic blood pressure were measured in millimeters of mercury (mmHg) and were obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below.

All participants who received at least 1 dose of ipilimumab and had available data at baseline and the specific timepoint.

Pulse Rate was measured in beats per minute (bpm) and was obtained after the participant had been seated for 5 minutes. Vital sign measurements were collected at Screening (baseline), Weeks 1, 4, 7, 10, 12, 24 and every 12 weeks thereafter in the Maintenance Phase, and at the End of Treatment visit. The change from baseline in blood pressure one hour post end of infusion at the end of induction Period, Week 36 of Maintenance Period, and end of treatment, up to data cutoff for July 2010 are presented below.

All participants who received at least 1 dose of ipilimumab and had available data at baseline and the specific timepoint.

Common Terminology Criteria (CTC), Version 3 used to assess parameters. Lower limit of normal (LLN); grams per deciliter (g/dL); Grade (GR); cells per microliter (c/µL). Hemoglobin Gr 1:\

All participants who received at least 1 dose of ipilimumab and had available data at baseline and post baseline.

Alanine transaminase (ALT); Aspartate aminotransferase (AST); Alkaline phosphatase (ALP); upper limits of normal (ULN). ALT Gr 1:>1.0 to 2.5*ULN; Gr 2: >2.5 to 5.0*ULN; Gr 3: >5.0 to 20.0*ULN; Gr 4: >20.0*ULN. AST Gr 1: >1.0 to 2.5*ULN; Gr 2: >2.5 to 5.0*ULN; Gr 3: >5.0 to 20.0*ULN; Gr 4: >20.0*ULN. Total bilirubin Gr 1: >1.0 to 1.5*ULN; Gr 2: >1.5 to 3.0*ULN; Gr 3: >3.0 to 10..0*ULN; Gr 4: >10.0.0*ULN. ALP (U/L) Gr1:>1.0 to 2.5*ULN, Gr2:>2.5 to 5.0*ULN, Gr3:>5.0 to 20.0*ULN, Gr4:>20.0*ULN. Albumin (low) Gr 1:<LLN to 3 g/dL; Gr 2: <3.0 - 2.0 g/L; Gr 3: < 2 g/dL. Creatinine Gr 1: >1 - 1.5*ULN; Gr 2: >1.5 - 3.0*ULN; Gr 3: >3.0- 6.0*ULN; Gr 4: >6.0*ULN. Lipase (U/L) Gr 1: 1.0 to 1.5*ULN; Gr 2: >1.5 to 2.0*ULN; Gr 3: 2.0 to 5; Gr 4: >5*ULN. Amylase (U/L) Gr 1: >ULN to 1.5*ULN; Grade 2 >1.5 to 2.0*ULN, Grade 3 >2.0 to 5.0*ULN, Grade 4 >5.0*ULN. Baseline was screening or Day 1, prior to first dose of drug.

All participants who received at least 1 dose of ipilimumab and had available data at baseline and post baseline.

Sodium high (H) Gr 1:>ULN - 150; Gr 2: >150 - 155; Gr 3: >155 - 160; Gr 4: >160 mmol/L; Sodium low(L) Gr 1:<LLN - 130; Gr 3: <130 - 120; Gr 4: <120 mmol/L. Potassium (H) Gr 1: >ULN - 5.5; Gr 2: >5.5 - 6.0; Gr 3: > 6.0 - 7.0; Gr 4: >7.0 mmol/L; Potassium (L) Gr 1: <LLN - 3.0; Gr 2: <LLN - 3.0; Gr 3: < 3.0 - 2.5; Gr 4: <2.5 mmol/L. Bicarbonate Gr1: 16-<LLN, Gr2: 11-16, Gr3, 8-11, Gr4: <8 milliequivalents per liter (mEq/L). Phosphorus Gr 1: 2.5 - <LLN, Gr2 2.0-<2.5, Gr3: 1.0-<2.0, Gr4: <1.0. Calcium (L) Gr 1: <LLN to 8.0; Gr2: 7.0 - 8.0; Gr3: 6.0-7.0; Gr 4: <6.0 mg/dL; calcium (H) Gr1:>ULN - 11.5, Gr2:>11.5 - 12.5, Gr3: 12.5 - 13.5, Gr4: >13.5. Baseline is screening or Day 1, prior to first dose of drug.

All participants who received at least 1 dose of ipilimumab and had available data at baseline and post baseline.

10 mg/kg ipilimumab was given IV once every 3 weeks (up to 4 doses) in the induction phase (Weeks 1, 4, 7, and 10); it was given once every 12 weeks in the maintenance phase for 48 weeks. In Process C, ipilimumab was manufactured by the Sponsor using material from a sub-clone of the original transfectoma cell line, modified cell culture and purification steps.