Comparison of Ipilimumab Manufactured by 2 Different Processes in Participants With Advanced Melanoma

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00920907
• Collaborator: Medarex (Industry)
• Enrollment: 99
• Locations: 7
• Arms: 2
• Duration (Months): 38
• Patients Per Site: 14.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to compare pharmacokinetics of ipilimumab manufactured by two different processes

Condition or Disease	Intervention/Treatment	Phase
Advanced Melanoma	Biological: Ipilimumab	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 99 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Parallel, Open-Label Study to Compare the Pharmacokinetics of Ipilimumab (BMS-734016) Process C to Process B in Subjects With Advanced Melanoma
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ipilimumab (Process B) Reference	Biological: Ipilimumab; Solution, Intravenous, 10 mg/kg, Every 3 weeks (up to 4 doses) in induction phase, every 12 weeks in maintenance phase, 48 weeks; Other Names: BMS-734016 MDX010
Experimental: Ipilimumab (Process C) Test	Biological: Ipilimumab; Solution, Intravenous, 10 mg/kg, Every 3 weeks (up to 4 doses) in induction phase, every 12 weeks in maintenance phase, 48 weeks; Other Names: BMS-734016 MDX010

Outcome Measures

Primary Outcome Measures

1. Maximum Observed Serum Concentration (Cmax) of Ipilimumab Manufactured by Process C Relative to the Cmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population [Day 1 to Day 84]

   Single-dose Pharmacokinetic (PK) parameters of ipilimumab were derived from serum concentration versus time data. Cmax was measured from first dose to end of the induction period (4 doses) as micrograms per milliliter (μg/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]).

2. Area Under the Serum Concentration-time Curve (AUC) From Time Zero to Day 21, AUC(0-21d), of Ipilimumab Manufactured by Process C Relative to the AUC(0-21d) of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population [Day 1 to Day 84]

   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]).

Secondary Outcome Measures

1. Time of Maximum Observed Serum Concentration (Tmax) of Ipilimumab Manufactured by Process C Relative to the Tmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population [Day 1 to Day 84]

   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]).

2. Terminal Elimination Half Life (T-HALF) of Ipilimumab Manufactured by Process C Relative to the T-HALF of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population [Day 1 to Day 84]

   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]).

3. Clearance (CLT) of Ipilimumab Manufactured by Process C Relative to the CLT of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population [Day 1 to Day 84]

   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]).

4. Volume of Distribution at Steady State (Vss) of Ipilimumab Manufactured by Process C Relative to the Vss of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population [Day 1 to Day 84]

   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]).

5. Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants [Day 1 to last patient, last visit, approximately 3 years]

   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)

6. Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants [Day 1 to last patient, last visit, approximately 3 years]

   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.

7. Median Overall Survival Following First Ipilimumab Dose - All Treated Participants [Week 1 (first dose) to last patient, last visit, approximately 3 years]

   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.

8. Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period [Day 0 (prior to first dose) to Day 84]

   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).

9. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation [Day 1 to last patient, last visit, approximately 3 years]

   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.

10. Number of Participants Who Developed Antibodies and Neutralizing Antibodies [Prior to start of drug Week 1 to Week 24 on treatment or end of treatment]

    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.

11. Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff [Screening to data cut off for July 2010, approximately 36 Weeks]

    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.

12. Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff [Screening to data cut off for July 2010, approximately 36 Weeks]

    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.

13. Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants [Screening to data cut off for July 2010, approximately 36 Weeks]

    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:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL. Absolute neutrophil (ANC) and ANC plus bands: Gr 1:<LLN to 1.5*10^3 c/µL, Gr 2:<1.5 to 1.0*10^3 c/µL, Gr 3:<1.0 to 0.5*10^3 c/µL, Gr 4:<0.5*10^3 c/µL. Platelet count Gr 1:LLN to 75.0*10^9 c/L, Gr 2:<75.0 to 50.0*10^9 c/L, Gr 3:<50.0 to 25.0*10^9 c/L, Gr 4:<25.0 to 10^9 c/L. Lymphocytes Gr 1: <1.5 to 0.8 *10^3 c/µL, Gr 2 <0.8 to 0.5 *10^3 c/µL, Gr 3: <0.5 to 0.2 *10^3 c/µL, Gr 4: <0.2*10^3 c/µL. Leukocytes Gr 1:<LLN to 3.0 *10^3 c/µL, Gr 2; <3.0 to 2.0 *10^3 c/µL, Gr 3: <2.0 to 1.0 *10^3 c/µL, Gr 4: <1.0 *10^3 c/µL. Baseline is screening or Day 1, prior to dosing.

14. Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants [Screening to data cut off for July 2010, approximately 36 Weeks]

    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.

15. Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants [Screening to data cut off for July 2010, approximately 36 Weeks]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologic diagnosis of malignant melanoma

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Measurable/evaluable disease per modified World Health Organization (mWHO) criteria

Exclusion Criteria:

• Active Brain Metastasis

• Primary ocular or mucosal melanoma

• Prior Autoimmune disease

• Inadequate hematologic, hepatic or renal function

• Use of immunosuppressants

• Prior treatment with a CD137 agonist or cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Angeles Clinic & Research Inst.	Los Angeles	California	United States	90025
2	California Pacific Medical Center	San Francisco	California	United States	94115
3	H Lee Moffitt Cancer Center	Tampa	Florida	United States	33612-9416
4	Memorial Sloan Kettering Cancer Center	New York	New York	United States	11065
5	Carolinas Medical Center	Charlotte	North Carolina	United States	28204
6	St Luke'S Hospital And Health Network	Bethlehem	Pennsylvania	United States	18015
7	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023

Sponsors and Collaborators

• Bristol-Myers Squibb
• Medarex

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT00920907
• Other Study ID Numbers: CA184-087
• First Posted: Jun 15, 2009
• Last Update Posted: Jun 20, 2014
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Melanoma; Ipilimumab

Study Results

Participant Flow

Recruitment Details	Study started August 3, 2009, ended October 31, 2012; Induction Phase (Weeks 1, 4, 7, 10), Maintenance Phase (participants without immune-related progressive disease (irPD) received ipilimumab every 12 weeks until disease progression, toxicity, pregnancy, death, withdrew consent, lost to follow up); Patients followed for 10 weeks post last dose.
Pre-assignment Detail	99 participants enrolled; 75 participants randomized and treated. 24 participants not treated due to violations of inclusion or exclusion criteria.

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	Intravenous (IV) solution of 10 milligrams (mg) ipilimumab per kilogram (kg) of body weight was given 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 B, ipilimumab was manufactured by the Lonza company using material from transfectoma cell line.	Intravenous (IV) solution of 10 milligrams (mg)ipilimumab per kilogram (kg) of body weight was given 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 Sponsor using material from a sub-clone of the original transfectoma cell line, modified cell culture and purification steps.
Period Title: Induction Period
STARTED	37	38
COMPLETED	15	16
NOT COMPLETED	22	22
Period Title: Induction Period
STARTED	15	15
COMPLETED	3	2
NOT COMPLETED	12	13

Baseline Characteristics

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)	Total
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.	Total of all reporting groups
Overall Participants	37	38	75
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 67.6%	24 63.2%	49 65.3%
>=65 years	12 32.4%	14 36.8%	26 34.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (14)	59 (12)	58 (13)
Sex: Female, Male (Count of Participants)
Female	12 32.4%	14 36.8%	26 34.7%
Male	25 67.6%	24 63.2%	49 65.3%
Region of Enrollment (participants) [Number]
United States	37 100%	38 100%	75 100%
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	81.3 (13.4)	80.7 (13.3)	81.0 (13.3)
Eastern Cooperative Oncology Group (ECOG) (participants) [Number]
ECOG=0	25 67.6%	21 55.3%	46 61.3%
ECOG=1	12 32.4%	17 44.7%	29 38.7%

Outcome Measures

1. Primary Outcome

Title	Maximum Observed Serum Concentration (Cmax) of Ipilimumab Manufactured by Process C Relative to the Cmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
Description	Single-dose Pharmacokinetic (PK) parameters of ipilimumab were derived from serum concentration versus time data. Cmax was measured from first dose to end of the induction period (4 doses) as micrograms per milliliter (μg/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]).
Time Frame	Day 1 to Day 84

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	36	38
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	252.68 (29)	251.26 (24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab (Process B), Ipilimumab (Process C)
	Comments	Biocomparability of ipilimumab Process C to ipilimumab Process B was concluded if the 90% confidence intervals (CIs) for the ratio of geometric means for Cmax were contained within 80% to 125%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric mean
	Estimated Value	1.010
	Confidence Interval	(2-Sided) 90%; 0.916 to 1.114
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time of Maximum Observed Serum Concentration (Tmax) of Ipilimumab Manufactured by Process C Relative to the Tmax of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
Description	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]).
Time Frame	Day 1 to Day 84

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	36	38
Median (Full Range) [h]	2.00	2.50

3. Secondary Outcome

Title	Terminal Elimination Half Life (T-HALF) of Ipilimumab Manufactured by Process C Relative to the T-HALF of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
Description	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]).
Time Frame	Day 1 to Day 84

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	33	36
Mean (Standard Deviation) [days]	15.45 (6.93)	15.23 (8.73)

4. Secondary Outcome

Title	Clearance (CLT) of Ipilimumab Manufactured by Process C Relative to the CLT of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
Description	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]).
Time Frame	Day 1 to Day 84

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	33	36
Geometric Mean (Geometric Coefficient of Variation) [mL/h]	12.590 (45)	12.934 (53)

5. Primary Outcome

Title	Area Under the Serum Concentration-time Curve (AUC) From Time Zero to Day 21, AUC(0-21d), of Ipilimumab Manufactured by Process C Relative to the AUC(0-21d) of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
Description	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]).
Time Frame	Day 1 to Day 84

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	33	36
Geometric Mean (Geometric Coefficient of Variation) [μg*h/mL]	40374.47 (25)	40085.9 (29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab (Process B), Ipilimumab (Process C)
	Comments	Biocomparability of ipilimumab Process C to ipilimumab Process B was to be concluded if the 90% confidence intervals (CIs) for the ratio of geometric means for ipilimumab Cmax were contained within 80% to 125%. Point estimates and 90% CIs were constructed for the ratio of geometric means (Process C/Process B) for ipilimumab Cmax.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric mean
	Estimated Value	1.032
	Confidence Interval	(2-Sided) 90%; 0.922 to 1.156
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Volume of Distribution at Steady State (Vss) of Ipilimumab Manufactured by Process C Relative to the Vss of Ipilimumab Manufactured by Process B - Evaluable Pharmacokinetic Population
Description	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]).
Time Frame	Day 1 to Day 84

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	33	36
Geometric Mean (Geometric Coefficient of Variation) [L]	6.06 (21)	5.96 (32)

7. Secondary Outcome

Title	Best Overall Tumor Response Per Investigator Based on Modified World Health Organization (mWHO) Criteria - All Randomized Participants
Description	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)
Time Frame	Day 1 to last patient, last visit, approximately 3 years

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	36	37
Complete Response mWHO	0 0%	1 2.6%
Partial Response mWHO	4 10.8%	10 26.3%
Stable Disease mWHO	11 29.7%	7 18.4%
Progression mWHO	14 37.8%	17 44.7%
Unable to determine mWHO	7 18.9%	2 5.3%

8. Secondary Outcome

Title	Best Overall Tumor Response Per Investigator Based on Immune-related (ir) Response Criteria (RC) - All Randomized Participants
Description	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.
Time Frame	Day 1 to last patient, last visit, approximately 3 years

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	33	34
ir Complete Response	0 0%	1 2.6%
ir Partial Response	2 5.4%	9 23.7%
ir Stable Disease	11 29.7%	8 21.1%
ir Progression	14 37.8%	14 36.8%
Unable to determine	6 16.2%	2 5.3%

9. Secondary Outcome

Title	Median Overall Survival Following First Ipilimumab Dose - All Treated Participants
Description	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.
Time Frame	Week 1 (first dose) to last patient, last visit, approximately 3 years

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of ipilimumab.

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	37	38
Median (95% Confidence Interval) [months]	20.58	24.79

10. Secondary Outcome

Title	Model Estimates of Mean Absolute Lymphocyte Count at Each Nominal Ipilimumab Induction Dose and at End of the Induction Dosing Period
Description	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).
Time Frame	Day 0 (prior to first dose) to Day 84

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	37	38
0 days since first dose	1.26	1.18
21 days since first dose	1.67	1.74
42 days since first dose	1.79	1.86
63 days since first dose	2.07	1.94
84 days since first dose	1.89	2.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab (Process B), Ipilimumab (Process C)
	Comments	Time-by-process interaction. Null hypothesis that the pattern of mean ALC values over time is the same for both processes.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments	Not corrected for multiple testing
	Method	F-test
	Comments	numerator 5 degrees freedom, denominator 782 degrees freedom
Method of Estimation	Estimation Parameter	omnibus conditional F-test
	Estimated Value	0.40
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ipilimumab (Process B), Ipilimumab (Process C)
	Comments	Overall time effect. Null hypothesis of no mean ALC changes over time in either process group (treatment arm).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	F-test
	Comments	numerator 10 degrees freedom, denominator 782 degrees freedom
Method of Estimation	Estimation Parameter	F-statistic
	Estimated Value	4.35
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and AEs Leading to Discontinuation
Description	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.
Time Frame	Day 1 to last patient, last visit, approximately 3 years

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of ipilimumab.

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	37	38
Participants with at least 1 AE	37 100%	38 100%
Participants with at least 1 treatment related AE	33 89.2%	36 94.7%
Participants with at least 1 SAE	22 59.5%	24 63.2%
Participants with at least 1 treatment related SAE	10 27%	13 34.2%
AE leading to discontinuation	14 37.8%	12 31.6%
Participants who died	17 45.9%	20 52.6%

12. Secondary Outcome

Title	Number of Participants Who Developed Antibodies and Neutralizing Antibodies
Description	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.
Time Frame	Prior to start of drug Week 1 to Week 24 on treatment or end of treatment

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	Intravenous (IV) solution of 10 milligrams (mg) ipilimumab per kilogram (kg) of body weight was given 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 B, ipilimumab was manufactured by the Lonza company using material from transfectoma cell line.	Intravenous (IV) solution of 10 milligrams (mg)ipilimumab per kilogram (kg) of body weight was given 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 Sponsor using material from a sub-clone of the original transfectoma cell line, modified cell culture and purification steps.
Measure Participants	34	36
Positive HAHA on treatment	0 0%	2 5.3%
Neutralizing antibodies present	0 0%	0 0%

13. Secondary Outcome

Title	Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants up to Data Cutoff
Description	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.
Time Frame	Screening to data cut off for July 2010, approximately 36 Weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	10	12
Diastolic at End of Induction (N=10, 12)	-1.6 (10.1)	-1.4 (9.7)
Diastolic at Week 36 of Maintenance (N=7, 7)	-7.0 (14.1)	-5.6 (6.8)
Diastolic at End of Treatment (N=6,7)	7.5 (7.1)	2.3 (12.4)
Systolic at End of Induction (N=10, 12)	-4.1 (19.6)	-8.6 (21.0)
Systolic at Week 36 of Maintenance (N=7, 7)	-5.7 (31.5)	-8.3 (18.3)
Systolic at End of Treatment (N=6,7)	11.5 (13.3)	-2.1 (14.7)

14. Secondary Outcome

Title	Mean Change From Baseline in Sitting Pulse Rate - All Treated Participants up to Data Cutoff
Description	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.
Time Frame	Screening to data cut off for July 2010, approximately 36 Weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	10	24
Pulse Rate at End of Induction (N=10, 24)	-4.3 (11.1)	-3.3 (11.1)
Pulse Rate at Week 36 (N=7,7))	-7.7 (15.3)	-7.1 (8.8)
Pulse Rate at end of treatment (N=6,7)	25.5 (15.8)	12.3 (10.5)

15. Secondary Outcome

Title	Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Hematology Laboratory Safety Tests - All Treated Participants
Description	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:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL. Absolute neutrophil (ANC) and ANC plus bands: Gr 1:<LLN to 1.5*10^3 c/µL, Gr 2:<1.5 to 1.0*10^3 c/µL, Gr 3:<1.0 to 0.5*10^3 c/µL, Gr 4:<0.5*10^3 c/µL. Platelet count Gr 1:LLN to 75.0*10^9 c/L, Gr 2:<75.0 to 50.0*10^9 c/L, Gr 3:<50.0 to 25.0*10^9 c/L, Gr 4:<25.0 to 10^9 c/L. Lymphocytes Gr 1: <1.5 to 0.8 *10^3 c/µL, Gr 2 <0.8 to 0.5 *10^3 c/µL, Gr 3: <0.5 to 0.2 *10^3 c/µL, Gr 4: <0.2*10^3 c/µL. Leukocytes Gr 1:<LLN to 3.0 *10^3 c/µL, Gr 2; <3.0 to 2.0 *10^3 c/µL, Gr 3: <2.0 to 1.0 *10^3 c/µL, Gr 4: <1.0 *10^3 c/µL. Baseline is screening or Day 1, prior to dosing.
Time Frame	Screening to data cut off for July 2010, approximately 36 Weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	37	38
Hemoglobin (N=37, 38)	2 5.4%	3 7.9%
Lymphocytes (N=37, 38)	3 8.1%	3 7.9%
Neutrophils, Absolute (N=31, 36)	0 0%	2 5.3%
Neutrophils + bands, Absolute (N=31, 36)	0 0%	1 2.6%
Platelet Count (N=37, 38)	0 0%	1 2.6%

16. Secondary Outcome

Title	Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Chemistry Laboratory Safety Tests (Non-electrolyte) - All Treated Participants
Description	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.
Time Frame	Screening to data cut off for July 2010, approximately 36 Weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	37	38
ALT (N=36, 37)	2 5.4%	1 2.6%
AST (N=36, 37)	2 5.4%	1 2.6%
Alkaline Phosphatase (N=36, 37)	2 5.4%	1 2.6%
Amylase (N=35, 35)	0 0%	2 5.3%
Lipase (N=10, 14)	0 0%	1 2.6%
Albumin (N=36, 37)	7 18.9%	8 21.1%
Creatinine (N= 37, 37)	2 5.4%	1 2.6%
Bilirubin (N=36, 37)	2 5.4%	0 0%

17. Secondary Outcome

Title	Number of Participants With 2-Grade or Greater Shift From Baseline (Worsening) in Electrolyte Laboratory Safety Tests - All Treated Participants
Description	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.
Time Frame	Screening to data cut off for July 2010, approximately 36 Weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ipilimumab (Process B)	Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.	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.
Measure Participants	37	38
Sodium (low) (N=37, 37)	4 10.8%	6 15.8%
Potassium (low) (N=36, 37)	1 2.7%	2 5.3%
Potassium (high) (N=36, 37)	0 0%	1 2.6%
Calcium (low) (N=37, 37)	1 2.7%	7 18.4%
Inorganic Phosphorus (N=37,37)	9 24.3%	7 18.4%
Bicarbonate (N=37, 37)	0 0%	1 2.6%

Adverse Events

Time Frame	Day 1 to last patient, last visit, approximately 3 years.
Adverse Event Reporting Description	SAEs and AEs 5% threshold up to last patient, last visit (31 Oct 2012) were in primary endpoint posting. Therefore, SAEs and AEs have not changed with this current PRS update from Maintenance Period. SAE/AE upload includes SAEs reported after the data cut off for the clinical study report and thus differs slightly from data in Outcome measure 11.
Arm/Group Title	Ipilimumab (Process B)		Ipilimumab (Process C)
Arm/Group Description	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 B, ipilimumab was manufactured by Lonza using material from transfectoma cell line.		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.
All Cause Mortality
	Ipilimumab (Process B)		Ipilimumab (Process C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ipilimumab (Process B)		Ipilimumab (Process C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/37 (64.9%)		26/38 (68.4%)
Cardiac disorders
Atrial flutter	0/37 (0%)		1/38 (2.6%)
Acute myocardial infarction	2/37 (5.4%)		0/38 (0%)
Endocrine disorders
Hypophysitis	1/37 (2.7%)		0/38 (0%)
Hypopituitarism	1/37 (2.7%)		1/38 (2.6%)
Adrenal insufficiency	1/37 (2.7%)		0/38 (0%)
Eye disorders
Uveitis	1/37 (2.7%)		0/38 (0%)
Gastrointestinal disorders
Abdominal distension	0/37 (0%)		1/38 (2.6%)
Vomiting	1/37 (2.7%)		3/38 (7.9%)
Gastritis	0/37 (0%)		1/38 (2.6%)
Intestinal perforation	0/37 (0%)		1/38 (2.6%)
Abdominal pain	0/37 (0%)		1/38 (2.6%)
Nausea	1/37 (2.7%)		3/38 (7.9%)
Colitis	4/37 (10.8%)		8/38 (21.1%)
Ascites	0/37 (0%)		1/38 (2.6%)
Pancreatitis	0/37 (0%)		1/38 (2.6%)
Colonic obstruction	1/37 (2.7%)		0/38 (0%)
Diarrhoea	0/37 (0%)		1/38 (2.6%)
Small intestinal obstruction	0/37 (0%)		1/38 (2.6%)
General disorders
Chest pain	0/37 (0%)		1/38 (2.6%)
Fatigue	0/37 (0%)		1/38 (2.6%)
Localised oedema	0/37 (0%)		1/38 (2.6%)
Oedema peripheral	0/37 (0%)		1/38 (2.6%)
Generalised oedema	1/37 (2.7%)		0/38 (0%)
Pyrexia	1/37 (2.7%)		1/38 (2.6%)
Asthenia	0/37 (0%)		2/38 (5.3%)
Hepatobiliary disorders
Hepatic function abnormal	1/37 (2.7%)		0/38 (0%)
Bile duct obstruction	2/37 (5.4%)		0/38 (0%)
Autoimmune hepatitis	0/37 (0%)		1/38 (2.6%)
Infections and infestations
Pseudomonas infection	0/37 (0%)		1/38 (2.6%)
H1N1 influenza	0/37 (0%)		1/38 (2.6%)
Pneumonia	1/37 (2.7%)		2/38 (5.3%)
Septic shock	1/37 (2.7%)		0/38 (0%)
Cellulitis	1/37 (2.7%)		1/38 (2.6%)
Sepsis	1/37 (2.7%)		0/38 (0%)
Infection	1/37 (2.7%)		0/38 (0%)
Wound infection	1/37 (2.7%)		0/38 (0%)
Investigations
Platelet count decreased	0/37 (0%)		1/38 (2.6%)
Amylase increased	0/37 (0%)		1/38 (2.6%)
Lipase increased	0/37 (0%)		1/38 (2.6%)
Metabolism and nutrition disorders
Dehydration	2/37 (5.4%)		1/38 (2.6%)
Hyperuricaemia	0/37 (0%)		1/38 (2.6%)
Hyponatraemia	0/37 (0%)		2/38 (5.3%)
Decreased appetite	0/37 (0%)		3/38 (7.9%)
Musculoskeletal and connective tissue disorders
Back pain	0/37 (0%)		2/38 (5.3%)
Neck pain	1/37 (2.7%)		0/38 (0%)
Polymyalgia rheumatica	1/37 (2.7%)		0/38 (0%)
Flank pain	1/37 (2.7%)		0/38 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/37 (2.7%)		0/38 (0%)
Malignant melanoma in situ	0/37 (0%)		1/38 (2.6%)
Basal cell carcinoma	1/37 (2.7%)		0/38 (0%)
Skin cancer metastatic	0/37 (0%)		1/38 (2.6%)
Metastases to adrenals	1/37 (2.7%)		0/38 (0%)
Malignant neoplasm progression	12/37 (32.4%)		6/38 (15.8%)
Metastatic squamous cell carcinoma	0/37 (0%)		2/38 (5.3%)
Nervous system disorders
Guillain-Barre syndrome	0/37 (0%)		1/38 (2.6%)
Myasthenia gravis	1/37 (2.7%)		0/38 (0%)
Cognitive disorder	0/37 (0%)		1/38 (2.6%)
Dizziness	0/37 (0%)		1/38 (2.6%)
Encephalopathy	0/37 (0%)		1/38 (2.6%)
Lethargy	1/37 (2.7%)		0/38 (0%)
Cerebral haemorrhage	0/37 (0%)		1/38 (2.6%)
Haemorrhage intracranial	1/37 (2.7%)		0/38 (0%)
Headache	1/37 (2.7%)		0/38 (0%)
Spinal cord compression	0/37 (0%)		2/38 (5.3%)
Tremor	0/37 (0%)		1/38 (2.6%)
Psychiatric disorders
Alcohol withdrawal syndrome	1/37 (2.7%)		0/38 (0%)
Mental status changes	0/37 (0%)		1/38 (2.6%)
Confusional state	2/37 (5.4%)		1/38 (2.6%)
Renal and urinary disorders
Renal failure acute	1/37 (2.7%)		0/38 (0%)
Renal failure	0/37 (0%)		3/38 (7.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/37 (2.7%)		1/38 (2.6%)
Pneumonia aspiration	1/37 (2.7%)		0/38 (0%)
Respiratory failure	0/37 (0%)		1/38 (2.6%)
Hypoxia	0/37 (0%)		1/38 (2.6%)
Atelectasis	0/37 (0%)		1/38 (2.6%)
Vascular disorders
Hypotension	1/37 (2.7%)		1/38 (2.6%)
Temporal arteritis	1/37 (2.7%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Ipilimumab (Process B)		Ipilimumab (Process C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/37 (100%)		38/38 (100%)
Blood and lymphatic system disorders
Anaemia	1/37 (2.7%)		2/38 (5.3%)
Endocrine disorders
Hypophysitis	2/37 (5.4%)		1/38 (2.6%)
Hypothyroidism	4/37 (10.8%)		5/38 (13.2%)
Eye disorders
Uveitis	3/37 (8.1%)		0/38 (0%)
Conjunctivitis	0/37 (0%)		3/38 (7.9%)
Vision blurred	1/37 (2.7%)		4/38 (10.5%)
Gastrointestinal disorders
Abdominal distension	3/37 (8.1%)		3/38 (7.9%)
Vomiting	7/37 (18.9%)		13/38 (34.2%)
Abdominal pain upper	4/37 (10.8%)		1/38 (2.6%)
Dysphagia	0/37 (0%)		2/38 (5.3%)
Abdominal pain	5/37 (13.5%)		12/38 (31.6%)
Flatulence	4/37 (10.8%)		3/38 (7.9%)
Nausea	14/37 (37.8%)		19/38 (50%)
Dyspepsia	1/37 (2.7%)		7/38 (18.4%)
Haemorrhoids	2/37 (5.4%)		0/38 (0%)
Abdominal discomfort	3/37 (8.1%)		1/38 (2.6%)
Colitis	3/37 (8.1%)		1/38 (2.6%)
Stomatitis	0/37 (0%)		2/38 (5.3%)
Ascites	1/37 (2.7%)		3/38 (7.9%)
Constipation	9/37 (24.3%)		16/38 (42.1%)
Diarrhoea	18/37 (48.6%)		26/38 (68.4%)
General disorders
Chest pain	2/37 (5.4%)		1/38 (2.6%)
Chills	2/37 (5.4%)		4/38 (10.5%)
Influenza like illness	1/37 (2.7%)		3/38 (7.9%)
Mucosal inflammation	1/37 (2.7%)		4/38 (10.5%)
Fatigue	29/37 (78.4%)		22/38 (57.9%)
Oedema peripheral	3/37 (8.1%)		7/38 (18.4%)
Pain	6/37 (16.2%)		4/38 (10.5%)
Pyrexia	7/37 (18.9%)		7/38 (18.4%)
Asthenia	2/37 (5.4%)		0/38 (0%)
Oedema	2/37 (5.4%)		1/38 (2.6%)
Nodule	2/37 (5.4%)		3/38 (7.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/37 (2.7%)		2/38 (5.3%)
Infections and infestations
Blastocystis infection	0/37 (0%)		2/38 (5.3%)
Candidiasis	2/37 (5.4%)		3/38 (7.9%)
Oral herpes	0/37 (0%)		2/38 (5.3%)
Nasopharyngitis	5/37 (13.5%)		1/38 (2.6%)
Rhinitis	0/37 (0%)		2/38 (5.3%)
Pneumonia	2/37 (5.4%)		1/38 (2.6%)
Cellulitis	2/37 (5.4%)		0/38 (0%)
Influenza	2/37 (5.4%)		1/38 (2.6%)
Sinusitis	2/37 (5.4%)		2/38 (5.3%)
Upper respiratory tract infection	6/37 (16.2%)		4/38 (10.5%)
Urinary tract infection	3/37 (8.1%)		2/38 (5.3%)
Oral candidiasis	3/37 (8.1%)		1/38 (2.6%)
Injury, poisoning and procedural complications
Contusion	0/37 (0%)		2/38 (5.3%)
Investigations
White blood cell count decreased	2/37 (5.4%)		3/38 (7.9%)
Alanine aminotransferase increased	6/37 (16.2%)		4/38 (10.5%)
Haemoglobin decreased	3/37 (8.1%)		5/38 (13.2%)
Neutrophil count decreased	1/37 (2.7%)		2/38 (5.3%)
Aspartate aminotransferase increased	5/37 (13.5%)		5/38 (13.2%)
Blood creatinine increased	2/37 (5.4%)		0/38 (0%)
Blood testosterone decreased	2/37 (5.4%)		0/38 (0%)
Platelet count decreased	2/37 (5.4%)		2/38 (5.3%)
Weight increased	0/37 (0%)		2/38 (5.3%)
Amylase increased	4/37 (10.8%)		2/38 (5.3%)
Blood alkaline phosphatase increased	1/37 (2.7%)		3/38 (7.9%)
Blood bilirubin increased	2/37 (5.4%)		1/38 (2.6%)
Lipase increased	4/37 (10.8%)		2/38 (5.3%)
Weight decreased	6/37 (16.2%)		5/38 (13.2%)
Metabolism and nutrition disorders
Dehydration	3/37 (8.1%)		5/38 (13.2%)
Hypocalcaemia	3/37 (8.1%)		3/38 (7.9%)
Hyponatraemia	6/37 (16.2%)		5/38 (13.2%)
Decreased appetite	14/37 (37.8%)		14/38 (36.8%)
Hyperglycaemia	5/37 (13.5%)		7/38 (18.4%)
Hyperkalaemia	3/37 (8.1%)		3/38 (7.9%)
Hypomagnesaemia	2/37 (5.4%)		1/38 (2.6%)
Hypophosphataemia	0/37 (0%)		3/38 (7.9%)
Hypercalcaemia	2/37 (5.4%)		1/38 (2.6%)
Hypokalaemia	3/37 (8.1%)		2/38 (5.3%)
Hypoalbuminaemia	4/37 (10.8%)		4/38 (10.5%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	2/37 (5.4%)		3/38 (7.9%)
Back pain	7/37 (18.9%)		8/38 (21.1%)
Myalgia	2/37 (5.4%)		1/38 (2.6%)
Neck pain	1/37 (2.7%)		6/38 (15.8%)
Arthralgia	8/37 (21.6%)		7/38 (18.4%)
Muscular weakness	2/37 (5.4%)		5/38 (13.2%)
Musculoskeletal chest pain	0/37 (0%)		3/38 (7.9%)
Pain in extremity	5/37 (13.5%)		6/38 (15.8%)
Nervous system disorders
Hypoaesthesia	1/37 (2.7%)		2/38 (5.3%)
Syncope	2/37 (5.4%)		0/38 (0%)
Peripheral sensory neuropathy	2/37 (5.4%)		1/38 (2.6%)
Dizziness	4/37 (10.8%)		1/38 (2.6%)
Dysgeusia	0/37 (0%)		2/38 (5.3%)
Headache	9/37 (24.3%)		14/38 (36.8%)
Neuropathy peripheral	1/37 (2.7%)		3/38 (7.9%)
Paraesthesia	0/37 (0%)		2/38 (5.3%)
Psychiatric disorders
Depression	2/37 (5.4%)		2/38 (5.3%)
Agitation	3/37 (8.1%)		0/38 (0%)
Mood swings	0/37 (0%)		2/38 (5.3%)
Confusional state	3/37 (8.1%)		2/38 (5.3%)
Insomnia	7/37 (18.9%)		3/38 (7.9%)
Anxiety	4/37 (10.8%)		4/38 (10.5%)
Renal and urinary disorders
Pollakiuria	0/37 (0%)		2/38 (5.3%)
Urinary retention	2/37 (5.4%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	0/37 (0%)		3/38 (7.9%)
Dyspnoea	4/37 (10.8%)		8/38 (21.1%)
Oropharyngeal pain	3/37 (8.1%)		2/38 (5.3%)
Pleural effusion	2/37 (5.4%)		4/38 (10.5%)
Cough	7/37 (18.9%)		8/38 (21.1%)
Nasal congestion	2/37 (5.4%)		2/38 (5.3%)
Hiccups	0/37 (0%)		2/38 (5.3%)
Rhinorrhoea	3/37 (8.1%)		1/38 (2.6%)
Sinus congestion	2/37 (5.4%)		0/38 (0%)
Bronchial secretion retention	0/37 (0%)		2/38 (5.3%)
Dyspnoea exertional	2/37 (5.4%)		2/38 (5.3%)
Atelectasis	0/37 (0%)		2/38 (5.3%)
Pneumonitis	0/37 (0%)		2/38 (5.3%)
Productive cough	2/37 (5.4%)		1/38 (2.6%)
Skin and subcutaneous tissue disorders
Pruritus generalised	0/37 (0%)		2/38 (5.3%)
Alopecia	2/37 (5.4%)		0/38 (0%)
Rash pruritic	3/37 (8.1%)		0/38 (0%)
Vitiligo	8/37 (21.6%)		1/38 (2.6%)
Hyperhidrosis	2/37 (5.4%)		0/38 (0%)
Pruritus	19/37 (51.4%)		24/38 (63.2%)
Dry skin	2/37 (5.4%)		1/38 (2.6%)
Rash	21/37 (56.8%)		25/38 (65.8%)
Decubitus ulcer	2/37 (5.4%)		2/38 (5.3%)
Vascular disorders
Hypotension	3/37 (8.1%)		0/38 (0%)
Hot flush	2/37 (5.4%)		0/38 (0%)
Flushing	0/37 (0%)		3/38 (7.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.