Trial Outcomes & Findings for Study of MDX-010 in Patients With Metastatic Hormone-Refractory Prostate Cancer (NCT NCT00323882)

NCT ID: NCT00323882

Last Updated: 2014-08-28

Results Overview

AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AE (irAE) was defined as a clinically significant AE of any organ that is associated with drug exposure, of unknown etiology, and is consistent with an immune-mediated mechanism. Day 1=first day of study treatment.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 75 participants
• Primary outcome timeframe: Day 1 to last day of study treatment (+70 days) up to 2 years
• Results posted on: 2014-08-28

Participant Flow

Study initiated January 2006; Primary endpoint last visit September 2009; follow up period last visit July 2013 with data cut off September 2013. Male patients with castrate-resistant prostate cancer (CRPC) who met study criteria were enrolled.

75 participants enrolled and were assigned to treatment; 71 were treated. Reasons for the 4 participants not receiving treatment were not specified by the investigators. Ipilimumab was administered at escalating dosage levels of 3, 5, and 10 mg/kg/dose.

Participant milestones

Measure	Ipilimumab Monotherapy 3 mg/kg A single dose of 3 mg/kg ipilimumab was administered over 90 minutes intravenously (IV) on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of stable disease (SD) or conflicting disease response assessment (CDRA) at the end of the induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses (maintenance). The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to Response Evaluation Criteria in Solid Tumors (RECIST), target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Overall Study STARTED	8	6	16	7	34
Overall Study COMPLETED	0	0	3	0	2
Overall Study NOT COMPLETED	8	6	13	7	32

Reasons for withdrawal

Measure	Ipilimumab Monotherapy 3 mg/kg A single dose of 3 mg/kg ipilimumab was administered over 90 minutes intravenously (IV) on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of stable disease (SD) or conflicting disease response assessment (CDRA) at the end of the induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses (maintenance). The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to Response Evaluation Criteria in Solid Tumors (RECIST), target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Overall Study Adverse Event	2	1	1	1	3
Overall Study Disease Progression	6	4	10	5	22
Overall Study Death	0	1	1	0	5
Overall Study Lost to Follow-up	0	0	1	0	1
Overall Study Other	0	0	0	1	1

Baseline Characteristics

Study of MDX-010 in Patients With Metastatic Hormone-Refractory Prostate Cancer

Baseline characteristics by cohort

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes intravenously (IV) on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of stable disease (SD) or conflicting disease response assessment (CDRA) at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Total n=71 Participants Total of all reporting groups
Age, Continuous	68.0 years STANDARD_DEVIATION 8.1 • n=5 Participants	58.2 years STANDARD_DEVIATION 5.6 • n=7 Participants	65.2 years STANDARD_DEVIATION 7.7 • n=5 Participants	67.6 years STANDARD_DEVIATION 8.5 • n=4 Participants	65.7 years STANDARD_DEVIATION 9.1 • n=21 Participants	65.4 years STANDARD_DEVIATION 8.5 • n=10 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	6 Participants n=7 Participants	16 Participants n=5 Participants	7 Participants n=4 Participants	34 Participants n=21 Participants	71 Participants n=10 Participants
Race/Ethnicity, Customized Asian	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants	1 participants n=10 Participants
Race/Ethnicity, Customized Black	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	3 participants n=21 Participants	4 participants n=10 Participants
Race/Ethnicity, Customized White	8 participants n=5 Participants	6 participants n=7 Participants	16 participants n=5 Participants	6 participants n=4 Participants	30 participants n=21 Participants	66 participants n=10 Participants
Region of Enrollment United States	8 participants n=5 Participants	6 participants n=7 Participants	16 participants n=5 Participants	7 participants n=4 Participants	34 participants n=21 Participants	71 participants n=10 Participants
Mean Prostate-Specific Antigen (PSA) in ng/mL	121.6 ng/mL STANDARD_DEVIATION 140.2 • n=5 Participants	48.8 ng/mL STANDARD_DEVIATION 43.9 • n=7 Participants	302.7 ng/mL STANDARD_DEVIATION 521.2 • n=5 Participants	66.6 ng/mL STANDARD_DEVIATION 68.1 • n=4 Participants	250.1 ng/mL STANDARD_DEVIATION 324.1 • n=21 Participants	212.9 ng/mL STANDARD_DEVIATION 346.5 • n=10 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 0	5 participants n=5 Participants	5 participants n=7 Participants	10 participants n=5 Participants	4 participants n=4 Participants	9 participants n=21 Participants	33 participants n=10 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 1	3 participants n=5 Participants	1 participants n=7 Participants	6 participants n=5 Participants	2 participants n=4 Participants	22 participants n=21 Participants	34 participants n=10 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 2	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	0 participants n=21 Participants	1 participants n=10 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS Not Reported	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	3 participants n=21 Participants	3 participants n=10 Participants

PRIMARY outcome

Timeframe: Day 1 to last day of study treatment (+70 days) up to 2 years

Population: All participants in the study who received either ipilimumab or radiation were analyzed.

AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AE (irAE) was defined as a clinically significant AE of any organ that is associated with drug exposure, of unknown etiology, and is consistent with an immune-mediated mechanism. Day 1=first day of study treatment.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants irAE (Any Grade)	6 participants	5 participants	16 participants	4 participants	24 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants Grade 3-4 irAE	1 participants	3 participants	10 participants	3 participants	6 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants SAE	3 participants	2 participants	9 participants	2 participants	19 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants Drug-Related SAE	2 participants	1 participants	7 participants	2 participants	7 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants AEs leading to discontinuation	2 participants	2 participants	7 participants	3 participants	13 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants Related-AEs leading to discontinuation	2 participants	2 participants	6 participants	3 participants	8 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants Grade 3-4 AE	2 participants	5 participants	12 participants	3 participants	20 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants Related AE (Any Grade)	8 participants	5 participants	16 participants	6 participants	29 participants	—
Number of Participants With Serious AEs (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs - Treated Participants Grade 3-4 Related AE	2 participants	3 participants	10 participants	3 participants	13 participants	—

PRIMARY outcome

Timeframe: Day 85

Population: PSA-evaluable participants, including all participants in cohorts with monotherapy and with radiotherapy who received any ipilimumab and had a baseline PSA, were analyzed.

Response by investigator using National Cancer Institute (NCI) PSA Working Group recommendations= PSA < 50% of PSA reference value occurring on or before Day 85; response confirmed at least 4 weeks after the first measurement. PSA reference=PSA measured immediately prior to treatment. Complete response (CR)=PSA < 2 nanograms per milliliter (ng/mL), confirmed at least 4 weeks after 1st value; Partial response (PR)=PSA ≤ 50% of PSA reference, confirmed at least 4 weeks after 1st value; Unconfirmed=not confirmed by repeat measurements; Stable disease(SD)=No change from PSA reference; Progressive disease (PD) defined: If PSA nadir was ≥ 100% of the reference: PSA ≥ 125% of PSA reference and with a difference of absolute value of ≥ 5 ng/mL; If PSA nadir was < 100% and ≥ 50% of the reference: PSA ≥ 125% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL: If PSA nadir was < 50% of the reference: PSA ≥ 150% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=6 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants With Best PSA Response at Day 85 by Category - PSA Evaluable Participants Complete Response	0 participants	0 participants	1 participants	0 participants	1 participants	—
Number of Participants With Best PSA Response at Day 85 by Category - PSA Evaluable Participants Partial Response	1 participants	1 participants	2 participants	0 participants	3 participants	—
Number of Participants With Best PSA Response at Day 85 by Category - PSA Evaluable Participants Unconfirmed Partial Response	0 participants	0 participants	2 participants	0 participants	1 participants	—
Number of Participants With Best PSA Response at Day 85 by Category - PSA Evaluable Participants Stable Disease	4 participants	4 participants	7 participants	4 participants	14 participants	—
Number of Participants With Best PSA Response at Day 85 by Category - PSA Evaluable Participants Progressive Disease	3 participants	1 participants	3 participants	2 participants	11 participants	—
Number of Participants With Best PSA Response at Day 85 by Category - PSA Evaluable Participants Unknown	0 participants	0 participants	1 participants	0 participants	4 participants	—

SECONDARY outcome

Timeframe: Day 1 to last day of study treatment (+70 days) up to 2 years

Population: PSA-evaluable participants, including all participants in cohorts with monotherapy and with radiotherapy who received any ipilimumab and had a baseline PSA, were analyzed.

Best Overall PSA response per investigator, using NCI PSA Working Group: PSA with CR or PR at any time after treatment initiation and was confirmed at least 4 weeks after the first measurement. PSA reference=PSA measured immediately prior to treatment. CR=PSA concentration < 2 nanograms per milliliter (ng/mL), confirmed at least 4 weeks after 1st value; PR=PSA concentration ≤ 50% of PSA reference, confirmed at least 4 weeks after 1st value; Unconfirmed=not confirmed by repeat measurements; SD=No change from PSA reference value; PD = If PSA nadir was ≥ 100% of the reference value: PSA ≥ 125% of PSA reference and with a difference of absolute value of ≥ 5 ng/mL; If PSA nadir was < 100% and ≥ 50% of the reference value: PSA ≥ 125% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL: If PSA nadir was < 50% of the reference value: PSA ≥ 150% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=6 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants With Best Overall PSA Response by Category - PSA Evaluable Participants Complete Response (CR)	0 participants	0 participants	1 participants	0 participants	2 participants	—
Number of Participants With Best Overall PSA Response by Category - PSA Evaluable Participants Partial Response (PR)	2 participants	1 participants	3 participants	2 participants	2 participants	—
Number of Participants With Best Overall PSA Response by Category - PSA Evaluable Participants Unconfirmed Partial Response	0 participants	0 participants	2 participants	0 participants	2 participants	—
Number of Participants With Best Overall PSA Response by Category - PSA Evaluable Participants Stable Disease (SD)	3 participants	4 participants	6 participants	2 participants	14 participants	—
Number of Participants With Best Overall PSA Response by Category - PSA Evaluable Participants Progressive Disease (PD)	3 participants	1 participants	3 participants	2 participants	11 participants	—
Number of Participants With Best Overall PSA Response by Category - PSA Evaluable Participants Unknown	0 participants	0 participants	1 participants	0 participants	3 participants	—

SECONDARY outcome

Timeframe: Day 1 to last day of study treatment (+70 days) up to 2 years

Population: Tumor-evaluable participants, including all participants in cohorts with monotherapy and with radiotherapy who received any ipilimumab and had measurable disease at baseline, were analyzed.

For those with measurable disease, tumor response based upon tumor lesions (per investigator) using Response Evaluation Criteria in Solid Tumors (RECIST). Best Overall=Participants with a best tumor response of CR or PR at anytime during the study. CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference, baseline sum LD. For a status of CR or PR, changes in tumor measurements were confirmed by repeat studies no less than 4 weeks after the criteria for response were first met; Unconfirmed=not confirmed by repeat measurements; SD=Neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=1 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=1 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=8 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=2 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=20 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants With Best Overall Tumor Response by Category - Tumor Evaluable Participants Complete Response	0 participants	0 participants	1 participants	0 participants	0 participants	—
Number of Participants With Best Overall Tumor Response by Category - Tumor Evaluable Participants Partial Response	0 participants	0 participants	0 participants	0 participants	0 participants	—
Number of Participants With Best Overall Tumor Response by Category - Tumor Evaluable Participants Unconfirmed Partial Response	0 participants	0 participants	1 participants	0 participants	1 participants	—
Number of Participants With Best Overall Tumor Response by Category - Tumor Evaluable Participants Stable Disease	1 participants	1 participants	1 participants	1 participants	5 participants	—
Number of Participants With Best Overall Tumor Response by Category - Tumor Evaluable Participants Progressive Disease	0 participants	0 participants	3 participants	1 participants	5 participants	—
Number of Participants With Best Overall Tumor Response by Category - Tumor Evaluable Participants Unknown	0 participants	0 participants	2 participants	0 participants	9 participants	—

SECONDARY outcome

Timeframe: Day 1 to Day 85

Population: All participants in cohorts with monotherapy and with radiotherapy who received any ipilimumab, had a baseline PSA, and had a confirmed Complete Response (CR) or Partial Response (PR) at Day 85.

Time to PSA response was measured in months. Time to PSA response was analyzed in those participants with CR or PR at Day 85. CR=PSA concentration < 2 ng/mL, confirmed at least 4 weeks after 1st value; PR=PSA concentration ≤ 50% of PSA reference, confirmed at least 4 weeks after 1st value.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=1 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=1 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=3 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=2 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) n=2 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Time to PSA Response at Day 85 in Participants With Complete Response (CR) or Confirmed Partial Response (PR) at Day 85	1.41 Months Interval 1.41 to 1.41	1.54 Months Interval 1.54 to 1.54	1.4 Months Interval 0.9 to 2.3	—	1.1 Months Interval 0.8 to 1.5	1.1 Months Interval 0.8 to 1.4

SECONDARY outcome

Timeframe: Day 1 to last day of study treatment (+70 days) up to 2 years

Population: All participants in cohorts with 10 mg/kg ipilimumab monotherapy and with 10 mg/kg ipilimumab combination therapy with XRT who received any ipilimumab and had a baseline PSA, were analyzed.

Tumor response rate was defined as the number of participants with a best response of partial or complete response divided by the total number of tumor evaluable participants. Overall Tumor Response was defined as participants with a tumor response of CR or PR at anytime during the study. CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference, baseline sum LD. For a status of CR or PR, changes in tumor measurements were confirmed by repeat studies no less than 4 weeks after the criteria for response were first met

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=16 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=4 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Overall Tumor Response Rate in 10 mg/kg Ipilimumab Monotherapy and Ipilimumab/XRT Combination Therapy	12.5 percentage of participants Interval 0.3 to 52.7	0 percentage of participants Interval 0.0 to 0.0	0 percentage of participants Interval 0.0 to 0.0	—	—	—

SECONDARY outcome

Timeframe: Day 85, Day 1 to last day of study treatment (+70 days) up to 2 years

Population: All participants in cohorts with 10 mg/kg ipilimumab monotherapy and with 10 mg/kg ipilimumab combination therapy with XRT who received any ipilimumab and had a baseline PSA, were analyzed.

PSA response rate was defined as the number of participants with a PSA response (PR or CR) divided by the total number of PSA evaluable participants. PSA response at Day 85, as reported by the investigator, was defined as a PSA concentration < 50% of the PSA reference value occurring on or before Day 85 and this response was confirmed at least 4 weeks after the first determination. The PSA reference value was the PSA concentration measured immediately prior to treatment. Overall Response is < 50% of the PSA reference value occurring anytime after treatment was initiated and this response was confirmed at least 4 weeks after the first determination. Complete response=PSA concentration < 2 ng/mL, confirmed at least 4 weeks after first value; Partial response=PSA concentration ≤ 50% of PSA reference value, confirmed at least 4 weeks after first determination.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=16 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=21 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=13 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
PSA Response Rate at Day 85 and Overall PSA Response Rate in 10 mg/kg Monotherapy and Combination Therapy PSA Response Rate at Day 85	18.8 percentage of participants Interval 4.0 to 45.6	9.5 percentage of participants Interval 1.2 to 30.4	15.4 percentage of participants Interval 1.9 to 45.4	—	—	—
PSA Response Rate at Day 85 and Overall PSA Response Rate in 10 mg/kg Monotherapy and Combination Therapy Overall PSA Response Rate	25.0 percentage of participants Interval 7.3 to 52.4	9.5 percentage of participants Interval 1.2 to 30.4	15.4 percentage of participants Interval 1.9 to 45.4	—	—	—

SECONDARY outcome

Timeframe: Day 1 to 5 years post treatment

Population: Treated participants population included all participants in the study who received either ipilimumab or radiation.

Primary analysis was conducted on data from Day 1 up to 2 years post treatment, data available as of September 2009. Final Follow-Up analysis was conducted on data up to 5 years post treatment, data available as of September 2013 (minimum time of eligibility 54 months to a maximum of 85 months). Primary causes of deaths are listed under each timepoint.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) n=71 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Total Deaths at Primary Analysis	5 participants	4 participants	7 participants	3 participants	18 participants	37 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Maliginant Disease	0 participants	0 participants	0 participants	0 participants	3 participants	3 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Prostate Cancer	1 participants	4 participants	6 participants	4 participants	13 participants	28 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Toxicity	0 participants	1 participants	0 participants	0 participants	0 participants	1 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Other	0 participants	1 participants	1 participants	0 participants	5 participants	7 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Unknown	5 participants	0 participants	4 participants	3 participants	8 participants	20 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants No cause specified	1 participants	0 participants	0 participants	0 participants	0 participants	1 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Total Deaths at Completion of Follow Up	7 participants	6 participants	11 participants	7 participants	29 participants	60 participants
Number of Participants Who Died by Date of Primary Analysis and by Date of Completion of Follow Up - All Treated Participants Malignant Disease	0 participants	0 participants	0 participants	0 participants	3 participants	3 participants

SECONDARY outcome

Timeframe: Day 1 to 5 years post treatment

Population: All participants in cohorts with monotherapy and with radiotherapy who received any ipilimumab were analyzed.

Overall Survival (OS) was defined as the time from the first date of study treatment until the date of death and was measured in months. For those participants who have not died, OS was censored at the last date the participant was known to be alive. Completion of follow-up for OS was a minimum time of eligibility 54 months to a maximum of 85 months.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) n=71 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Overall Survival at Completion of Follow Up Period - Treated Participants	22.5 Months Interval 11.5 to 59.9	36.3 Months Interval 28.0 to 41.8	26.6 Months Interval 8.6 to 49.9	18.2 Months Interval 10.0 to 24.7	9.7 Months Interval 5.6 to 16.4	17.4 Months Interval 11.5 to 24.7

SECONDARY outcome

Timeframe: Day 1 to last day of study treatment (+70 days) up to 2 years

Population: All participants in the study who received either ipilimumab or radiation and had a laboratory measurement were analyzed.

NCI CTC version(v) 3.0 was used to determine Grade (Gr). Screening was Day -28 to Day -1. On-study laboratories were reported after the first dose date, every 21 days during a treatment cycle, and within 70 days of last dose of study therapy (ie, Days 1, 22, 43, 64, 85, etc). Hemoglobin grams per liter (g/L): Gr 1: 10.0 - less than (<) lower limit of normal (LLN); Gr 2: 8.0 - < 10.0; Gr 3: 6.5 - < 8.0; Gr 4: < 6.5. White blood cells(WBC) 10^9 cells per liter (c/L): Gr1: 3.0 - < LLN; Gr 2: 2.0 - < 3.0; Gr 3: 1.0 - < 2.0; Gr4: < 1.0. Lymphocytes (absolute) 10^9 c/L: Gr1: 0.8 - < 1.5; Gr 2: 0.5 - < 0.8; Gr 3): 0.2 - < 0.5; Gr 4: < 0.2. Neutrophils (absolute) 10^9 c/L: Gr 1: 1.5 - < 2.0; Gr 2: 1.0 - < 1.5; Gr 3: 0.5 - < 1.0; Gr 4: < 0.5. Platelets 10^9 c/L: Gr 1: 75.0 - < lower limits of normal (LLN); Gr 2: 50.0 - < 75.0; Gr 3: 25.0 - < 50.0; Gr 4: < 25.0.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=5 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=15 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=6 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants WBC Grade 1-4 (n=8, 5, 15, 6, 34)	0 participants	0 participants	0 participants	1 participants	2 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants WBC Grade 3-4 (n=8, 5, 15, 6, 34)	0 participants	0 participants	0 participants	0 participants	0 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Neutrophils Grade 1-4 (n=8, 5, 15, 6, 34)	2 participants	0 participants	0 participants	1 participants	2 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Neutrophils Grade 3-4 (n=8, 5, 15, 6, 34)	0 participants	0 participants	0 participants	0 participants	0 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Platelets Grade 1-4 (n=8, 5, 15, 6, 34)	0 participants	0 participants	1 participants	1 participants	2 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Platelets Grade 3-4 (n=8, 5, 15, 6, 34)	0 participants	0 participants	0 participants	0 participants	0 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Hemoglobin Grade 1-4 (n=8, 5, 15, 6, 34)	7 participants	4 participants	12 participants	6 participants	28 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Hemoglobin Grade 3-4 (n=8, 5, 15, 6, 34)	0 participants	0 participants	1 participants	0 participants	6 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Lymphocytes Grade 1-4 (n=8, 5, 15, 6, 34)	7 participants	3 participants	12 participants	5 participants	31 participants	—
Number of Participants With On-Study Hematology Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Lymphocytes Grade 3-4 (n=8, 5, 15, 6, 34)	0 participants	0 participants	2 participants	1 participants	3 participants	—

SECONDARY outcome

Timeframe: Day 1 to last day of study treatment (+70 days) up to 2 years

Population: All participants in the study who received either ipilimumab or radiation and had a laboratory measurement were analyzed.

CTC v3.0 used. On-study serum chemistry laboratories were reported after first dose date, every 21 days during a treatment cycle, and within 70 days of last dose of study therapy (ie, Days 1, 22, 43, 64, 85, etc). Alanine Aminotransferase (ALT) Units per Liter (U/L) Gr 1: > 1.0 - 2.5 * upper limits of normal (ULN); Gr 2: > 2.5 - 5.0 * ULN; Gr 3: > 5.0 - 20.0 * ULN; Gr 4: > 20.0 * ULN. Aspartate Aminotransferase (AST) U/L: Gr 1: > 1.0 - 2.5 * ULN; Gr 2: > 2.5 - 5.0 * ULN; Gr 3: > 5.0 - 20.0 * ULN; Gr 4: > 20.0 * ULN. Total Bilirubin micromoles per liter (µmol/L): Gr 1: > 1.0 - 1.5 * ULN; Gr 2: > 1.5 - 3.0 * ULN; Gr 3: > 3.0 - 10.0 * ULN; Gr 4: > 10.0 * ULN. Alkaline Phosphatase U/L: Gr 1: > 1.0 - 2.5 * ULN; Gr 2: > 2.5 - 5.0 * ULN; Gr 3: > 5.0 - 20.0 * ULN; Gr 4: > 20.0 * ULN. Amylase U/L: Gr1: > 1.0 - 1.5 * ULN; Gr 2: > 1.5 - 2.0 * ULN; Gr 3: > 2.0 - 5.0 * ULN; Gr4: > 5.0 * ULN. Creatinine µmol/L: Gr1: > 1.0 - 1.5*ULN; Gr2: > 1.5 - 3.0*ULN; Gr3: > 3.0 - 6.0*ULN; Gr4: > 6.0*ULN.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=5 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=15 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=6 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants ALT Grade 3-4 (n=8,5,15,6,34)	0 participants	1 participants	2 participants	0 participants	1 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants AST Grade 1-4 (n=8,5,15,6,34)	0 participants	2 participants	6 participants	2 participants	8 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants AST Grade 3-4 (n=8,5,15,6,34)	0 participants	1 participants	2 participants	0 participants	0 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Bilirubin Grade 1-4 (n=8,5,15,6,34)	0 participants	0 participants	2 participants	1 participants	1 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Bilirubin Grade 3-4 (n=8,5,15,6,34)	0 participants	0 participants	0 participants	0 participants	0 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Phosphatase Grade 1-4 (n=8,5,15,6,34)	3 participants	4 participants	7 participants	5 participants	21 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Phosphatase Grade 3-4 (n=8,5,15,6,34)	0 participants	0 participants	1 participants	1 participants	5 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Amylase Grade 1-4 (n=8,5,15,6,34)	2 participants	3 participants	4 participants	0 participants	4 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Amylase Grade 3-4 (n=8,5,15,6,34)	0 participants	0 participants	0 participants	0 participants	1 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants ALT Grade 1-4 (n=8,5,15,6,34)	0 participants	2 participants	7 participants	2 participants	10 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Creatinine Grade 1-4 (n=8,5,15,6,34)	0 participants	0 participants	4 participants	1 participants	5 participants	—
Number of Participants With On-Study Serum Chemistry Laboratory Tests Worst Common Terminology Criteria (CTC) Grade - Treated Participants Creatinine Grade 3-4 (n=8,5,15,6,34)	0 participants	0 participants	0 participants	0 participants	0 participants	—

SECONDARY outcome

Timeframe: Baseline up to 2 years

Population: All participants in the study who received either ipilimumab or radiation and had an ECG were analyzed.

12 Lead Electrocardiograms (ECGs) were performed at screening (Day -28 to Day -1), and on Day 85 during a treatment cycle, and at the end of treatment period. Clinically significant abnormalities could include atrial fibrillation, anterior fascicular block, marked sinus bradycardia, possible lateral infarct, and T-wave abnormality (other potential abnormalities were not excluded from consideration).

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=15 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=31 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities at Baseline and During Treatment Period - Treated Participants ECG Abnormalities at Baseline (n=8, 6, 15, 7, 31)	0 participants	0 participants	2 participants	0 participants	0 participants	—
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities at Baseline and During Treatment Period - Treated Participants ECG Abnormalities During Treatment (n=4,3,11,4,20)	0 participants	0 participants	2 participants	0 participants	0 participants	—

SECONDARY outcome

Timeframe: Day 1 up to 2 years

Population: All participants in the study who received either ipilimumab or radiation and had a measurement were analyzed.

HAHA was measured by electrochemiluminescent (ECL) immunoassay for the detection of antibodies in human heparin plasma. Testing was performed on Days 1 (prior to ipilimumab infusion), 64, 85, and at completion of treatment.

Outcome measures

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 Participants A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 Participants A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 Participants A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination (Chemotherapy Naive) A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Number of Participants Positive for Human Anti-Human Antibodies (HAHA) - Treated Participants	0 participants	0 participants	0 participants	0 participants	0 participants	—

Adverse Events

Ipilimumab Monotherapy 3 mg/kg

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

Ipilimumab Monotherapy 5 mg/kg

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Ipilimumab Monotherapy 10 mg/kg

Serious events: 9 serious events

Other events: 16 other events

Deaths: 0 deaths

Ipilimumab 3 mg/kg + XRT Combination Therapy

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Ipilimumab 10 mg/kg + XRT Combination

Serious events: 19 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 participants at risk A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 participants at risk A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 participants at risk A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 participants at risk A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 participants at risk A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Abdominal pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Abdominal pain upper	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Confusional state	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Haemoglobin decreased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Hepatobiliary disorders Hepatitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Hypophysitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Hypopituitarism	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Vascular disorders Orthostatic hypotension	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Secondary adrenocortical insufficiency	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Blood and lymphatic system disorders Anaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Spinal cord compression	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Vomiting	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Dehydration	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Diverticulitis	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Cardiac disorders Acute myocardial infarction	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Cardiac disorders Atrial fibrillation	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Hepatobiliary disorders Autoimmune hepatitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	18.8% 3/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Cardiac disorders Cardio-respiratory arrest	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Vascular disorders Hypotension	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Renal failure acute	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Spinal cord neoplasm	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Appendicitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Pyrexia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Cardiac disorders Atrial flutter	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Colitis	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	25.0% 4/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Diarrhoea	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Congenital, familial and genetic disorders Gastrointestinal angiodysplasia haemorrhagic	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Pseudomembranous colitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Ascites	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Clostridium difficile colitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Disease progression	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Diarrhoea infectious	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Haematochezia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Injury, poisoning and procedural complications Hip fracture	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Hydronephrosis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Hyperthyroidism	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Mental status changes	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Nausea	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Pneumonia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	11.8% 4/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Sepsis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years

Other adverse events

Measure	Ipilimumab Monotherapy 3 mg/kg n=8 participants at risk A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 5 mg/kg n=6 participants at risk A single dose of 5 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses (induction). Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab Monotherapy 10 mg/kg n=16 participants at risk A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total of 16 doses in the maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 3 mg/kg + XRT Combination Therapy n=7 participants at risk A single dose of 3 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal radiotherapy (XRT) to each target lesion within 48 hours before the first infusion of ipilimumab during the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral computed tomography (CT). Those participants with a clinical response of SD or CDRA at the end of induction could have received additional treatment up to a total 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.	Ipilimumab 10 mg/kg + XRT Combination n=34 participants at risk A single dose of 10 mg/kg ipilimumab was administered over 90 minutes IV on Days 1, 22, 43, and 64 for a total of 4 doses in the induction period. In addition, participants received a single dose of 800 rads (8 Gray) of focal XRT to each target lesion within 48 hours before the first infusion of ipilimumab in the induction period. According to RECIST, target or measurable lesions were defined as lesions that could be accurately measured in at least one dimension (longest diameter recorded) as ≥ 10 mm with spiral CT. Those participants with a clinical response of SD or CDRA at the end of induction period could have received additional treatment up to a total of 16 doses in the maintenance period. Radiotherapy was not administered during maintenance period. The length of time on study for an individual could be up to 2 years. Follow up for survival status was for up to 5 years after enrollment.
Gastrointestinal disorders Abdominal pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	50.0% 3/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	18.8% 3/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	8.8% 3/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Injury, poisoning and procedural complications Adverse event following immunisation	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Bone pain	25.0% 2/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	8.8% 3/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Confusional state	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.7% 5/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Cystitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Decreased appetite	25.0% 2/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	37.5% 6/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	42.9% 3/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	38.2% 13/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Depression	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Early satiety	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Gingival bleeding	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Haemoglobin decreased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	18.8% 3/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Vascular disorders Hot flush	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Hypophysitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Hypopituitarism	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Paraesthesia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Surgical and medical procedures Tooth extraction	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Upper respiratory tract infection	25.0% 2/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Viral infection	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Affect lability	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Blood and lymphatic system disorders Anaemia	25.0% 2/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	17.6% 6/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Bronchitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Chest pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Cardiac disorders Congestive cardiomyopathy	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Constipation	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	37.5% 6/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	42.9% 3/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	32.4% 11/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hypochloraemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Intervertebral disc disorder	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Night sweats	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	11.8% 4/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Postnasal drip	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Rash	25.0% 2/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	50.0% 3/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	62.5% 10/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	20.6% 7/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Rash maculo-papular	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Vomiting	37.5% 3/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	31.2% 5/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	57.1% 4/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	29.4% 10/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Weight increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Alanine aminotransferase increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	8.8% 3/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Aspartate aminotransferase increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.7% 5/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood lactate dehydrogenase increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood phosphorus decreased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Chills	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Dehydration	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	37.5% 6/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Dyspepsia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Dysphoria	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Fatigue	87.5% 7/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	83.3% 5/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	56.2% 9/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	57.1% 4/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	55.9% 19/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hyperuricaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Infected sebaceous cyst	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Lipase	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Mucosal inflammation	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Musculoskeletal discomfort	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Reproductive system and breast disorders Pelvic pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Sinusitis	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Injury, poisoning and procedural complications Stress fracture	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Ear and labyrinth disorders Vertigo	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Abdominal discomfort	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Abdominal distension	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Adrenal insufficiency	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	28.6% 2/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Asthenia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	18.8% 3/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	20.6% 7/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Hepatobiliary disorders Autoimmune hepatitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Azotaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood corticotrophin decreased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood creatine increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood potassium decreased	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Eye disorders Conjunctival haemorrhage	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Injury, poisoning and procedural complications Contusion	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Dizziness	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.7% 5/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Groin pain	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Hallucination	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Vascular disorders Hypotension	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Neuropathy peripheral	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Nocturia	25.0% 2/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Oedema	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Pruritus generalised	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Sciatica	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Yellow skin	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Arthralgia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	28.6% 2/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	23.5% 8/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood alkaline phosphatase increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood amylase increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood pressure increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Eye disorders Conjunctivitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Cushingoid	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Eye disorders Dry eye	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Iron deficiency	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Malaise	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Muscle atrophy	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	8.8% 3/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Neck pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Oedema peripheral	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.7% 5/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Pyrexia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	11.8% 4/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Rash papular	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Reproductive system and breast disorders Sexual dysfunction	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Transaminases increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Weight decreased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	43.8% 7/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	71.4% 5/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	20.6% 7/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Injury, poisoning and procedural complications Arthropod sting	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood bilirubin increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Candidiasis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Colitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	18.8% 3/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	11.8% 4/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Diarrhoea	50.0% 4/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	50.0% 3/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	81.2% 13/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	42.9% 3/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	50.0% 17/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Dysgeusia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Reproductive system and breast disorders Gynaecomastia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Headache	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	8.8% 3/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hypoproteinaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Hypothyroidism	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Infusion related reaction	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Lipase increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Liver function test abnormal	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	11.8% 4/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Musculoskeletal pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	11.8% 4/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Myalgia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Pain	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Proctalgia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Renal impairment	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Cardiac disorders Tachycardia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Urinary tract infection	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Injury, poisoning and procedural complications Wrist fracture	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood alkaline phosphatase abnormal	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Blood glucose increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Euthyroid sick syndrome	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Eye disorders Eye pain	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Eye disorders Eye pruritus	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Gamma-glutamyltransferase increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Hyperaesthesia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Vascular disorders Hypertension	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Hyporeflexia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Incontinence	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Large intestinal obstruction	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Malabsorption	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
General disorders Mucosal exfoliation	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Reproductive system and breast disorders Penis disorder	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Rash erythematous	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Anal fissure	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Cardiac disorders Angina pectoris	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Anxiety	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Musculoskeletal and connective tissue disorders Back pain	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	25.0% 4/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	17.6% 6/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Dermatitis acneiform	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Diarrhoea infectious	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Flatulence	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Folliculitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Fungal skin infection	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Gout	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Haematochezia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	8.8% 3/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Haematuria	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Renal and urinary disorders Hydronephrosis	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hyperlipidaemia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Endocrine disorders Hyperthyroidism	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	12.5% 2/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Hypoaesthesia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	5.9% 2/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Metabolism and nutrition disorders Hypomagnesaemia	12.5% 1/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Insomnia	25.0% 2/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	17.6% 6/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Nasopharyngitis	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Gastrointestinal disorders Nausea	50.0% 4/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	33.3% 2/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	50.0% 8/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	57.1% 4/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	44.1% 15/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Oral herpes	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Psychiatric disorders Panic attack	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Infections and infestations Pneumonia	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	6.2% 1/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	2.9% 1/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Skin and subcutaneous tissue disorders Pruritus	37.5% 3/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	37.5% 6/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	11.8% 4/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Nervous system disorders Restless legs syndrome	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Investigations Rheumatoid factor increased	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years
Eye disorders Vision blurred	0.00% 0/8 • Day 1 to last day of study treatment (+70 days) up to 2 years	16.7% 1/6 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/16 • Day 1 to last day of study treatment (+70 days) up to 2 years	14.3% 1/7 • Day 1 to last day of study treatment (+70 days) up to 2 years	0.00% 0/34 • Day 1 to last day of study treatment (+70 days) up to 2 years

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: Clinical.Trials@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER