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PD-1: PH 1 Biomarker Study of Nivolumab and Ipilimumab and Nivolumab in Combination With Ipilimumab in Advanced Melanoma

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT01621490
Collaborator
(none)
227
Enrollment
14
Locations
6
Arms
72.9
Actual Duration (Months)
16.2
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate pharmacodynamic changes of Nivolumab and Nivolumab in combination with Ipilimumab treatment on the biomarkers measured in the peripheral blood and tumor tissues of subjects with advanced melanoma (unresectable or advanced)

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

Allocation:

Part 1 and 2: Single Arm study

Part 3 and 4: Randomized Controlled Trial

Intervention Model:

Part 1 and 2: Single group: Single arm study

Part 3 and 4: Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study

Minimum Age:

Part 1: 18

Part 2, 3 and 4: 16

Study Design

Study Type:
Interventional
Actual Enrollment :
227 participants
Allocation:
Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
An Exploratory Study of the Biologic Effects of Nivolumab and Ipilimumab Monotherapy and Nivolumab in Combination With Ipilimumab Treatment in Subjects With Advanced Melanoma (Unresectable or Metastatic)
Actual Study Start Date :
Sep 27, 2012
Actual Primary Completion Date :
Sep 12, 2017
Actual Study Completion Date :
Oct 25, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1-Cohort 1 and 2: Nivolumab

Nivolumab 3 mg/kg solution intravenously Every 2 weeks, Up to 2 years depending on response

Biological: Nivolumab
Other Names:
  • BMS-936558 (MDX1106)

    		•
    Experimental: Part 2-Arm A: Nivolumab + Ipilimumab

    Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified

    Biological: Nivolumab
    Other Names:
  • BMS-936558 (MDX1106)

    • Drug: Ipilimumab
    Other Names:
  • BMS734016
  • Yervoy

    		•
    Experimental: Part 3-Arm A: Nivolumab + Ipilimumab

    Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified

    Biological: Nivolumab
    Other Names:
  • BMS-936558 (MDX1106)

    • Drug: Ipilimumab
    Other Names:
  • BMS734016
  • Yervoy

    		•
    Experimental: Part 3-Arm B: Nivolumab

    Nivolumab 3 mg/kg solution intravenously as specified

    Biological: Nivolumab
    Other Names:
  • BMS-936558 (MDX1106)

    		•
    Experimental: Part 4-Arm D: Nivolumab + Ipilimumab

    Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified

    Biological: Nivolumab
    Other Names:
  • BMS-936558 (MDX1106)

    • Drug: Ipilimumab
    Other Names:
  • BMS734016
  • Yervoy

    		•
    Experimental: Part 4-Arm E: Nivolumab

    Nivolumab 3 mg/kg solution intravenously as specified

    Biological: Nivolumab
    Other Names:
  • BMS-936558 (MDX1106)

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors [From last non-missing value prior to first dose to week 7 day 1]

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

    2. Tumor Infiltrating Lymphocytes (TILs) as Measured by Medians in Percent Positive CD8 and Positive CD4 at Baseline and On-treatment Biopsy, Both Using the Mosaic Singleplex IHC Assay [From last non-missing value prior to first dose to week 4 day 1]

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

    Secondary Outcome Measures

    1. Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Deaths and AEs [Includes events reported between first dose and up to 100 days after last dose of study medication.]

      The assessment of safety was based on frequency of deaths, AEs, SAEs, AEs leading to discontinuation of study drug, and abnormalities in specific clinical laboratory assessments. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0.

    2. Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by SAEs and AEs Leading to Discontinuation of Study Drug. [From enrollment to 100 days after the last dose date]

      The assessment of safety was based on frequency of SAEs and AEs leading to discontinuation of study drug. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0.

    3. Number of Laboratory Abnormalities in Specific Liver Tests [101-120 days after last dose.]

      Abnormalities in hepatic parameters measured included those in aspartate aminotransferase (AST), alanine aminotransferase (ALT)and total bilirubin, with respect to upper limit of normal (ULN)

    4. Number of Laboratory Abnormalities in Specific Thyroid Tests [101-120 days after last dose.]

      Abnormalities in thyroid parameters measured included those in thyroid stimulating hormone (TSH) levels with respect to upper limit of normal (ULN) and lower limit of normal (LLN)

    5. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Objective Response Rate (ORR) [Approximately every 8 weeks until disease progression and in follow-up if no progression]

      The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (eg, all treated subjects or response-evaluable subjects). The BOR was defined as the subject's best response designation, over the study as a whole, recorded between the date of first study drug administration and the date of objectively documented progression per RECIST 1.1, with subsequent confirmation, or date of subsequent anti-cancer therapy, whichever occurred first in the study.

    6. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Duration of Response (mDOR) [2 years from the first dose of treatment]

      Median duration of response (mDOR) was calculated for subjects with BOR of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.

    7. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Time to Response (mTTR) [2 years from the first dose of treatment]

      Median time to response (mTTR) for a participant with a BOR of CR or PR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR).

    8. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Progression Free Survival Rate (PFSR) [2 years from the first dose of treatment]

      The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.

    9. Immunogenicity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Serum Anti-drug Antibody (ADA) Positive Participants and the Number of Neutralizing ADA Positive Participants [Up to follow-up visit 2 (101-120 days since last treatment)]

      Time Frame: Part 1: Day 1, Day 15, Day 43 of cycle 1, Day 1 of cycle 2, Day 15 of cycle 3, every 16 weeks after cycle 3 up to 2 years, follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment) Part 2, 3 and 4: Weeks 1, 3, 4, 7, 9, 10, 13, 25, 53, 79, 95 follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment)

    10. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Objective Response Rate (PD-L1 ORR) [2 years from first dose of treatment; Assessed up to September 2017]

      For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (all response-evaluable participants).

    11. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as the Duration of Response (PD-L1 DOR) [2 years from first dose of treatment; Assessed up to September 2017]

      For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. Median duration of response (mDOR) was calculated for all response-evaluable participants with best overall response of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.

    12. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Progression Free Survival (PD-L1 PFS) [2 years from first dose of treatment; Assessed up to September 2017]

      For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.

    13. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Overall Survival Rate (PD-L1 OSR) [2 years from first dose of treatment; Assessed up to September 2017]

      For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive

    14. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Overall Survival Rate (OSR) [2 years from first dose of treatment; Assessed up to September 2017]

      The proportion of subjects surviving to time t, where t is a specific length of time, eg, 12 months, which was determined by the available data for final analysis and was documented in the DPP. The proportion was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive

    Eligibility Criteria

    Criteria

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

    For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

    Part 1:
    Inclusion Criteria:

    • Men and women >18 years

    • Eastern Cooperative Oncology Group (ECOG) status = 0 to 1

    • Subjects with unresectable Stage III or IV melanoma who are either refractory or intolerant to, or have refused standard therapy for treatment of metastatic melanoma

    • Subject must have histologic or cytologic confirmation of advanced melanoma

    • Subjects must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

    • Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk and must consent to pre- and post-treatment biopsies

    Exclusion Criteria:

    • Active or progressing brain metastases

    • Other concomitant malignancies (with some exceptions per protocol)

    • Active or history of autoimmune disease

    • Positive test for human immunodeficiency virus (HIV) 1&2 or known acquired immunodeficiency syndrome (AIDS)

    • History of any hepatitis

    • Prior therapy with any antibody/drug that targets the T cell coregulatory proteins, including but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40,and anti-CD40 antibodies. However, half the patients must have progressed on anti Cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA4) monoclonal antibody therapy

    Part 2, 3 and 4:

    Inclusion Criteria

    • Men and women >16 years

    • Eastern Cooperative Oncology Group (ECOG) status = 0 to 1

    • Subjects with unresectable Stage III or IV melanoma who are either refractory or intolerant to, or have refused standard therapy for treatment of metastatic melanoma

    • Subjects must never received anti-CTLA4 therapy

    • Subjects must have histologic or cytologic confirmation of advanced melanoma

    • Subjects must have at least two measurable lesions at baseline by CT or MRI as per RECIST 1.1 criteria

    • Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk and must consent to pre- and post-treatment biopsies

    • Subjects in Part 4 must have brain metastases

    Exclusion Criteria

    • Active or progressing brain metastases (except for Part 4 subjects)

    • Other concomitant malignancies (with some exceptions per protocol)

    • Active or history of autoimmune disease

    • Positive test for HIV 1&2 or known AIDS

    • History of any hepatitis

    • Prior therapy with any antibody/drug that targets the T cell coregulatory proteins, including but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40,and anti-CD40 antibodies

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Ucla Los Angeles California United States 90095
    2 University Of Chicago Chicago Illinois United States 60637
    3 Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins Lutherville Maryland United States 21093
    4 Beth Israel Deaconess Medical Center (BIDMC) Boston Massachusetts United States 02215
    5 Dana Farber Cancer Institute Boston Massachusetts United States 02215
    6 Massachusetts General Hospital Boston Massachusetts United States 02215
    7 Memorial Sloan-Kettering Cancer Center New York New York United States 10065
    8 Providence Portland Medical Center Portland Oregon United States 97213
    9 Vanderbilt-Ingram Cancer Ctr Nashville Tennessee United States 37232
    10 The University Of Texas MD Anderson Cancer Center Houston Texas United States 77030
    11 University Of Virginia Charlottesville Virginia United States 22908
    12 Seattle Cancer Care Alliance Seattle Washington United States 98109
    13 Local Institution Amsterdam Netherlands 1066 CX
    14 Local Institution Pamplona Spain 31192

    Sponsors and Collaborators

    • Bristol-Myers Squibb

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01621490
    Other Study ID Numbers:
    • CA209-038
    • 2012-001840-23
    First Posted:
    Jun 18, 2012
    Last Update Posted:
    Dec 3, 2019
    Last Verified:
    Nov 1, 2019
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Melanoma
    Nivolumab
    Ipilimumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 227 participants were enrolled; 55 did not enter the treatment period: 41 did not meet study criteria; 6 other; 5 withdrew consent; 1 adverse events; 2 deaths. 172 entered the treatment period.2 were not treated;1 received ipilimumab monotherapy prior to the closure of Arm C; 1 received an unplanned treatment;168 were treated
    Arm/Group Title N3 60 M Naive N3 60M Prog N1 60M + I3 90M, W2 N1 60M + I3 90M, W4 N1 60M +I3 90M, WU N1 30M + I3 30M Non-BM N3 30M Non-BM N1 30M +I3 30M BM N3 30M BM
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; 30M = 30 minute infusion; NAIVE = Anti-CTLA4 Naive Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg;30M = 30 minute infusion; BM = Brain metastases Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases
    Period Title: Overall Study
    STARTED 41 44 11 10 6 25 11 10 10
    COMPLETED 0 0 0 1 0 1 0 0 2
    NOT COMPLETED 41 44 11 9 6 24 11 10 8

    Baseline Characteristics

    Arm/Group Title N3 60 M Naive N3 60M Prog N1 60M + I3 90M, W2 N1 60M + I3 90M, W4 N1 60M +I3 90M, WU N1 30M + I3 30M Non-BM N3 30M Non-BM N1 30M +I3 30M BM N3 30M BM Total
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; 30M = 30 minute infusion; NAIVE = Anti-CTLA4 Naive Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg;30M = 30 minute infusion; BM = Brain metastases Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases Total of all reporting groups
    Overall Participants 41 44 11 10 6 25 11 10 10 168
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    55.5
    (12.49)
    53.7
    (15.10)
    61.0
    (11.82)
    58.5
    (13.29)
    56.8
    (9.64)
    56.9
    (13.52)
    51.5
    (15.55)
    56.9
    (9.37)
    58.9
    (13.46)
    55.8
    (13.33)
    Sex: Female, Male (Count of Participants)
    Female
    19
    46.3%
    18
    40.9%
    3
    27.3%
    4
    40%
    3
    50%
    8
    32%
    4
    36.4%
    4
    40%
    5
    50%
    68
    40.5%
    Male
    22
    53.7%
    26
    59.1%
    8
    72.7%
    6
    60%
    3
    50%
    17
    68%
    7
    63.6%
    6
    60%
    5
    50%
    100
    59.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    4.9%
    0
    0%
    2
    18.2%
    0
    0%
    0
    0%
    0
    0%
    1
    9.1%
    1
    10%
    0
    0%
    6
    3.6%
    Not Hispanic or Latino
    34
    82.9%
    41
    93.2%
    6
    54.5%
    10
    100%
    5
    83.3%
    15
    60%
    5
    45.5%
    3
    30%
    7
    70%
    126
    75%
    Unknown or Not Reported
    5
    12.2%
    3
    6.8%
    3
    27.3%
    0
    0%
    1
    16.7%
    10
    40%
    5
    45.5%
    6
    60%
    3
    30%
    36
    21.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    1
    2.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White
    41
    100%
    43
    97.7%
    11
    100%
    10
    100%
    6
    100%
    25
    100%
    11
    100%
    10
    100%
    10
    100%
    167
    99.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors
    Description Baseline and post-treatment modulation of serum levels of chemokines, cytokines and other immune mediators were assessed by techniques that included ELISA or other multiplex-based assay methods. Primary analysis included IFN-gamma and IFN-gamma inducible factors, including chemokine [C-X-C motif] ligand 9 (CXCL9) and CXCL10
    Time Frame From last non-missing value prior to first dose to week 7 day 1

    Outcome Measure Data

    Analysis Population Description
    All response evaluable participants
    Arm/Group Title N3 60M Naive N3 60M PROG N1 60M + I3 90M N1 30M + I3 30M Non-BM N3 30M Non-BM N1 30M + I3 30M BM N3 30M BM N1+ I3 Non-BM Naive Nivo Mono All Nivo All Combo Total
    Arm/Group Description Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Treatment Group: Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Treatment Group: Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Treatment Group: Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases Treatment Group: Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases Nivolumab Monotherapy CTLA-4 Naive Treatment Group: All Nivolumab Monotherapy Treatment Group: All Combination Therapy All treatments
    Measure Participants 40 40 27 23 11 8 7 50 58 98 58 156
    IFN-gamma Simoa
    0.0130
    (0.1740)
    0.0320
    (0.0817)
    0.2310
    (0.4528)
    0.1600
    (1.2047)
    0.0520
    (0.1207)
    0.0950
    (1.5082)
    0.0375
    (0.1868)
    0.2200
    (0.8198)
    0.0130
    (0.1674)
    0.0240
    (0.1373)
    0.1520
    (1.0023)
    0.0515
    (0.5944)
    CXL9 (aka MIG)
    1105.0
    (10467.4)
    1890.0
    (8706.0)
    4680.0
    (18096.9)
    3542.0
    (12133.1)
    -29.0
    (1684.2)
    5692.0
    (6796.0)
    3610.0
    (2197.4)
    458.5
    (1651.0)
    1056.5
    (9167.8)
    1235.0
    (8984.2)
    4680.0
    (14792.5)
    2027.0
    (11491.9)
    CXL10 (aka IP10)
    184.0
    (514.1)
    160.0
    (539.9)
    684.0
    (2563.1)
    934.5
    (2842.0)
    26.0
    (172.7)
    514.0
    (612.3)
    318.0
    (354.0)
    695.0
    (2627.7)
    185.0
    (474.6)
    184.0
    (500.7)
    684.0
    (2450.6)
    234.5
    (1566.3)
    2. Primary Outcome
    Title Tumor Infiltrating Lymphocytes (TILs) as Measured by Medians in Percent Positive CD8 and Positive CD4 at Baseline and On-treatment Biopsy, Both Using the Mosaic Singleplex IHC Assay
    Description Biomarkers examined were percent positive CD8 and percent positive CD4, both using the Mosaic Singleplex IHC assay. Analyses are presented with the medians at baseline and on-treatment, rather than the median change because the baseline values differed across groups. Baseline was defined as the last non-missing value on or prior to the first dose of study therapy. Biopsies were also collected on treatment.
    Time Frame From last non-missing value prior to first dose to week 4 day 1

    Outcome Measure Data

    Analysis Population Description
    Response evaluable participants
    Arm/Group Title N3 60M Naive N3 60M PROG N1 60M + I3 90M W2 N1 60M + I3 90M W4 N1 30M + I3 30M Non-BM N3 30M Non-BM N3 30M + I3 30M BM N3 30M BM Nivo Mono Nivo Mono Reduced Infusion Week 2 Biopsy Combo Week 2 Biopsy Non-BM Combo Naive Nivo Mono Non-BM N1 + I3 Non-BM
    Arm/Group Description Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 2 Biopsy Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 4 Biopsy Treatment Group: Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Treatment Group: Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Treatment Group: Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases Treatment Group: Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases Treatment Group: Part 1: Regular Infusion Nivolumab Mono Treatment Group: Reduced Infusion Nivolumab Monotherapy Treatment Group: Week 2 Biopsy Combo Treatment Group: Week 2 Biopsy Non-Brain Metastases Combo Treatment Group: Naive Nivolumab Mono Non-Brain Metastases Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases
    Measure Participants 25 23 11 10 15 10 3 2 48 12 29 26 35 40
    Percent CD8 Baseline
    3.73
    (10.994)
    7.230
    (10.712)
    3.260
    (9.259)
    11.105
    (9.524)
    4.700
    (9.810)
    5.615
    (12.475)
    18.590
    (8.132)
    6.135
    (5.664)
    6.360
    (10.727)
    5.615
    (11.472)
    4.700
    (9.292)
    4.230
    (9.401)
    5.210
    (11.288)
    4.230
    (9.844)
    Percent positive CD8 Week 2
    11.345
    (21.316)
    7.970
    (15.132)
    10.100
    (10.909)
    8.470
    (7.740)
    29.735
    (5.254)
    10.910
    (12.387)
    9.080
    (17.510)
    9.125
    (18.654)
    10.100
    (10.909)
    9.125
    (18.654)
    Percent positive CD8 Week 4
    18.435
    (17.108)
    7.140
    (25.204)
    32.455
    (15.967)
    37.465
    (5.706)
    15.150
    (21.475)
    37.465
    (5.706)
    37.465
    (5.706)
    18.435
    (17.108)
    34.785
    (13.856)
    Percent CD4 Baseline
    0.360
    (1.844)
    0.600
    (2.268)
    0.840
    (1.852)
    0.470
    (3.833)
    4.155
    (6.624)
    4.950
    (4.992)
    6.500
    (8.108)
    2.780
    (NA)
    0.375
    (2.057)
    4.600
    (4.807)
    2.750
    (5.833)
    2.610
    (5.607)
    0.870
    (3.727)
    1.510
    (6.023)
    Percent positive CD4 Week 2
    4.500
    (10.741)
    6.260
    (8.518)
    4.210
    (5.029)
    6.420
    (14.778)
    20.830
    (NA)
    6.155
    (6.585)
    6.125
    (10.222)
    5.990
    (9.602)
    4.210
    (5.029)
    5.990
    (9.602)
    Percent positive CD4 Week 4
    1.585
    (3.071)
    1.260
    (4.641)
    9.005
    (13.324)
    24.520
    (2.659)
    1.275
    (3.921)
    24.520
    (2.659)
    24.520
    (2.659)
    1.585
    (3.071)
    10.155
    (12.707)
    3. Secondary Outcome
    Title Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Deaths and AEs
    Description The assessment of safety was based on frequency of deaths, AEs, SAEs, AEs leading to discontinuation of study drug, and abnormalities in specific clinical laboratory assessments. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0.
    Time Frame Includes events reported between first dose and up to 100 days after last dose of study medication.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title N3 60M Naive N3 60M PROG N1 60M + I3 90M N1 30M + I3 30M Non-BM N3 30M Non-BM N1 30M + I3 30M BM N3 30M BM N3 60M N3 30M N1 30M + I3 30M N3 NAIVE All N3 Total
    Arm/Group Description N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion N3 = Nivolumab 3mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All treatments
    Measure Participants 41 44 27 25 11 10 10 85 21 35 62 106 168
    Participants who died
    26
    25
    10
    12
    4
    2
    4
    51
    8
    14
    34
    59
    83
    Participants who died within 30 days of last dose
    3
    2
    4
    0
    0
    1
    0
    5
    0
    1
    3
    5
    10
    Participants who died within 100 days of last dose
    5
    8
    5
    0
    1
    2
    2
    13
    3
    2
    8
    16
    23
    Participants with an AE
    41
    44
    27
    25
    11
    10
    10
    85
    21
    35
    62
    106
    168
    4. Secondary Outcome
    Title Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by SAEs and AEs Leading to Discontinuation of Study Drug.
    Description The assessment of safety was based on frequency of SAEs and AEs leading to discontinuation of study drug. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0.
    Time Frame From enrollment to 100 days after the last dose date

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title N3 60M Naive N3 60M Prog N1 60M + I3 90M N1 30M + I3 30M Non-BM N3 30M Non-BM N1 30M I3 30M BM N3 30M BM Nivo Mono Reduced Nivo Mono Reduced Combo Naive Nivo Mono All Nivo Mono All Combo Total
    Arm/Group Description Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases Part 1: Regular Infusion Nivolumab Mono Reduced Infusion Nivolumab Mono Reduced Infusion Combo Naive Nivolumab Mono All Nivolumab Mono All Combinations All treatments
    Measure Participants 41 44 27 25 11 10 10 85 21 35 62 106 62 168
    SAEs by Worst CTC Grade
    16
    16
    20
    13
    2
    6
    4
    32
    6
    19
    22
    38
    39
    77
    AEs Leading to Discontinuation by Worst CTC Grade
    3
    6
    12
    9
    1
    4
    3
    9
    4
    13
    7
    13
    25
    38
    5. Secondary Outcome
    Title Number of Laboratory Abnormalities in Specific Liver Tests
    Description Abnormalities in hepatic parameters measured included those in aspartate aminotransferase (AST), alanine aminotransferase (ALT)and total bilirubin, with respect to upper limit of normal (ULN)
    Time Frame 101-120 days after last dose.

    Outcome Measure Data

    Analysis Population Description
    Participants with at least one on-treatment measurement of the corresponding laboratory parameter
    Arm/Group Title N3 60M NAIVE N3 60M PROG N1 60M +I3 90M N1 30M + I3 30M Non-BM N3 30M Non-BM N1 30M + I3 30M BM N3 30M BM N3 60M N3 30M N1 30M + I3 30M N3 NAIVE All N3 Total
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg;30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All treatments
    Measure Participants 41 44 27 25 11 10 10 85 21 35 62 106 168
    ALT OR AST > 3XULN
    2
    4
    8
    5
    0
    3
    0
    6
    0
    8
    2
    6
    22
    ALT OR AST> 5XULN
    1
    2
    6
    4
    0
    1
    0
    3
    0
    5
    1
    3
    14
    ALT OR AST> 10XULN
    1
    0
    3
    2
    0
    1
    0
    1
    0
    3
    1
    1
    7
    ALT OR AST > 20XULN
    0
    0
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    2
    TOTAL BILIRUBIN > 2XULN
    0
    0
    2
    1
    0
    2
    0
    0
    0
    3
    0
    0
    5
    ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY
    0
    0
    2
    1
    0
    1
    0
    0
    0
    2
    0
    0
    4
    ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAY
    0
    0
    2
    1
    0
    1
    0
    0
    0
    2
    0
    0
    4
    6. Secondary Outcome
    Title Number of Laboratory Abnormalities in Specific Thyroid Tests
    Description Abnormalities in thyroid parameters measured included those in thyroid stimulating hormone (TSH) levels with respect to upper limit of normal (ULN) and lower limit of normal (LLN)
    Time Frame 101-120 days after last dose.

    Outcome Measure Data

    Analysis Population Description
    Participants with at least one on-treatment measurement of TSH
    Arm/Group Title N3 60M NAIVE N3 60M PROG N1 60M +I3 90M N1 30M + I3 30M Non-BM N3 30M Non-BM N1 30M + I3 30M BM N3 30M BM N3 60M N3 30M N1 30M + I3 30M N3 NAIVE All N3 Total
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg;30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All treatments
    Measure Participants 29 33 21 25 11 10 8 62 19 35 48 81 137
    TSH > ULN
    9
    16
    7
    7
    1
    3
    4
    25
    5
    10
    14
    30
    47
    TSH > ULN WITH TSH <= ULN AT BASELINE
    4
    9
    7
    4
    1
    3
    2
    13
    3
    7
    7
    16
    30
    TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN
    0
    0
    3
    3
    0
    2
    2
    0
    2
    5
    2
    2
    10
    TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    TSH > ULN WITH FT3/FT4 TEST MISSING
    9
    16
    4
    4
    1
    1
    2
    25
    3
    5
    12
    28
    37
    TSH < LLN
    3
    4
    11
    12
    2
    6
    5
    7
    7
    18
    10
    14
    43
    TSH <LLN WITH TSH >= LLN AT BASELINE
    3
    4
    11
    12
    2
    6
    5
    7
    7
    18
    10
    14
    43
    TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN
    0
    0
    5
    4
    0
    2
    2
    0
    2
    6
    2
    2
    13
    TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN
    0
    0
    3
    1
    0
    0
    1
    0
    1
    1
    1
    1
    5
    TSH < LLN WITH FT3/FT4 TEST MISSING
    3
    4
    3
    7
    2
    4
    2
    7
    4
    11
    7
    11
    25
    7. Secondary Outcome
    Title Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Objective Response Rate (ORR)
    Description The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (eg, all treated subjects or response-evaluable subjects). The BOR was defined as the subject's best response designation, over the study as a whole, recorded between the date of first study drug administration and the date of objectively documented progression per RECIST 1.1, with subsequent confirmation, or date of subsequent anti-cancer therapy, whichever occurred first in the study.
    Time Frame Approximately every 8 weeks until disease progression and in follow-up if no progression

    Outcome Measure Data

    Analysis Population Description
    All treated subjects
    Arm/Group Title N3 60M Naive N3 60M Prog N1 60M+I3 90M N1 30M + I3 30M Non-BM N3 30M Non-BM N3 30M + I3 30M BM N3 30M BM N1 + I3 Non-BM N3 Naive N3 Only N1 + I3 Total
    Arm/Group Description N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases; N3 = Nivolumab 3mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All combination treatments All treatments
    Measure Participants 41 44 27 25 11 10 10 52 62 106 62 168
    Number (95% Confidence Interval) [Percentage of participants]
    31.7
    77.3%
    22.7
    51.6%
    44.4
    403.6%
    40.0
    400%
    27.3
    455%
    70.0
    280%
    60.0
    545.5%
    42.3
    423%
    35.5
    355%
    30.2
    18%
    46.8
    NaN
    36.3
    NaN
    8. Secondary Outcome
    Title Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Duration of Response (mDOR)
    Description Median duration of response (mDOR) was calculated for subjects with BOR of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.
    Time Frame 2 years from the first dose of treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title N3 60M Naive N3 60M PROG N1 60M + I3 90M N1 30M + I3 30M NON-BM N3 30M NON-BM N1 30M + I3 30M BM N3 30M BM N1 + I3 NON-BM N3 NAIVE All N3 N1 + I3 Total
    Arm/Group Description N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All combination treatments All treatments
    Measure Participants 41 44 27 25 11 10 10 52 62 106 62 168
    Median (95% Confidence Interval) [Months]
    15.21
    NA
    NA
    26.25
    NA
    NA
    20.27
    NA
    20.27
    NA
    NA
    NA
    9. Secondary Outcome
    Title Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Time to Response (mTTR)
    Description Median time to response (mTTR) for a participant with a BOR of CR or PR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR).
    Time Frame 2 years from the first dose of treatment

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group Title N3 60M Naive N3 60M PROG N1 60M + I3 90M N1 30M + I3 30M NON-BM N3 30M NON-BM N1 30M + I3 30M BM N3 30M BM N1 + I3 NON-BM N3 NAIVE All N3 N1 + I3 Total
    Arm/Group Description N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All combination All treatments
    Measure Participants 41 44 27 25 11 10 10 52 62 106 62 168
    Median (95% Confidence Interval) [Months]
    1.87
    2.78
    1.41
    2.51
    1.41
    1.71
    2.14
    1.41
    1.87
    1.87
    1.45
    1.87
    10. Secondary Outcome
    Title Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Progression Free Survival Rate (PFSR)
    Description The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.
    Time Frame 2 years from the first dose of treatment

    Outcome Measure Data

    Analysis Population Description
    All treated subjects
    Arm/Group Title N3 60M Naive N3 60M PROG N1 60M + I3 90M N1 30M + I3 30M NON-BM N3 30M NON-BM N1 30M + I3 30M BM N3 30M BM N1 + I3 NON-BM N3 NAIVE All N3 N1 + I3 Total
    Arm/Group Description N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All combination treatments All treatments
    Measure Participants 41 44 27 25 11 10 10 52 62 106 62 168
    Median (95% Confidence Interval) [Percentage]
    3.68
    5.62
    7.00
    9.69
    4.93
    NA
    23.00
    7.23
    3.91
    4.93
    10.55
    5.78
    11. Secondary Outcome
    Title Immunogenicity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Serum Anti-drug Antibody (ADA) Positive Participants and the Number of Neutralizing ADA Positive Participants
    Description Time Frame: Part 1: Day 1, Day 15, Day 43 of cycle 1, Day 1 of cycle 2, Day 15 of cycle 3, every 16 weeks after cycle 3 up to 2 years, follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment) Part 2, 3 and 4: Weeks 1, 3, 4, 7, 9, 10, 13, 25, 53, 79, 95 follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment)
    Time Frame Up to follow-up visit 2 (101-120 days since last treatment)

    Outcome Measure Data

    Analysis Population Description
    A subset of all treated subjects who had a baseline and at least 1 post-baseline ADA assessment for nivolumab and ipilimumab separately
    Arm/Group Title N3 60M NAIVE N3 60M PROG N1 60M + I3 (Nivo ADA N1 60M + I3 90M (Ipi ADA) N1 30M + I3 30M Non-BM (Nivo ADA) N1 30M + I3 30M Non-BM (Ipi ADA) N3 30M Non-BM N1 30M + I3 30M (Nivo ADA) N1 30M + I3 30M (Ipi ADA) N3 30M BM Total (Nivo ADA) Total (Ipi ADA)
    Arm/Group Description Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Progressed Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases Part 4: Nivolumab 3 mg/kg 30 Minute Infusion Brain Metastases Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment) Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment)
    Measure Participants 38 42 22 22 24 23 11 10 9 7 154 54
    ADA positive
    2
    4.9%
    5
    11.4%
    10
    90.9%
    1
    10%
    16
    266.7%
    4
    16%
    1
    9.1%
    7
    70%
    0
    0%
    1
    0.6%
    42
    NaN
    5
    NaN
    Neutralizing ADA positive
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    2
    20%
    0
    0%
    3
    1.8%
    0
    NaN
    12. Secondary Outcome
    Title Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Objective Response Rate (PD-L1 ORR)
    Description For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (all response-evaluable participants).
    Time Frame 2 years from first dose of treatment; Assessed up to September 2017

    Outcome Measure Data

    Analysis Population Description
    All response-evaluable participants
    Arm/Group Title N3 60M NAIVE, W4 N3 60M PROG, W4 N1 60M + I3 90M, W2 N1 60M + I3 90M, W4 N1 60M + I3 90M, WU N1 30M + I3 30M NON-BM N3 30M NON-BM, W2 N1 30M + I3 30M BM, W2 N3 30M BM, W2 N3 60M, W4 N3 30M, W2 N1 + I3, W2 N1 + I3 W2, NON-BM N3 NAIVE, NON-BM N1 + I3 NON-BM Total
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy; Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases All treatments
    Measure Participants 39 36 11 10 6 22 9 4 3 75 12 37 33 48 49 140
    STTU 1 - 1% Level PD-L1 Status: Met criteria
    40.0
    35.3
    85.7
    50.0
    50.0
    63.6
    40.0
    100.0
    100.0
    37.8
    50.0
    75.0
    72.2
    40.0
    65.4
    50.7
    STTU 1 - 5% Level PD-L1 Status: Met criteria
    40.0
    33.3
    80.0
    60.0
    100.0
    71.4
    50.0
    100.0
    100.0
    36.8
    66.7
    78.6
    75.0
    41.7
    72.2
    57.1
    STTU 1 - 10% Level PD-L1 Status: Met criteria
    42.9
    20.0
    100.0
    75.0
    100.0
    66.7
    100.0
    100.0
    100.0
    33.3
    100.0
    87.5
    83.3
    50.0
    81.8
    63.0
    13. Secondary Outcome
    Title Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as the Duration of Response (PD-L1 DOR)
    Description For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. Median duration of response (mDOR) was calculated for all response-evaluable participants with best overall response of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication.
    Time Frame 2 years from first dose of treatment; Assessed up to September 2017

    Outcome Measure Data

    Analysis Population Description
    All response-evaluable participants
    Arm/Group Title N3 60M NAIVE, W4 N3 60M PROG, W4 N1 60M + I3 90M, W2 N1 60M + I3 90M, W4 N1 60M + I3 90M, WU N1 30M + I3 30M NON-BM N3 30M NON-BM, W2 N1 30M + I3 30M BM, W2 N3 30M BM, W2 N3 60M, W4 N3 30M, W2 N1 + I3, W2 N1 + I3 W2, NON-BM N3 NAIVE, NON-BM N1 + I3 NON-BM Total
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy; Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases All treatments
    Measure Participants 39 36 11 10 6 22 9 4 3 75 12 37 33 48 49 140
    STTU 1 - 1% Level PD-L1 Status: Met criteria
    15.21
    NA
    NA
    NA
    NA
    26.25
    NA
    22.01
    NA
    15.57
    NA
    26.25
    NA
    15.21
    NA
    26.25
    STTU 1 - 5% Level PD-L1 Status: Met criteria
    13.36
    NA
    NA
    NA
    NA
    26.25
    NA
    22.01
    NA
    15.57
    NA
    26.25
    NA
    15.21
    NA
    26.25
    STTU 1 - 10% Level PD-L1 Status: Met criteria
    15.21
    15.57
    NA
    NA
    NA
    NA
    NA
    22.01
    NA
    15.21
    NA
    NA
    NA
    15.21
    NA
    NA
    14. Secondary Outcome
    Title Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Progression Free Survival (PD-L1 PFS)
    Description For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication.
    Time Frame 2 years from first dose of treatment; Assessed up to September 2017

    Outcome Measure Data

    Analysis Population Description
    All response-evaluable participants
    Arm/Group Title N3 60M NAIVE, W4 N3 60M PROG, W4 N1 60M + I3 90M, W2 N1 60M + I3 90M, W4 N1 60M + I3 90M, WU N1 30M + I3 30M NON-BM N3 30M NON-BM, W2 N1 30M + I3 30M BM, W2 N3 30M BM, W2 N3 60M, W4 N3 30M, W2 N1 + I3, W2 N1 + I3 W2, NON-BM N3 NAIVE, NON-BM N1 + I3 NON-BM Total
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy; Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases All treatments
    Measure Participants 39 36 11 10 6 22 9 4 3 75 12 37 33 48 49 140
    STTU 1 - 1% Level PD-L1 Status: Met criteria
    4.50
    9.66
    NA
    NA
    NA
    29.01
    8.77
    NA
    NA
    6.24
    8.77
    29.01
    29.01
    5.36
    29.01
    10.58
    STTU 1 - 5% Level PD-L1 Status: Met criteria
    6.28
    19.29
    NA
    NA
    NA
    29.01
    NA
    NA
    NA
    7.20
    NA
    29.01
    29.01
    6.28
    29.01
    17.05
    STTU 1 - 10% Level PD-L1 Status: Met criteria
    5.36
    19.29
    NA
    NA
    NA
    NA
    NA
    NA
    NA
    6.24
    NA
    NA
    NA
    11.20
    NA
    19.29
    15. Secondary Outcome
    Title Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Overall Survival Rate (PD-L1 OSR)
    Description For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive
    Time Frame 2 years from first dose of treatment; Assessed up to September 2017

    Outcome Measure Data

    Analysis Population Description
    Biomarker evaluable participants
    Arm/Group Title N3 60M NAIVE, W4 N3 60M PROG, W4 N1 60M + I3 90M, W2 N1 60M + I3 90M, W4 N1 60M + I3 90M, WU N1 30M + I3 30M NON-BM N3 30M NON-BM, W2 N1 30M + I3 30M BM, W2 N3 30M BM, W2 N3 60M, W4 N3 30M, W2 N1 + I3, W2 N1 + I3 W2, NON-BM N3 NAIVE, NON-BM N1 + I3 NON-BM Total
    Arm/Group Description Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy; Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; 30M = 30 minute infusion; W4 = Week 4 Biopsy; Treatment Group: N3 = Nivolumab 3mg/kg; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases All treatments
    Measure Participants 39 36 11 10 6 22 9 4 3 75 12 37 33 48 49 140
    STTU 1 - 1% Level; PD-L1 : Met criteria 3 months
    90.0
    219.5%
    100.0
    227.3%
    100.0
    909.1%
    83.3
    833%
    NA
    NaN
    100.0
    400%
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    94.6
    56.3%
    100.0
    NaN
    100.0
    NaN
    100.0
    NaN
    92.0
    NaN
    92.3
    NaN
    94.4
    NaN
    STTU 1 - 1% Level PD-L1 : Met criteria 6 months
    90.0
    219.5%
    94.1
    213.9%
    100.0
    909.1%
    83.3
    833%
    NA
    NaN
    100.0
    400%
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    91.9
    54.7%
    100.0
    NaN
    100.0
    NaN
    100.0
    NaN
    92.0
    NaN
    92.3
    NaN
    93.0
    NaN
    STTU 1 - 1% Level PD-L1: Met criteria 9 months
    80.0
    195.1%
    88.2
    200.5%
    100.0
    909.1%
    83.3
    833%
    NA
    NaN
    100.0
    400%
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    83.8
    49.9%
    100.0
    NaN
    100.0
    NaN
    100.0
    NaN
    84.0
    NaN
    92.3
    NaN
    88.7
    NaN
    STTU 1 - 1% Level PD-L1 : Met criteria 12 months
    75.0
    182.9%
    70.6
    160.5%
    100.0
    909.1%
    83.3
    833%
    NA
    NaN
    100.0
    400%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    73.0
    43.5%
    83.3
    NaN
    100.0
    NaN
    100.0
    NaN
    76.0
    NaN
    92.3
    NaN
    81.7
    NaN
    STTU 1 - 1% Level PD-L1: Met criteria 24 months
    55.0
    134.1%
    44.9
    102%
    100.0
    909.1%
    83.3
    833%
    NA
    NaN
    77.9
    311.6%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    50.5
    30.1%
    NA
    NaN
    82.2
    NaN
    87.7
    NaN
    52.0
    NaN
    84.0
    NaN
    60.8
    NaN
    STTU 5 - 5% Level PD-L1 : Met criteria 3 months
    80.0
    195.1%
    100.0
    227.3%
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    100.0
    400%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    89.5
    53.3%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    83.3
    NaN
    94.4
    NaN
    92.9
    NaN
    STTU 5 - 5% Level PD-L1: Met criteria 6 months
    80.0
    195.1%
    88.9
    202%
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    100.0
    400%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    84.2
    50.1%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    83.3
    NaN
    94.4
    NaN
    90.5
    NaN
    STTU 5 - 5% Level PD-L1 : Met criteria 9 months
    80.0
    195.1%
    88.9
    202%
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    100.0
    400%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    84.2
    50.1%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    83.3
    NaN
    94.4
    NaN
    90.5
    NaN
    STTU 5 - 5% Level PD-L1 : Met criteria 12 months
    70.0
    170.7%
    66.7
    151.6%
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    100.0
    400%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    68.4
    40.7%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    75
    NaN
    94.4
    NaN
    83.3
    NaN
    STTU 5 - 5% Level PD-L1 : Met criteria 24 months
    50.0
    122%
    NA
    NaN
    100.0
    909.1%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    45.6
    27.1%
    NA
    NaN
    76.0
    NaN
    81.5
    NaN
    50.0
    NaN
    82.5
    NaN
    60.7
    NaN
    STTU 10 - 10% Level PD-L1 : Met criteria 3 months
    71.4
    174.1%
    100.0
    227.3%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    83.3
    49.6%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    75.0
    NaN
    100.0
    NaN
    92.6
    NaN
    STTU 10 - 10% Level PD-L1 : Met criteria 6 months
    71.4
    174.1%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    75.0
    44.6%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    75.0
    NaN
    100.0
    NaN
    88.9
    NaN
    STTU 10 - 10% Level PD-L1: Met criteria 9 months
    71.4
    174.1%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    75.0
    44.6%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    75.0
    NaN
    100.0
    NaN
    88.9
    NaN
    STTU 10 - 10% Level PD-L1 : Met criteria 12 months
    71.4
    174.1%
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    58.3
    34.7%
    NA
    NaN
    100.0
    NaN
    100.0
    NaN
    75.0
    NaN
    100.0
    NaN
    81.5
    NaN
    STTU 10 - 10% Level PD-L1 : Met criteria 24 months
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    NA
    NaN
    75.0
    NaN
    83.3
    NaN
    NA
    NaN
    90.9
    NaN
    62.2
    NaN
    16. Secondary Outcome
    Title Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Overall Survival Rate (OSR)
    Description The proportion of subjects surviving to time t, where t is a specific length of time, eg, 12 months, which was determined by the available data for final analysis and was documented in the DPP. The proportion was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive
    Time Frame 2 years from first dose of treatment; Assessed up to September 2017

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group Title N3 60M Naive N3 60M PROG N1 60M + I3 90M N1 30M + I3 30M NON-BM N3 30M NON-BM N1 30M + I3 30M BM N3 30M BM N1 + I3 NON-BM N3 NAIVE All N3 N1 + I3 Total
    Arm/Group Description N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion;PROG = Anti-CTLA4 Progressed; N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive N3 = Nivolumab 3mg/kg All combination All treatments
    Measure Participants 41 44 27 25 11 10 10 52 62 106 62 168
    3 months
    92.7
    226.1%
    90.8
    206.4%
    85.2
    774.5%
    100.0
    1000%
    90.0
    1500%
    90.0
    360%
    80.0
    727.3%
    92.3
    923%
    90.2
    902%
    90.5
    53.9%
    91.9
    NaN
    91.0
    NaN
    6 months
    85.3
    208%
    78.9
    179.3%
    81.5
    740.9%
    100.0
    1000%
    90.0
    1500%
    90.0
    360%
    80.0
    727.3%
    90.4
    904%
    85.3
    853%
    82.6
    49.2%
    90.3
    NaN
    85.5
    NaN
    9 months
    75.0
    182.9%
    71.7
    163%
    81.5
    740.9%
    88.0
    880%
    90.0
    1500%
    90.0
    360%
    68.6
    623.6%
    84.6
    846%
    76.6
    766%
    74.6
    44.4%
    85.5
    NaN
    78.7
    NaN
    12 months
    72.4
    176.6%
    64.5
    146.6%
    77.6
    705.5%
    88.0
    880%
    80.0
    1333.3%
    90.0
    360%
    68.6
    623.6%
    82.6
    826%
    73.1
    731%
    69.5
    41.4%
    83.8
    NaN
    74.9
    NaN
    24 months
    51.0
    124.4%
    46.8
    106.4%
    69.6
    632.7%
    58.5
    585%
    58.3
    971.7%
    77.1
    308.4%
    NA
    NaN
    64.2
    642%
    53.1
    531%
    50.5
    30.1%
    66.5
    NaN
    56.6
    NaN

    Adverse Events

    Time Frame From First dose up to 100 days after last dose of study drug, assessed up to September 2017 (approximately 59 months)
    Adverse Event Reporting Description
    Arm/Group Title UNPLANNED NIV3-NAIVE NIV3-PROG NIV1+IPI3 P2 NIV1+IPI3 P3 NIV3-Q2W P3 IPI3-Q3W P3 NIV1+IPI3 P4 NIV3-Q2W P4
    Arm/Group Description Unplanned Treatment Group: NIV3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive Treatment Group: NIV3 = Nivolumab 3mg/kg; PROG = Anti-CTLA4 Progressed Treatment Group:NIV1 = Nivolumab 1mg/kg; IPI3 = Ipilimumab 3 mg/kg; P2 = Part 2 Treatment Group: NIV1 = Nivolumab 1mg/kg; IPI3 = Ipilimumab 3 mg/kg; P3 = Part 3 Treatment Group: NIV3 = Nivolumab 3mg/kg; Q2W = every 2 weeks; P3 = Part 3 Treatment Group: IPI3 = Ipilimumab 3 mg/kg; Q3W = Every 3 weeks; P3 = Part 3 Treatment Group: NIV1 = Nivolumab 1mg/kg; IPI3 = Ipilimumab 3 mg/kg; P4 = Part 4 Treatment Group: N3 = Nivolumab 3mg/kg; Q2W = Every 2 weeks; P4 = Part 4
    All Cause Mortality
    UNPLANNED NIV3-NAIVE NIV3-PROG NIV1+IPI3 P2 NIV1+IPI3 P3 NIV3-Q2W P3 IPI3-Q3W P3 NIV1+IPI3 P4 NIV3-Q2W P4
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/1 (100%) 26/41 (63.4%) 25/44 (56.8%) 10/27 (37%) 12/25 (48%) 4/11 (36.4%) 1/1 (100%) 2/10 (20%) 4/10 (40%)
    Serious Adverse Events
    UNPLANNED NIV3-NAIVE NIV3-PROG NIV1+IPI3 P2 NIV1+IPI3 P3 NIV3-Q2W P3 IPI3-Q3W P3 NIV1+IPI3 P4 NIV3-Q2W P4
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/1 (100%) 16/41 (39%) 16/44 (36.4%) 20/27 (74.1%) 13/25 (52%) 2/11 (18.2%) 1/1 (100%) 6/10 (60%) 4/10 (40%)
    Blood and lymphatic system disorders
    Anaemia 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Autoimmune haemolytic anaemia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Immune thrombocytopenic purpura 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Thrombocytopenia 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Cardiac disorders
    Cardiac failure congestive 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Myocardial infarction 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Endocrine disorders
    Adrenal insufficiency 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Hyperthyroidism 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Hypophysitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Autoimmune colitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Colitis 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 3/27 (11.1%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Constipation 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Diarrhoea 0/1 (0%) 0/41 (0%) 0/44 (0%) 4/27 (14.8%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Enterocolitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Gastrointestinal necrosis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Intra-abdominal fluid collection 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Nausea 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pancreatitis 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Small intestinal obstruction 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Vomiting 1/1 (100%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    General disorders
    Malaise 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Non-cardiac chest pain 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pain 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pyrexia 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 3/27 (11.1%) 4/25 (16%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hepatobiliary disorders
    Autoimmune hepatitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Bile duct obstruction 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hepatitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hepatotoxicity 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Immune system disorders
    Hypersensitivity 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Infections and infestations
    Clostridium difficile infection 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Liver abscess 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Meningitis 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pneumonia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Respiratory tract infection 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Sepsis 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Sinusitis 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Staphylococcal infection 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Urinary tract infection 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Injury, poisoning and procedural complications
    Fall 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Lower limb fracture 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Investigations
    Alanine aminotransferase increased 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Blood bilirubin increased 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Hepatic enzyme increased 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Lipase increased 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Metabolism and nutrition disorders
    Dehydration 1/1 (100%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Failure to thrive 1/1 (100%) 0/41 (0%) 0/44 (0%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hyperglycaemia 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hyperkalaemia 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hypokalaemia 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hyponatraemia 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Musculoskeletal and connective tissue disorders
    Arthritis 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Bone disorder 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Flank pain 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Musculoskeletal chest pain 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pain in extremity 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Malignant neoplasm progression 0/1 (0%) 3/41 (7.3%) 2/44 (4.5%) 4/27 (14.8%) 2/25 (8%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Metastases to central nervous system 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Metastatic neoplasm 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Squamous cell carcinoma 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Tumour pain 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 1/1 (100%) 0/10 (0%) 0/10 (0%)
    Nervous system disorders
    Aphasia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Dysaesthesia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Guillain-barre syndrome 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hemiparesis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Monoplegia 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Nystagmus 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Paraesthesia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Seizure 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Psychiatric disorders
    Confusional state 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Haematuria 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Renal failure 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Reproductive system and breast disorders
    Pelvic pain 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Dyspnoea 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hypoxia 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pneumonitis 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pneumothorax 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pulmonary embolism 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Respiratory failure 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    Rash 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Surgical and medical procedures
    Brain tumour operation 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Liver operation 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Vascular disorders
    Hypotension 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Other (Not Including Serious) Adverse Events
    UNPLANNED NIV3-NAIVE NIV3-PROG NIV1+IPI3 P2 NIV1+IPI3 P3 NIV3-Q2W P3 IPI3-Q3W P3 NIV1+IPI3 P4 NIV3-Q2W P4
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/1 (100%) 41/41 (100%) 44/44 (100%) 27/27 (100%) 25/25 (100%) 10/11 (90.9%) 1/1 (100%) 10/10 (100%) 9/10 (90%)
    Blood and lymphatic system disorders
    Anaemia 0/1 (0%) 9/41 (22%) 7/44 (15.9%) 4/27 (14.8%) 5/25 (20%) 0/11 (0%) 1/1 (100%) 1/10 (10%) 2/10 (20%)
    Haemolytic anaemia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Thrombocytopenia 0/1 (0%) 2/41 (4.9%) 1/44 (2.3%) 2/27 (7.4%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Cardiac disorders
    Acute coronary syndrome 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Angina pectoris 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Palpitations 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 2/27 (7.4%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Tachycardia 0/1 (0%) 0/41 (0%) 0/44 (0%) 4/27 (14.8%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Ear and labyrinth disorders
    Hypoacusis 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 0/10 (0%)
    Endocrine disorders
    Adrenal insufficiency 0/1 (0%) 0/41 (0%) 0/44 (0%) 2/27 (7.4%) 4/25 (16%) 0/11 (0%) 0/1 (0%) 3/10 (30%) 0/10 (0%)
    Endocrine disorder 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Hyperthyroidism 0/1 (0%) 1/41 (2.4%) 2/44 (4.5%) 6/27 (22.2%) 4/25 (16%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Hypophysitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hypothyroidism 1/1 (100%) 5/41 (12.2%) 5/44 (11.4%) 5/27 (18.5%) 4/25 (16%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 1/10 (10%)
    Eye disorders
    Conjunctival oedema 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Dry eye 0/1 (0%) 2/41 (4.9%) 1/44 (2.3%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 1/10 (10%)
    Eye disorder 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Eye pain 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 1/27 (3.7%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Uveitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Vision blurred 0/1 (0%) 2/41 (4.9%) 3/44 (6.8%) 0/27 (0%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 2/10 (20%)
    Visual impairment 0/1 (0%) 0/41 (0%) 2/44 (4.5%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Gastrointestinal disorders
    Abdominal discomfort 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Abdominal distension 0/1 (0%) 2/41 (4.9%) 3/44 (6.8%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Abdominal pain 0/1 (0%) 9/41 (22%) 4/44 (9.1%) 7/27 (25.9%) 4/25 (16%) 3/11 (27.3%) 1/1 (100%) 0/10 (0%) 1/10 (10%)
    Abdominal pain upper 0/1 (0%) 2/41 (4.9%) 2/44 (4.5%) 1/27 (3.7%) 3/25 (12%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 0/10 (0%)
    Anal pruritus 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Constipation 1/1 (100%) 11/41 (26.8%) 13/44 (29.5%) 7/27 (25.9%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 1/10 (10%) 2/10 (20%)
    Diarrhoea 0/1 (0%) 13/41 (31.7%) 14/44 (31.8%) 10/27 (37%) 9/25 (36%) 4/11 (36.4%) 0/1 (0%) 6/10 (60%) 1/10 (10%)
    Dry mouth 0/1 (0%) 2/41 (4.9%) 6/44 (13.6%) 1/27 (3.7%) 2/25 (8%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Dyspepsia 0/1 (0%) 2/41 (4.9%) 4/44 (9.1%) 1/27 (3.7%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Dysphagia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Flatulence 0/1 (0%) 0/41 (0%) 2/44 (4.5%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Gastritis 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Gastrointestinal haemorrhage 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Nausea 1/1 (100%) 9/41 (22%) 11/44 (25%) 8/27 (29.6%) 12/25 (48%) 4/11 (36.4%) 0/1 (0%) 7/10 (70%) 2/10 (20%)
    Stomatitis 0/1 (0%) 3/41 (7.3%) 2/44 (4.5%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Vomiting 1/1 (100%) 4/41 (9.8%) 4/44 (9.1%) 4/27 (14.8%) 9/25 (36%) 1/11 (9.1%) 0/1 (0%) 3/10 (30%) 1/10 (10%)
    General disorders
    Asthenia 0/1 (0%) 3/41 (7.3%) 1/44 (2.3%) 5/27 (18.5%) 3/25 (12%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Axillary pain 1/1 (100%) 1/41 (2.4%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Chest pain 1/1 (100%) 1/41 (2.4%) 1/44 (2.3%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 2/10 (20%)
    Chills 0/1 (0%) 2/41 (4.9%) 4/44 (9.1%) 7/27 (25.9%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 2/10 (20%)
    Fatigue 1/1 (100%) 21/41 (51.2%) 29/44 (65.9%) 14/27 (51.9%) 13/25 (52%) 5/11 (45.5%) 1/1 (100%) 6/10 (60%) 6/10 (60%)
    Hernia pain 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Influenza like illness 0/1 (0%) 4/41 (9.8%) 3/44 (6.8%) 4/27 (14.8%) 3/25 (12%) 1/11 (9.1%) 0/1 (0%) 3/10 (30%) 3/10 (30%)
    Localised oedema 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Malaise 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 2/27 (7.4%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Mucosal inflammation 0/1 (0%) 3/41 (7.3%) 0/44 (0%) 0/27 (0%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Non-cardiac chest pain 0/1 (0%) 2/41 (4.9%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Oedema peripheral 0/1 (0%) 8/41 (19.5%) 4/44 (9.1%) 4/27 (14.8%) 4/25 (16%) 0/11 (0%) 0/1 (0%) 3/10 (30%) 1/10 (10%)
    Pain 0/1 (0%) 3/41 (7.3%) 11/44 (25%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Peripheral swelling 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Pyrexia 0/1 (0%) 10/41 (24.4%) 9/44 (20.5%) 15/27 (55.6%) 8/25 (32%) 3/11 (27.3%) 0/1 (0%) 5/10 (50%) 3/10 (30%)
    Temperature intolerance 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Hepatobiliary disorders
    Hepatic pain 0/1 (0%) 0/41 (0%) 3/44 (6.8%) 1/27 (3.7%) 0/25 (0%) 2/11 (18.2%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hypertransaminasaemia 0/1 (0%) 0/41 (0%) 0/44 (0%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Immune system disorders
    Drug hypersensitivity 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Hypersensitivity 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 2/27 (7.4%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Infections and infestations
    Cellulitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Conjunctivitis 0/1 (0%) 0/41 (0%) 0/44 (0%) 2/27 (7.4%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 0/10 (0%)
    Influenza 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Nasopharyngitis 1/1 (100%) 3/41 (7.3%) 0/44 (0%) 3/27 (11.1%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Pneumonia 0/1 (0%) 2/41 (4.9%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Rash pustular 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Respiratory tract infection 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Rhinitis 0/1 (0%) 1/41 (2.4%) 2/44 (4.5%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Sepsis 0/1 (0%) 0/41 (0%) 0/44 (0%) 4/27 (14.8%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Sinusitis 0/1 (0%) 2/41 (4.9%) 2/44 (4.5%) 2/27 (7.4%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Skin infection 0/1 (0%) 3/41 (7.3%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Upper respiratory tract infection 0/1 (0%) 4/41 (9.8%) 4/44 (9.1%) 2/27 (7.4%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Urinary tract infection 0/1 (0%) 2/41 (4.9%) 2/44 (4.5%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Injury, poisoning and procedural complications
    Contusion 0/1 (0%) 5/41 (12.2%) 2/44 (4.5%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Fall 1/1 (100%) 2/41 (4.9%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Infusion related reaction 0/1 (0%) 1/41 (2.4%) 2/44 (4.5%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Procedural pain 0/1 (0%) 0/41 (0%) 2/44 (4.5%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Investigations
    Activated partial thromboplastin time prolonged 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Alanine aminotransferase increased 0/1 (0%) 3/41 (7.3%) 2/44 (4.5%) 10/27 (37%) 4/25 (16%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 0/10 (0%)
    Amylase increased 0/1 (0%) 2/41 (4.9%) 0/44 (0%) 1/27 (3.7%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 1/10 (10%)
    Aspartate aminotransferase increased 0/1 (0%) 5/41 (12.2%) 2/44 (4.5%) 11/27 (40.7%) 5/25 (20%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Blood alkaline phosphatase increased 0/1 (0%) 5/41 (12.2%) 4/44 (9.1%) 3/27 (11.1%) 3/25 (12%) 0/11 (0%) 1/1 (100%) 0/10 (0%) 0/10 (0%)
    Blood bilirubin increased 0/1 (0%) 2/41 (4.9%) 0/44 (0%) 3/27 (11.1%) 1/25 (4%) 1/11 (9.1%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Blood creatinine increased 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 3/27 (11.1%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Blood thyroid stimulating hormone decreased 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 2/10 (20%)
    Blood thyroid stimulating hormone increased 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 2/10 (20%)
    Cortisol increased 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Hepatic enzyme increased 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    International normalised ratio increased 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Lipase increased 0/1 (0%) 7/41 (17.1%) 7/44 (15.9%) 5/27 (18.5%) 3/25 (12%) 0/11 (0%) 0/1 (0%) 3/10 (30%) 1/10 (10%)
    Lymphocyte count decreased 0/1 (0%) 4/41 (9.8%) 1/44 (2.3%) 2/27 (7.4%) 0/25 (0%) 1/11 (9.1%) 1/1 (100%) 0/10 (0%) 0/10 (0%)
    Norovirus test positive 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Platelet count decreased 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Transaminases increased 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Weight decreased 1/1 (100%) 8/41 (19.5%) 4/44 (9.1%) 5/27 (18.5%) 3/25 (12%) 0/11 (0%) 1/1 (100%) 0/10 (0%) 1/10 (10%)
    Weight increased 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 0/10 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 1/1 (100%) 10/41 (24.4%) 15/44 (34.1%) 9/27 (33.3%) 4/25 (16%) 1/11 (9.1%) 1/1 (100%) 4/10 (40%) 1/10 (10%)
    Dehydration 1/1 (100%) 1/41 (2.4%) 0/44 (0%) 6/27 (22.2%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Hypercalcaemia 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Hyperglycaemia 0/1 (0%) 4/41 (9.8%) 4/44 (9.1%) 2/27 (7.4%) 2/25 (8%) 1/11 (9.1%) 0/1 (0%) 1/10 (10%) 2/10 (20%)
    Hyperuricaemia 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Hypoalbuminaemia 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Hypoglycaemia 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 2/10 (20%)
    Hypokalaemia 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 7/27 (25.9%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hypomagnesaemia 0/1 (0%) 2/41 (4.9%) 1/44 (2.3%) 2/27 (7.4%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Hyponatraemia 0/1 (0%) 1/41 (2.4%) 3/44 (6.8%) 6/27 (22.2%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Hypophosphataemia 0/1 (0%) 2/41 (4.9%) 2/44 (4.5%) 4/27 (14.8%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Lactic acidosis 0/1 (0%) 0/41 (0%) 0/44 (0%) 3/27 (11.1%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Malnutrition 0/1 (0%) 0/41 (0%) 0/44 (0%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/1 (0%) 7/41 (17.1%) 13/44 (29.5%) 7/27 (25.9%) 5/25 (20%) 1/11 (9.1%) 0/1 (0%) 3/10 (30%) 2/10 (20%)
    Arthritis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Back pain 0/1 (0%) 10/41 (24.4%) 8/44 (18.2%) 3/27 (11.1%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 2/10 (20%)
    Bone pain 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Flank pain 1/1 (100%) 2/41 (4.9%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Joint range of motion decreased 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Muscle spasms 0/1 (0%) 0/41 (0%) 3/44 (6.8%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Musculoskeletal pain 0/1 (0%) 4/41 (9.8%) 5/44 (11.4%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 1/10 (10%)
    Myalgia 0/1 (0%) 2/41 (4.9%) 7/44 (15.9%) 4/27 (14.8%) 3/25 (12%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Neck pain 0/1 (0%) 1/41 (2.4%) 5/44 (11.4%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Pain in extremity 0/1 (0%) 7/41 (17.1%) 5/44 (11.4%) 1/27 (3.7%) 1/25 (4%) 2/11 (18.2%) 0/1 (0%) 2/10 (20%) 1/10 (10%)
    Pain in jaw 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Oncologic complication 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Tumour pain 0/1 (0%) 3/41 (7.3%) 2/44 (4.5%) 3/27 (11.1%) 2/25 (8%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Nervous system disorders
    Autonomic nervous system imbalance 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Balance disorder 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Cerebrovascular accident 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Disturbance in attention 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Dizziness 0/1 (0%) 5/41 (12.2%) 8/44 (18.2%) 4/27 (14.8%) 1/25 (4%) 3/11 (27.3%) 0/1 (0%) 2/10 (20%) 2/10 (20%)
    Dysaesthesia 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 4/10 (40%)
    Dysarthria 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Dysgeusia 0/1 (0%) 0/41 (0%) 0/44 (0%) 4/27 (14.8%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Headache 0/1 (0%) 9/41 (22%) 8/44 (18.2%) 6/27 (22.2%) 8/25 (32%) 0/11 (0%) 0/1 (0%) 5/10 (50%) 2/10 (20%)
    Hemiparesis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Neuropathy peripheral 0/1 (0%) 0/41 (0%) 3/44 (6.8%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Paraesthesia 0/1 (0%) 2/41 (4.9%) 1/44 (2.3%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Presyncope 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Restless legs syndrome 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Seizure 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Psychiatric disorders
    Anxiety 1/1 (100%) 1/41 (2.4%) 4/44 (9.1%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 1/1 (100%) 0/10 (0%) 1/10 (10%)
    Confusional state 0/1 (0%) 0/41 (0%) 0/44 (0%) 2/27 (7.4%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Depression 1/1 (100%) 2/41 (4.9%) 1/44 (2.3%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Insomnia 1/1 (100%) 4/41 (9.8%) 5/44 (11.4%) 4/27 (14.8%) 2/25 (8%) 1/11 (9.1%) 0/1 (0%) 2/10 (20%) 1/10 (10%)
    Mental status changes 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Sleep disorder 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/1 (0%) 0/41 (0%) 0/44 (0%) 2/27 (7.4%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Chromaturia 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Dysuria 0/1 (0%) 3/41 (7.3%) 2/44 (4.5%) 3/27 (11.1%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pollakiuria 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Reproductive system and breast disorders
    Nipple pain 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Spermatic cord haemorrhage 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Cough 1/1 (100%) 10/41 (24.4%) 13/44 (29.5%) 8/27 (29.6%) 4/25 (16%) 1/11 (9.1%) 0/1 (0%) 2/10 (20%) 3/10 (30%)
    Dyspnoea 1/1 (100%) 3/41 (7.3%) 7/44 (15.9%) 7/27 (25.9%) 5/25 (20%) 1/11 (9.1%) 0/1 (0%) 2/10 (20%) 2/10 (20%)
    Nasal congestion 0/1 (0%) 6/41 (14.6%) 1/44 (2.3%) 2/27 (7.4%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Oropharyngeal pain 0/1 (0%) 3/41 (7.3%) 2/44 (4.5%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Pleural effusion 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 3/27 (11.1%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Pneumonitis 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 2/27 (7.4%) 2/25 (8%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Productive cough 0/1 (0%) 2/41 (4.9%) 0/44 (0%) 0/27 (0%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Rhinitis allergic 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 0/27 (0%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Rhinorrhoea 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 2/27 (7.4%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Upper-airway cough syndrome 0/1 (0%) 0/41 (0%) 4/44 (9.1%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Alopecia 0/1 (0%) 0/41 (0%) 0/44 (0%) 3/27 (11.1%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Dermatitis acneiform 0/1 (0%) 0/41 (0%) 0/44 (0%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Dermatitis exfoliative 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Dry skin 0/1 (0%) 6/41 (14.6%) 4/44 (9.1%) 1/27 (3.7%) 0/25 (0%) 2/11 (18.2%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Eczema nummular 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Facial wasting 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Hyperhidrosis 1/1 (100%) 2/41 (4.9%) 1/44 (2.3%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Lichenoid keratosis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Livedo reticularis 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Pruritus 1/1 (100%) 10/41 (24.4%) 12/44 (27.3%) 13/27 (48.1%) 8/25 (32%) 1/11 (9.1%) 0/1 (0%) 3/10 (30%) 4/10 (40%)
    Rash 0/1 (0%) 11/41 (26.8%) 11/44 (25%) 9/27 (33.3%) 6/25 (24%) 1/11 (9.1%) 0/1 (0%) 1/10 (10%) 3/10 (30%)
    Rash erythematous 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Rash maculo-papular 0/1 (0%) 4/41 (9.8%) 4/44 (9.1%) 5/27 (18.5%) 4/25 (16%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 1/10 (10%)
    Rash papular 0/1 (0%) 1/41 (2.4%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Rash pruritic 0/1 (0%) 0/41 (0%) 1/44 (2.3%) 2/27 (7.4%) 3/25 (12%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Scab 0/1 (0%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Skin hypopigmentation 0/1 (0%) 1/41 (2.4%) 1/44 (2.3%) 2/27 (7.4%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 2/10 (20%) 2/10 (20%)
    Vitiligo 0/1 (0%) 4/41 (9.8%) 6/44 (13.6%) 3/27 (11.1%) 0/25 (0%) 1/11 (9.1%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Vascular disorders
    Embolism 0/1 (0%) 2/41 (4.9%) 0/44 (0%) 1/27 (3.7%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Flushing 0/1 (0%) 1/41 (2.4%) 2/44 (4.5%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 1/10 (10%)
    Hypertension 1/1 (100%) 6/41 (14.6%) 1/44 (2.3%) 1/27 (3.7%) 1/25 (4%) 0/11 (0%) 0/1 (0%) 1/10 (10%) 0/10 (0%)
    Hypotension 0/1 (0%) 0/41 (0%) 0/44 (0%) 3/27 (11.1%) 2/25 (8%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Lymphoedema 0/1 (0%) 2/41 (4.9%) 0/44 (0%) 2/27 (7.4%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)
    Orthostatic hypotension 1/1 (100%) 0/41 (0%) 0/44 (0%) 0/27 (0%) 0/25 (0%) 0/11 (0%) 0/1 (0%) 0/10 (0%) 0/10 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

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

    Results Point of Contact

    Name/Title Bristol-Myers Squibb Study Director
    Organization Bristol-Myers Squibb
    Phone Please email
    Email Clinical.Trials@bms.com
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01621490
    Other Study ID Numbers:
    • CA209-038
    • 2012-001840-23
    First Posted:
    Jun 18, 2012
    Last Update Posted:
    Dec 3, 2019
    Last Verified:
    Nov 1, 2019