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Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT01024231
Collaborator
Medarex (Industry), Ono Pharma USA Inc (Industry)
127
Enrollment
4
Locations
8
Arms
111.5
Actual Duration (Months)
31.8
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and tolerability of treatment with BMS-936558 (MDX-1106) in combination with Ipilimumab (BMS-734016) when given at the same time or as a sequenced regimen in subjects with unresectable Stage III or Stage IV malignant melanoma (MEL)

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
127 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1b, Open-label, Multicenter, Multidose, Dose-escalation Study of BMS-936558 (MDX-1106) in Combination With Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma
Actual Study Start Date :
Dec 14, 2009
Actual Primary Completion Date :
Feb 4, 2014
Actual Study Completion Date :
Apr 1, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1: BMS-936558 (0.3 mg/kg)+Ipilimumab (3 mg/kg)

BMS-936558 (MDX1106-04) 0.3 mg/kg solution, 60 minutes intravenous infusion every 3 (q3) weeks for 21 weeks in induction and every 12 (q12) weeks for 84 weeks in maintenance Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

Drug: BMS-936558 (MDX1106-04)
Other Names:
  • Nivolumab

    • Drug: Ipilimumab
    Other Names:
  • BMS-734016

    		•
    Experimental: Cohort 2: BMS-936558 (1 mg/kg)+Ipilimumab (3 mg/kg)

    Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance

    Drug: BMS-936558 (MDX1106-04)
    Other Names:
  • Nivolumab

    • Drug: Ipilimumab
    Other Names:
  • BMS-734016

    		•
    Experimental: Cohort 3: BMS-936558 (3 mg/kg)+Ipilimumab (3 mg/kg)

    Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance

    Drug: BMS-936558 (MDX1106-04)
    Other Names:
  • Nivolumab

    • Drug: Ipilimumab
    Other Names:
  • BMS-734016

    		•
    Experimental: Cohort 4: BMS-936558 (10 mg/kg)+Ipilimumab (3 mg/kg)

    BMS-936558 (MDX1106-04) 10 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

    Drug: BMS-936558 (MDX1106-04)
    Other Names:
  • Nivolumab

    • Drug: Ipilimumab
    Other Names:
  • BMS-734016

    		•
    Experimental: Cohort 5: BMS-936558 (10 mg/kg)+Ipilimumab (10 mg/kg)

    BMS-936558 (MDX1106-04) 10 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance Ipilimumab (BMS-734016) 10 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance

    Drug: BMS-936558 (MDX1106-04)
    Other Names:
  • Nivolumab

    • Drug: Ipilimumab
    Other Names:
  • BMS-734016

    		•
    Experimental: Cohort 6: BMS-936558 (1 mg/kg)

    BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks

    Drug: BMS-936558 (MDX1106-04)
    Other Names:
  • Nivolumab

    		•
    Experimental: Cohort 7: BMS-936558 (3 mg/kg)

    BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks

    Drug: BMS-936558 (MDX1106-04)
    Other Names:
  • Nivolumab

    		•
    Experimental: Cohort 8: Nivolumab+Ipilimumab

    Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg solution intravenously q3 weeks, 4 doses for 12 weeks Followed by Nivolumab 3 mg/kg solution alone intravenously q2 weeks, 48 doses for a maximum of 96 weeks

    Drug: BMS-936558 (MDX1106-04)
    Other Names:
  • Nivolumab

    • Drug: Ipilimumab
    Other Names:
  • BMS-734016

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With an Adverse Event (AE) [Up to 3 years]

      incidence of all cause and treatment related adverse events

    2. Number of Participants With a Serious Adverse Event (AE) [Up to 3 years]

      incidence of all cause and treatment related serious adverse events

    3. Number of Participants With an Adverse Event (AE) Which Lead to Discontinuation [Up to 3 years]

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

    4. Number of Deaths [Up to 3 years]

      incidence of all cause and treatment related deaths

    5. Number of Participants With Select AEs [Up to 3 years]

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

    6. Laboratory Abnormalities: Specific Liver Tests [Up to 3 years]

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

    7. Laboratory Abnormalities: Specific Thyroid Tests [Up to 3 years]

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

    Secondary Outcome Measures

    1. Objective Response Rate [Up to 3 years]

      the total number of participants whose best overall response (BOR) is either irCR or irPR divided by the total number of response-evaluable participants.

    2. Time to Response [Up to 3 Years]

      the time from the first dose of study drug until the first documentation of irCR or irPR, as related to current database lock date or most current tumor measurement

    3. Duration of Response [from the first documented response (irCR or irPR) until progression or death]

      the time from the first documented response (irCR or irPR) until progression or death, whichever occurs first. For participants who did not progress or die, duration of response will be censored on the date of the last tumor assessment.

    4. Progression Free Survival [156 weeks]

      the time from the first dose to the first observation of disease progression or death due to any cause. If a participant has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. Participants who did not have any on-study tumor assessments and did not die will be censored on the date of the first dose of study medication.

    5. Number of Participants With an Anti-Drug Antibody (ADA) Response for Nivolumab (Nivo) and Ipilimumab (Ipi) [Up to 3 years]

      Serum samples will be collected to evaluate the development of antibodies to BMS-936558 and to ipilimumab.

    6. Peak and Trough Concentrations [Up to 64 Weeks]

      The peak and trough concentrations of BMS-936558 (MDX-1106) and ipilimumab in participants with quantifiable data

    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

    Inclusion Criteria:

    • Histologic diagnosis of malignant melanoma (MEL)

    • Measurable unresectable Stage III or IV MEL

    • ECOG performance status score of 0 or 1

    • Life expectancy ≥4 months

    • For those enrolled in amendment 5 and later, tumor tissue (archival or recent acquisition) must be available

    • For Cohorts 1-5, subjects may have been treated with up to 3 prior systemic standard treatments for metastatic melanoma not including any post-incisional adjuvant therapy. Subjects may be treatment naïve. All metastatic melanoma regardless of primary site of disease will be allowed

    • For Cohorts 6-7, subjects may have been treated with up to 3 prior systemic standard treatments for metastatic melanoma; this does not include any post-incisional adjuvant therapy. Specifically, subjects must have received ≥3 doses of Ipilimumab therapy and the last dose having been administered within 4-12 weeks of initiation of study treatment

    Exclusion Criteria:

    • History of severe hypersensitivity reactions to other mAbs

    • Prior malignancy active within the previous 2 years except for localized cancers that are considered to have been cured and in the opinion of the investigator present a low risk for recurrence

    • Active autoimmune disease or a history of known or suspected autoimmune disease

    • History of recently active diverticulitis or symptomatic peptic ulcer disease and history of adrenal insufficiency

    • Regular narcotic analgesia

    • Active, untreated central nervous system metastasis

    • For subjects enrolled in Cohorts 1-5, prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibody

    • For subjects enrolled in Cohorts 6-7, prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CD137 antibodies

    • Any non-oncology vaccine therapy used for prevention of infectious disease

    • Concomitant therapy with any other anti-cancer therapy, concurrent medical conditions requiring use of immunosuppressive medications or use of other investigational drugs

    • Positive tests for human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), hepatitis B, hepatitis C

    • Subjects weighing ≥125 kg are excluded from Cohort 5

    • Subjects in Cohorts 6 and 7 must have received Ipilimumab monotherapy immediately prior to study entry, but must not have received that Ipilimumab as part of a clinical trial

    • Subjects with ocular melanoma are excluded from Cohort 8

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Yale University School Of Medicine New Haven Connecticut United States 06520
    2 Medstar Georgetown-Lombardi Comprehensive Cancer Center Washington District of Columbia United States 20007
    3 Memorial Sloan Kettering Nassau New York New York United States 11065
    4 Hillman Cancer Research Pavilion Pittsburgh Pennsylvania United States 15232

    Sponsors and Collaborators

    • Bristol-Myers Squibb
    • Medarex
    • Ono Pharma USA Inc

    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:
    NCT01024231
    Other Study ID Numbers:
    • CA209-004
    • (MDX1106-04)
    First Posted:
    Dec 2, 2009
    Last Update Posted:
    Mar 22, 2021
    Last Verified:
    Mar 1, 2021
    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 127 Randomized and Treated
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Cohort 6 Cohorot 7 Cohort 8
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses
    Period Title: Overall Study
    STARTED 14 17 16 6 17 16 41
    COMPLETED 2 2 6 1 0 0 20
    NOT COMPLETED 12 15 10 5 17 16 21

    Baseline Characteristics

    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Cohort 6 Cohorot 7 Cohort 8 Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses Total of all reporting groups
    Overall Participants 14 17 16 6 17 16 41 127
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    57.9
    (9.58)
    53.5
    (14.14)
    59.1
    (14.65)
    56.2
    (11.99)
    63.9
    (14.37)
    60.6
    (17.56)
    55.2
    (15.83)
    57.6
    (13.78)
    Age, Customized (Count of Participants)
    <65 Years
    11
    78.6%
    14
    82.4%
    10
    62.5%
    5
    83.3%
    7
    41.2%
    11
    68.8%
    32
    78%
    90
    70.9%
    ≥ 65 Years
    3
    21.4%
    3
    17.6%
    6
    37.5%
    1
    16.7%
    10
    58.8%
    5
    31.3%
    9
    22%
    37
    29.1%
    Sex: Female, Male (Count of Participants)
    Female
    5
    35.7%
    7
    41.2%
    4
    25%
    5
    83.3%
    8
    47.1%
    7
    43.8%
    23
    56.1%
    59
    46.5%
    Male
    9
    64.3%
    10
    58.8%
    12
    75%
    1
    16.7%
    9
    52.9%
    9
    56.3%
    18
    43.9%
    68
    53.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    5.9%
    0
    0%
    2
    4.9%
    3
    2.4%
    Not Hispanic or Latino
    14
    100%
    17
    100%
    16
    100%
    6
    100%
    15
    88.2%
    16
    100%
    39
    95.1%
    123
    96.9%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    5.9%
    0
    0%
    0
    0%
    1
    0.8%
    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%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.4%
    1
    0.8%
    Native Hawaiian or Other Pacific Islander
    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%
    1
    5.9%
    0
    0%
    0
    0%
    1
    0.8%
    White
    14
    100%
    17
    100%
    16
    100%
    6
    100%
    16
    94.1%
    16
    100%
    37
    90.2%
    122
    96.1%
    More than one race
    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%
    3
    7.3%
    3
    2.4%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With an Adverse Event (AE)
    Description incidence of all cause and treatment related adverse events
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    All Cause
    14
    100%
    17
    100%
    16
    100%
    6
    100%
    53
    311.8%
    17
    106.3%
    16
    39%
    33
    26%
    41
    NaN
    94
    NaN
    127
    NaN
    Treatment Related
    13
    92.9%
    17
    100%
    15
    93.8%
    6
    100%
    51
    300%
    15
    93.8%
    13
    31.7%
    28
    22%
    40
    NaN
    91
    NaN
    119
    NaN
    2. Primary Outcome
    Title Number of Participants With a Serious Adverse Event (AE)
    Description incidence of all cause and treatment related serious adverse events
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    All Cause
    10
    71.4%
    15
    88.2%
    10
    62.5%
    5
    83.3%
    40
    235.3%
    9
    56.3%
    10
    24.4%
    19
    15%
    26
    NaN
    66
    NaN
    85
    NaN
    Treatment Related
    5
    35.7%
    13
    76.5%
    9
    56.3%
    4
    66.7%
    31
    182.4%
    4
    25%
    4
    9.8%
    8
    6.3%
    18
    NaN
    49
    NaN
    57
    NaN
    3. Primary Outcome
    Title Number of Participants With an Adverse Event (AE) Which Lead to Discontinuation
    Description incidence of all cause and treatment related adverse events which lead to discontinuation
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    All Cause
    2
    14.3%
    8
    47.1%
    5
    31.3%
    1
    16.7%
    16
    94.1%
    5
    31.3%
    1
    2.4%
    6
    4.7%
    13
    NaN
    29
    NaN
    35
    NaN
    Treatment Related
    2
    14.3%
    6
    35.3%
    5
    31.3%
    1
    16.7%
    14
    82.4%
    2
    12.5%
    0
    0%
    2
    1.6%
    11
    NaN
    25
    NaN
    27
    NaN
    4. Primary Outcome
    Title Number of Deaths
    Description incidence of all cause and treatment related deaths
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    All Cause
    8
    57.1%
    4
    23.5%
    2
    12.5%
    0
    0%
    14
    82.4%
    7
    43.8%
    8
    19.5%
    15
    11.8%
    8
    NaN
    22
    NaN
    37
    NaN
    Treatment Related
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    NaN
    1
    NaN
    1
    NaN
    5. Primary Outcome
    Title Number of Participants With Select AEs
    Description incidence of all cause and treatment related Adverse events in certain organ systems
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    Endrocrine
    2
    14.3%
    5
    29.4%
    3
    18.8%
    3
    50%
    13
    76.5%
    4
    25%
    1
    2.4%
    5
    3.9%
    12
    NaN
    25
    NaN
    30
    NaN
    Gastrointestinal
    5
    35.7%
    7
    41.2%
    10
    62.5%
    4
    66.7%
    26
    152.9%
    3
    18.8%
    4
    9.8%
    7
    5.5%
    20
    NaN
    46
    NaN
    53
    NaN
    Hepatic
    5
    35.7%
    6
    35.3%
    4
    25%
    3
    50%
    18
    105.9%
    1
    6.3%
    1
    2.4%
    2
    1.6%
    8
    NaN
    26
    NaN
    28
    NaN
    Pulmonary
    1
    7.1%
    2
    11.8%
    1
    6.3%
    0
    0%
    4
    23.5%
    0
    0%
    1
    2.4%
    1
    0.8%
    2
    NaN
    6
    NaN
    7
    NaN
    Renal
    2
    14.3%
    1
    5.9%
    1
    6.3%
    1
    16.7%
    5
    29.4%
    0
    0%
    1
    2.4%
    1
    0.8%
    1
    NaN
    6
    NaN
    7
    NaN
    Skin
    12
    85.7%
    15
    88.2%
    15
    93.8%
    4
    66.7%
    46
    270.6%
    8
    50%
    10
    24.4%
    18
    14.2%
    34
    NaN
    80
    NaN
    98
    NaN
    Hypersensitivity/Infusion Reaction
    0
    0%
    1
    5.9%
    1
    6.3%
    0
    0%
    2
    11.8%
    1
    6.3%
    1
    2.4%
    2
    1.6%
    1
    NaN
    3
    NaN
    5
    NaN
    6. Primary Outcome
    Title Laboratory Abnormalities: Specific Liver Tests
    Description Number of Participants with On-Treatment Laboratory Abnormalities in Specific Liver Tests Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN)
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    ALT or AST > 3xULN
    1
    7.1%
    0
    0%
    2
    12.5%
    3
    50%
    6
    35.3%
    0
    0%
    1
    2.4%
    1
    0.8%
    6
    NaN
    12
    NaN
    13
    NaN
    ALT or AST > 5xULN
    3
    21.4%
    1
    5.9%
    1
    6.3%
    1
    16.7%
    6
    35.3%
    0
    0%
    0
    0%
    0
    0%
    5
    NaN
    11
    NaN
    11
    NaN
    ALT or AST > 10xULN
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    1
    5.9%
    0
    0%
    0
    0%
    0
    0%
    4
    NaN
    5
    NaN
    5
    NaN
    ALT or AST > 20xULN
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    1
    5.9%
    0
    0%
    0
    0%
    0
    0%
    3
    NaN
    4
    NaN
    4
    NaN
    Total Bilirubin (Tbili) > 2xULN
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    1
    5.9%
    0
    0%
    0
    0%
    0
    0%
    2
    NaN
    3
    NaN
    3
    NaN
    ALT or AST > 3xULN w/ Tbili > 2xULN within 1 day
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    NaN
    1
    NaN
    1
    NaN
    7. Primary Outcome
    Title Laboratory Abnormalities: Specific Thyroid Tests
    Description Number of Participants with On-Treatment Laboratory Abnormalities in Specific Thyroid Tests Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    TSH > ULN
    7
    50%
    9
    52.9%
    7
    43.8%
    3
    50%
    26
    152.9%
    4
    25%
    3
    7.3%
    7
    5.5%
    8
    NaN
    34
    NaN
    41
    NaN
    TSH > ULN with TSH≤ ULN @ Baseline
    3
    21.4%
    6
    35.3%
    7
    43.8%
    1
    16.7%
    17
    100%
    3
    18.8%
    1
    2.4%
    4
    3.1%
    6
    NaN
    23
    NaN
    27
    NaN
    TSH > ULN: WITH ALL OTHER T3/T4 TEST ≥ LLN
    7
    50%
    9
    52.9%
    7
    43.8%
    2
    33.3%
    25
    147.1%
    4
    25%
    3
    7.3%
    7
    5.5%
    8
    NaN
    33
    NaN
    40
    NaN
    TSH > ULN: WITH AT LEAST ONE T3/T4 TEST < LLN
    5
    35.7%
    6
    35.3%
    5
    31.3%
    2
    33.3%
    18
    105.9%
    2
    12.5%
    1
    2.4%
    3
    2.4%
    5
    NaN
    23
    NaN
    26
    NaN
    TSH > ULN: WITH FT3/FT4 TEST MISSING
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    TSH < LLN
    3
    21.4%
    7
    41.2%
    7
    43.8%
    3
    50%
    20
    117.6%
    4
    25%
    1
    2.4%
    5
    3.9%
    14
    NaN
    34
    NaN
    39
    NaN
    TSH < LLN: WITH TSH >= LLN AT BASELINE
    3
    21.4%
    7
    41.2%
    7
    43.8%
    3
    50%
    20
    117.6%
    3
    18.8%
    0
    0%
    3
    2.4%
    14
    NaN
    34
    NaN
    37
    NaN
    TSH < LLN: WITH ALL OTHER FT3/FT4 TEST ≤ ULN
    2
    14.3%
    6
    35.3%
    6
    37.5%
    3
    50%
    17
    100%
    4
    25%
    1
    2.4%
    5
    3.9%
    11
    NaN
    28
    NaN
    33
    NaN
    TSH < LLN: WITH AT LEAST ONE T3/T4 TEST > ULN
    3
    21.4%
    3
    17.6%
    3
    18.8%
    2
    33.3%
    11
    64.7%
    2
    12.5%
    0
    0%
    2
    1.6%
    8
    NaN
    19
    NaN
    21
    NaN
    TSH < LLN: WITH FT3/FT4 TEST MISSING
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    8. Secondary Outcome
    Title Objective Response Rate
    Description the total number of participants whose best overall response (BOR) is either irCR or irPR divided by the total number of response-evaluable participants.
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    Number (95% Confidence Interval) [Percentage of Participants]
    21
    150%
    47
    276.5%
    50
    312.5%
    50
    833.3%
    42
    247.1%
    53
    331.3%
    19
    46.3%
    36
    28.3%
    44
    NaN
    43
    NaN
    41
    NaN
    9. Secondary Outcome
    Title Time to Response
    Description the time from the first dose of study drug until the first documentation of irCR or irPR, as related to current database lock date or most current tumor measurement
    Time Frame Up to 3 Years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 16 33 41 94 127
    Median (Full Range) [Weeks]
    11.9
    11.9
    11.9
    12.3
    11.9
    8
    15.7
    9.6
    12.1
    12
    12
    10. Secondary Outcome
    Title Duration of Response
    Description the time from the first documented response (irCR or irPR) until progression or death, whichever occurs first. For participants who did not progress or die, duration of response will be censored on the date of the last tumor assessment.
    Time Frame from the first documented response (irCR or irPR) until progression or death

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants with a response
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 53 17 3 33 41 94 127
    Median (95% Confidence Interval) [Weeks]
    NA
    105
    66.3
    59.1
    105
    73.1
    64.3
    73.1
    NA
    105
    105
    11. Secondary Outcome
    Title Progression Free Survival
    Description the time from the first dose to the first observation of disease progression or death due to any cause. If a participant has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. Participants who did not have any on-study tumor assessments and did not die will be censored on the date of the first dose of study medication.
    Time Frame 156 weeks

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) Combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi
    Measure Participants 14 17 16 6 0 17 16 0 41 0
    Median (95% Confidence Interval) [Weeks]
    12.50
    64.40
    58.40
    33.55
    24.60
    12.15
    37.10
    12. Secondary Outcome
    Title Number of Participants With an Anti-Drug Antibody (ADA) Response for Nivolumab (Nivo) and Ipilimumab (Ipi)
    Description Serum samples will be collected to evaluate the development of antibodies to BMS-936558 and to ipilimumab.
    Time Frame Up to 3 years

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants with baseline and at least one post baseline assessment
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 13 17 16 5 51 15 12 27 35 86 113
    Baseline ADA Positive (nivo)
    1
    7.1%
    1
    5.9%
    2
    12.5%
    0
    0%
    4
    23.5%
    1
    6.3%
    0
    0%
    1
    0.8%
    1
    NaN
    5
    NaN
    6
    NaN
    Baseline ADA Positive (ipi)
    0
    0%
    1
    5.9%
    0
    0%
    1
    16.7%
    2
    11.8%
    0
    0%
    0
    0%
    0
    0%
    1
    NaN
    3
    NaN
    3
    NaN
    ADA Positive (nivo)
    6
    42.9%
    10
    58.8%
    4
    25%
    0
    0%
    20
    117.6%
    4
    25%
    1
    2.4%
    5
    3.9%
    10
    NaN
    30
    NaN
    35
    NaN
    ADA Positive (ipi)
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    1
    5.9%
    1
    6.3%
    1
    2.4%
    2
    1.6%
    1
    NaN
    2
    NaN
    4
    NaN
    ADA Negative (nivo)
    7
    50%
    7
    41.2%
    12
    75%
    5
    83.3%
    31
    182.4%
    11
    68.8%
    11
    26.8%
    22
    17.3%
    25
    NaN
    56
    NaN
    78
    NaN
    ADA Negative (ipi)
    12
    85.7%
    17
    100%
    16
    100%
    5
    83.3%
    50
    294.1%
    13
    81.3%
    10
    24.4%
    23
    18.1%
    31
    NaN
    81
    NaN
    104
    NaN
    13. Secondary Outcome
    Title Peak and Trough Concentrations
    Description The peak and trough concentrations of BMS-936558 (MDX-1106) and ipilimumab in participants with quantifiable data
    Time Frame Up to 64 Weeks

    Outcome Measure Data

    Analysis Population Description
    All Treated Participants with quantifiable data
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Any BMS and Ipi Combo Cohort 6 Cohorot 7 Only BMS Cohort 8 Any BMS/Ipi Total
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab All participants who received treatment in Cohorts 1 through 3 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) combined total of participants who receive BMS only 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses All participants who received both BMS and Ipi All Participants who received treatment in any cohort combined
    Measure Participants 14 17 16 6 0 7 10 0 40 0 0
    Nivo Peak (Cmax)
    6.5
    (17.2)
    21.5
    (17.9)
    49.8
    (24.7)
    63.4
    (18.0)
    20.5
    (64.5)
    97.7
    (52.5)
    18.1
    (38.1)
    Nivo Trough (Cmin)
    1.5
    (44.9)
    2.6
    (94.4)
    27.7
    (23.9)
    23.9
    (37.5)
    13.2
    (40.9)
    53.1
    (49.8)
    5.9
    (49.3)
    Ipi Peak (Cmax)
    63.9
    (17.7)
    68.5
    (20.4)
    19.8
    (40.6)
    63.2
    (24.2)
    63.5
    (31.5)
    Ipi Trough (Cmin)
    9.7
    (33.7)
    11.9
    (29.5)
    3.6
    (30.4)
    9.2
    (34.4)
    9.8
    (43.7)

    Adverse Events

    Time Frame Within 100 days of discontinuation of dosing or within 30 days of the last visit for screen failures (Approximately 3 years)
    Adverse Event Reporting Description The Following arms: Any BMS and Ipi Combo, Only BMS and Total, were left out of the AE section because the participants in those arms are reflected in the other arms.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 2a Cohort 3 Cohort 6 Cohorot 7 Cohort 8
    Arm/Group Description 0.3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 1 mg/kg of ipilimumab 3 mg/kg of BMS-936558 (MDX-1106) + 3 mg/kg of ipilimumab 1mg/kg of BMS-936558 (MDX-1106) 3 mg/kg of BMS-936558 (MDX-1106) 1 mg/kg of BMS-936558 (MDX-1106) in combination with 3 mg/kg of ipilimumab every 3 weeks for 4 doses
    All Cause Mortality
    Cohort 1 Cohort 2 Cohort 2a Cohort 3 Cohort 6 Cohorot 7 Cohort 8
    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 8/14 (57.1%) 4/17 (23.5%) 2/16 (12.5%) 0/6 (0%) 7/17 (41.2%) 8/16 (50%) 8/41 (19.5%)
    Serious Adverse Events
    Cohort 1 Cohort 2 Cohort 2a Cohort 3 Cohort 6 Cohorot 7 Cohort 8
    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 10/14 (71.4%) 15/17 (88.2%) 10/16 (62.5%) 5/6 (83.3%) 9/17 (52.9%) 10/16 (62.5%) 26/41 (63.4%)
    Blood and lymphatic system disorders
    Anemia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Hemolysis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Cardiac disorders
    Supraventricular Tachycardia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Tachycardia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Atrial Fibrillation 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Endocrine disorders
    Adrenal Insufficiency 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Hyperthyroidism 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hypothyroidism 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Thyroiditis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hypophysitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 1/17 (5.9%) 1/16 (6.3%) 1/41 (2.4%)
    Eye disorders
    Uveitis 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Vision Blurred 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Dry Eye 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Gastrointestinal disorders
    Vomiting 2/14 (14.3%) 3/17 (17.6%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 2/41 (4.9%)
    Colitis 1/14 (7.1%) 2/17 (11.8%) 2/16 (12.5%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 4/41 (9.8%)
    Nausea 1/14 (7.1%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Pancreatitis 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Abdominal Pain 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 2/41 (4.9%)
    Appendix Disorders 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Constipation 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Small Intestinal Obstruction 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 2/16 (12.5%) 1/41 (2.4%)
    Diverticular Perforation 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Diarrhea 0/14 (0%) 2/17 (11.8%) 3/16 (18.8%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 7/41 (17.1%)
    Gastrointestinal Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Ascites 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Enterocolitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    General disorders
    Pain 2/14 (14.3%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Asthenia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Disease Progression 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 2/16 (12.5%) 2/41 (4.9%)
    Pyrexia 1/14 (7.1%) 1/17 (5.9%) 2/16 (12.5%) 1/6 (16.7%) 1/17 (5.9%) 1/16 (6.3%) 2/41 (4.9%)
    Death 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 2/41 (4.9%)
    Sudden Death 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Chest Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Multiorgan Failure 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Edema Peripheral 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Fatigue 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Hepatobiliary disorders
    Cholecystitis Acute 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hyperbilirubinemia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Acute Cholecystitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Immune system disorders
    Autoimmune Disorder 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Infections and infestations
    Superinfection 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Urinary Tract Infections 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Chorioretinitis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Viral Infection 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Device Related Infection 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Sepsis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Enterococcal Sepsis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Infection 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Diverticulitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Pneumonia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Pneumonitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Investigations
    Alanine Aminotransferase Increased 3/14 (21.4%) 3/17 (17.6%) 2/16 (12.5%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Aspartate Aminotransferase Increased 3/14 (21.4%) 3/17 (17.6%) 2/16 (12.5%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Blood Creatinine Increased 2/14 (14.3%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Amylase Increased 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 1/6 (16.7%) 1/17 (5.9%) 2/16 (12.5%) 0/41 (0%)
    Lipase Increased 0/14 (0%) 1/17 (5.9%) 2/16 (12.5%) 1/6 (16.7%) 1/17 (5.9%) 2/16 (12.5%) 0/41 (0%)
    Blood Urea Increased 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Troponin 1 Increased 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Blood Alkaline Phosphatase Increased 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Troponin T Increased 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Metabolism and nutrition disorders
    Dehydration 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Decreased Appetite 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hypokalemia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Hyponatremia 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Failure to Thrive 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Hyperuricemia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Musculoskeletal and connective tissue disorders
    Pain in Extremity 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Muscular Weakness 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Neck Pain 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Arthralgia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Back Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/41 (0%)
    Bone Lesion 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain Neoplasm 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Metastasis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Metastasis to Central Nervous System 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Nervous system disorders
    Convulsions 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Dizziness 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Headache 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Central Nervous System Necrosis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Cerebral Ischemia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Cognitive Disorders 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Syncope 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Aphasia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Dysarthria 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Hemorrhage 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Central Nervous System Hemorrhage 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Psychiatric disorders
    Confusional State 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Mental Status Changes 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Renal and urinary disorders
    Tubulointerstitial Nephritis 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Renal Failure Acute 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Urinary Tract Infection 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Urinary Tract Obstruction 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 2/14 (14.3%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 1/17 (5.9%) 0/16 (0%) 2/41 (4.9%)
    Pneumonitis 1/14 (7.1%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Pulmonary Embolism 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Pneumothorax 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Pleural Effusion 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Pulmonary Edema 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Skin and subcutaneous tissue disorders
    Rash 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Surgical and medical procedures
    Hospitalizations 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Vascular disorders
    Deep Vein Thrombosis 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Hypertension 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hypotension 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Embolism 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Other (Not Including Serious) Adverse Events
    Cohort 1 Cohort 2 Cohort 2a Cohort 3 Cohort 6 Cohorot 7 Cohort 8
    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 14/14 (100%) 17/17 (100%) 16/16 (100%) 6/6 (100%) 17/17 (100%) 15/16 (93.8%) 41/41 (100%)
    Blood and lymphatic system disorders
    Lymphadenopathy 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 3/41 (7.3%)
    Lymphopenia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 2/17 (11.8%) 0/16 (0%) 0/41 (0%)
    Anemia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Iron Deficiency Anemia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Lymph Node Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Neutropenia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Cardiac disorders
    Tachycardia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 3/41 (7.3%)
    Palpitations 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 2/17 (11.8%) 0/16 (0%) 0/41 (0%)
    Atrial Fibrillation 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Angina Pectoris 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Arrhythmia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Atrioventricular Block First Degree 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Pericardial Effusion 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Ear and labyrinth disorders
    Ear Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 1/41 (2.4%)
    Hearing Impaired 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Tinnitus 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Ear Pruritus 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hypoacusis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Vertigo 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Endocrine disorders
    Hypothyroidism 1/14 (7.1%) 1/17 (5.9%) 1/16 (6.3%) 1/6 (16.7%) 2/17 (11.8%) 0/16 (0%) 6/41 (14.6%)
    Hypophysitis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 2/17 (11.8%) 0/16 (0%) 3/41 (7.3%)
    Thyroiditis 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Adrenal Insufficiency 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Eye disorders
    Vision Blurred 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 2/6 (33.3%) 1/17 (5.9%) 0/16 (0%) 4/41 (9.8%)
    Dry Eye 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 1/6 (16.7%) 1/17 (5.9%) 2/16 (12.5%) 1/41 (2.4%)
    Uveitis 1/14 (7.1%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Ocular Hyperemia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Eye Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Eye Pruritus 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Eye Swelling 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Eyelid Margin Crusting 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hypermetropia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Ophthalmoplegia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Photophobia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Vitreous Floaters 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Gastrointestinal disorders
    Nausea 7/14 (50%) 5/17 (29.4%) 4/16 (25%) 3/6 (50%) 4/17 (23.5%) 6/16 (37.5%) 20/41 (48.8%)
    Diarrhea 5/14 (35.7%) 6/17 (35.3%) 8/16 (50%) 4/6 (66.7%) 3/17 (17.6%) 4/16 (25%) 17/41 (41.5%)
    Constipation 4/14 (28.6%) 4/17 (23.5%) 4/16 (25%) 2/6 (33.3%) 2/17 (11.8%) 4/16 (25%) 10/41 (24.4%)
    Abdominal Pain 3/14 (21.4%) 3/17 (17.6%) 3/16 (18.8%) 1/6 (16.7%) 0/17 (0%) 1/16 (6.3%) 11/41 (26.8%)
    Vomiting 3/14 (21.4%) 3/17 (17.6%) 3/16 (18.8%) 1/6 (16.7%) 0/17 (0%) 1/16 (6.3%) 10/41 (24.4%)
    Dry Mouth 1/14 (7.1%) 0/17 (0%) 2/16 (12.5%) 1/6 (16.7%) 2/17 (11.8%) 2/16 (12.5%) 6/41 (14.6%)
    Flatulence 1/14 (7.1%) 2/17 (11.8%) 2/16 (12.5%) 1/6 (16.7%) 0/17 (0%) 1/16 (6.3%) 2/41 (4.9%)
    Dyspepsia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 6/41 (14.6%)
    Abdominal Distension 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 3/41 (7.3%)
    Abdominal Pain Upper 1/14 (7.1%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Dysphagia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 2/16 (12.5%) 0/41 (0%)
    Gastroesophageal Reflux Disease 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Hemorrhoids 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Colitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Gingival Pain 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Glossodynia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Tongue Ulceration 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Anal Pruritis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Anorectal Discomfort 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Aphthous Stomatitis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Cheilitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Gingival Bleeding 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Lip Dry 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Pancreatitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Regurgitation 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Tongue Discoloration 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Tongue Edema 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    General disorders
    Fatigue 9/14 (64.3%) 11/17 (64.7%) 7/16 (43.8%) 4/6 (66.7%) 9/17 (52.9%) 7/16 (43.8%) 26/41 (63.4%)
    Pyrexia 5/14 (35.7%) 7/17 (41.2%) 3/16 (18.8%) 4/6 (66.7%) 2/17 (11.8%) 4/16 (25%) 14/41 (34.1%)
    Chills 3/14 (21.4%) 5/17 (29.4%) 1/16 (6.3%) 0/6 (0%) 1/17 (5.9%) 2/16 (12.5%) 7/41 (17.1%)
    Edema Peripheral 2/14 (14.3%) 2/17 (11.8%) 1/16 (6.3%) 1/6 (16.7%) 1/17 (5.9%) 3/16 (18.8%) 4/41 (9.8%)
    Pain 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 2/6 (33.3%) 0/17 (0%) 1/16 (6.3%) 2/41 (4.9%)
    Asthenia 0/14 (0%) 1/17 (5.9%) 2/16 (12.5%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Edema 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 2/17 (11.8%) 0/16 (0%) 2/41 (4.9%)
    Chest Pain 2/14 (14.3%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Chest Discomfort 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Influenza Like Illness 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Mucosal Inflammation 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 1/41 (2.4%)
    Xerosis 3/14 (21.4%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Axillary Pain 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Local Swelling 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Thirst 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Catheter Site Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Early Satiety 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Facial Pain 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Feeling Jittery 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hernia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Injection Site Reaction 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Sensation of Foreign Body 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Hepatobiliary disorders
    Hyperbilirubinemia 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Immune system disorders
    Hypersensitivity 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Infections and infestations
    Upper Respiratory Tract Infections 1/14 (7.1%) 2/17 (11.8%) 1/16 (6.3%) 1/6 (16.7%) 2/17 (11.8%) 1/16 (6.3%) 3/41 (7.3%)
    Urinary Tract Infections 0/14 (0%) 3/17 (17.6%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 2/41 (4.9%)
    Nasopharyngitis 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 1/6 (16.7%) 1/17 (5.9%) 1/16 (6.3%) 0/41 (0%)
    Bronchitis 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Candida Infection 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 3/41 (7.3%)
    Conjunctivitis 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Oral Herpes 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Sinusitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Herpes Zoster 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Influenza 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Appendicitis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Cellulitis Orbital 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Clostridium Difficile Colitis 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Escherichia Bacteremia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Respiratory Syncytial Virus Infection 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Tonsillitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Tooth Abscess 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Viral Infection 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Wound Infection 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Injury, poisoning and procedural complications
    Sunburn 1/14 (7.1%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Contusion 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Fall 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Infusion Related Reaction 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Alcohol Poisoning 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Laceration 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Procedural Pain 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Radiation Necrosis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Radiation Skin Injury 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Wound 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Investigations
    Lipase Increased 2/14 (14.3%) 4/17 (23.5%) 3/16 (18.8%) 4/6 (66.7%) 2/17 (11.8%) 1/16 (6.3%) 8/41 (19.5%)
    Amylase Increased 2/14 (14.3%) 4/17 (23.5%) 2/16 (12.5%) 3/6 (50%) 1/17 (5.9%) 0/16 (0%) 6/41 (14.6%)
    Aspartate Aminotransferase Increased 2/14 (14.3%) 1/17 (5.9%) 1/16 (6.3%) 4/6 (66.7%) 1/17 (5.9%) 0/16 (0%) 7/41 (17.1%)
    Weight Decreased 2/14 (14.3%) 1/17 (5.9%) 3/16 (18.8%) 2/6 (33.3%) 1/17 (5.9%) 2/16 (12.5%) 5/41 (12.2%)
    Alanine Aminotransferase Increased 1/14 (7.1%) 4/17 (23.5%) 0/16 (0%) 2/6 (33.3%) 0/17 (0%) 1/16 (6.3%) 7/41 (17.1%)
    Hemoglobin Decreased 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 1/6 (16.7%) 1/17 (5.9%) 1/16 (6.3%) 3/41 (7.3%)
    Weight Increased 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 1/17 (5.9%) 1/16 (6.3%) 3/41 (7.3%)
    Blood Lactate Dehydrogenase Increased 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 6/41 (14.6%)
    Blood Alkaline Phosphatase Increased 2/14 (14.3%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 3/41 (7.3%)
    Blood Creatinine Increased 2/14 (14.3%) 1/17 (5.9%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Gamma-Glutamyltransferase Increased 2/14 (14.3%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Blood Thyroid Stimulating Hormone Decreased 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Electrocardiogram QT Prolonged 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    International Normalized Ratio Increased 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Blood Albumin Decreased 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Blood Phosphorus Increased 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Blood Potassium Increased 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Blood Testosterone Decreased 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Blood Uric Acid Increased 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Breath Sounds Abnormal 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Chest X-Ray Abnormal 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Fungal Test Positive 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Thyroid Function Test Abnormal 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Transaminases Increased 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Metabolism and nutrition disorders
    Decreased Appetite 3/14 (21.4%) 4/17 (23.5%) 3/16 (18.8%) 0/6 (0%) 2/17 (11.8%) 1/16 (6.3%) 5/41 (12.2%)
    Hyperglycemia 2/14 (14.3%) 0/17 (0%) 1/16 (6.3%) 1/6 (16.7%) 2/17 (11.8%) 1/16 (6.3%) 2/41 (4.9%)
    Hypokalemia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 8/41 (19.5%)
    Hypoalbuminemia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 3/41 (7.3%)
    Dehydration 2/14 (14.3%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Hyponatremia 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 1/41 (2.4%)
    Hyperuricemia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 3/41 (7.3%)
    Hyperphosphatemia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 2/16 (12.5%) 1/41 (2.4%)
    Hypocalcemia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Hyperkalemia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Hypoglycemia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Increased Appetite 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Polydipsia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Musculoskeletal and connective tissue disorders
    Arthalgia 5/14 (35.7%) 3/17 (17.6%) 3/16 (18.8%) 2/6 (33.3%) 4/17 (23.5%) 7/16 (43.8%) 12/41 (29.3%)
    Back Pain 3/14 (21.4%) 1/17 (5.9%) 4/16 (25%) 2/6 (33.3%) 2/17 (11.8%) 2/16 (12.5%) 2/41 (4.9%)
    Myalgia 2/14 (14.3%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 3/17 (17.6%) 3/16 (18.8%) 4/41 (9.8%)
    Pain in Extremity 4/14 (28.6%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 2/17 (11.8%) 0/16 (0%) 3/41 (7.3%)
    Muscle Spasms 3/14 (21.4%) 0/17 (0%) 3/16 (18.8%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 4/41 (9.8%)
    Musculoskeletal Chest Pain 1/14 (7.1%) 1/17 (5.9%) 2/16 (12.5%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 3/41 (7.3%)
    Neck Pain 1/14 (7.1%) 2/17 (11.8%) 1/16 (6.3%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 2/41 (4.9%)
    Musculoskeletal Pain 1/14 (7.1%) 0/17 (0%) 1/16 (6.3%) 1/6 (16.7%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Joint Swelling 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Flank Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 2/17 (11.8%) 0/16 (0%) 0/41 (0%)
    Pain in Jaw 1/14 (7.1%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Groin Pain 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Joint Stiffness 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Muscle Tightness 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Musculoskeletal Stiffness 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor Pain 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Acrochordon 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Basal Cell Carcinoma 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Squamous Cell Carcinoma 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Tumor Hemorrhage 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Nervous system disorders
    Headache 2/14 (14.3%) 8/17 (47.1%) 4/16 (25%) 4/6 (66.7%) 1/17 (5.9%) 3/16 (18.8%) 13/41 (31.7%)
    Dizziness 2/14 (14.3%) 3/17 (17.6%) 1/16 (6.3%) 0/6 (0%) 2/17 (11.8%) 3/16 (18.8%) 4/41 (9.8%)
    Neuropathy Peripheral 4/14 (28.6%) 3/17 (17.6%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 1/41 (2.4%)
    Dysgeusia 1/14 (7.1%) 3/17 (17.6%) 2/16 (12.5%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 2/41 (4.9%)
    Ataxia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Hypoaesthesia 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 2/41 (4.9%)
    Tremor 0/14 (0%) 1/17 (5.9%) 2/16 (12.5%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Ageusia 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Amnesia 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Lethargy 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Presyncope 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Carpal Tunnel Syndrome 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Cognitive Disorder 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Dizziness Postural 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Dysarthria 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hemiparesis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Memory Impairment 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Migraine with Aura 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Mononeuropathy 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Narcolepsy 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Sciatica 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Sinus Headache 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Somnolence 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Psychiatric disorders
    Insomnia 2/14 (14.3%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 4/41 (9.8%)
    Anxiety 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Depression 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 2/41 (4.9%)
    Confusional State 0/14 (0%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Mood Altered 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 2/17 (11.8%) 0/16 (0%) 0/41 (0%)
    Mental Status Changes 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Renal and urinary disorders
    Pollakiuria 2/14 (14.3%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 1/41 (2.4%)
    Dysuria 2/14 (14.3%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Hematuria 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 2/16 (12.5%) 1/41 (2.4%)
    Micturition Urgency 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Chromaturia 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Polyuria 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Urethral Discharge 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Urinary Tract Disorder 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Reproductive system and breast disorders
    Breast Cyst 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Gynecomastia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Polymenorrhea 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Vaginal Hemorrhage 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Vulvovaginal Dryness 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 5/14 (35.7%) 6/17 (35.3%) 7/16 (43.8%) 2/6 (33.3%) 5/17 (29.4%) 6/16 (37.5%) 17/41 (41.5%)
    Dyspnea 3/14 (21.4%) 2/17 (11.8%) 3/16 (18.8%) 1/6 (16.7%) 1/17 (5.9%) 2/16 (12.5%) 7/41 (17.1%)
    Nasal Congestion 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 2/17 (11.8%) 1/16 (6.3%) 6/41 (14.6%)
    Dyspnea Exertional 2/14 (14.3%) 1/17 (5.9%) 0/16 (0%) 1/6 (16.7%) 3/17 (17.6%) 0/16 (0%) 0/41 (0%)
    Rhinorrhoea 2/14 (14.3%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 2/41 (4.9%)
    Sinus Congestion 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 4/41 (9.8%)
    Upper-Airway Cough Syndrome 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 2/17 (11.8%) 1/16 (6.3%) 2/41 (4.9%)
    Oropharyngeal Pain 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 3/41 (7.3%)
    Wheezing 1/14 (7.1%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 0/41 (0%)
    Dysphonia 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Epistaxis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Pneumonitis 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Productive Cough 0/14 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Respiratory Tract Inflammation 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Throat Tightness 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Pulmonary Mass 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Sleep Apnea Syndrome 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Skin and subcutaneous tissue disorders
    Rash 9/14 (64.3%) 11/17 (64.7%) 11/16 (68.8%) 4/6 (66.7%) 7/17 (41.2%) 5/16 (31.3%) 27/41 (65.9%)
    Pruritus 8/14 (57.1%) 11/17 (64.7%) 12/16 (75%) 3/6 (50%) 4/17 (23.5%) 4/16 (25%) 22/41 (53.7%)
    Vitiligo 2/14 (14.3%) 4/17 (23.5%) 3/16 (18.8%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 4/41 (9.8%)
    Alopecia 0/14 (0%) 1/17 (5.9%) 2/16 (12.5%) 0/6 (0%) 0/17 (0%) 3/16 (18.8%) 5/41 (12.2%)
    Dry Skin 1/14 (7.1%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 5/41 (12.2%)
    Night Sweats 2/14 (14.3%) 2/17 (11.8%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 2/41 (4.9%)
    Erythema 2/14 (14.3%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 1/41 (2.4%)
    Rash Papular 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 5/41 (12.2%)
    Rash Pruritic 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 3/41 (7.3%)
    Rash Macular 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 3/41 (7.3%)
    Urticaria 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Palmar-Plantar Erythrodysaesthesia Syndrome 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 2/16 (12.5%) 0/41 (0%)
    Rash Maculo-Papular 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 0/16 (0%) 1/41 (2.4%)
    Skin Fissures 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Acne 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Acute Febrile Neutrophilic Dermatosis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Blister 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Butterfly Rash 0/14 (0%) 0/17 (0%) 0/16 (0%) 1/6 (16.7%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Dermatitis 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hair Color Changes 0/14 (0%) 0/17 (0%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hyperhidrosis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)
    Lichenoid Keratosis 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Photodermatosis 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Photosensitivity Reaction 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Skin Irritation 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Vascular disorders
    Hypertension 1/14 (7.1%) 1/17 (5.9%) 3/16 (18.8%) 0/6 (0%) 0/17 (0%) 2/16 (12.5%) 2/41 (4.9%)
    Hypotension 3/14 (21.4%) 1/17 (5.9%) 1/16 (6.3%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Flushing 1/14 (7.1%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 1/41 (2.4%)
    Hemorrhage 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 1/17 (5.9%) 1/16 (6.3%) 0/41 (0%)
    Deep Vein Thrombosis 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Hot Flush 0/14 (0%) 1/17 (5.9%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 0/16 (0%) 0/41 (0%)
    Thrombophlebitis 0/14 (0%) 0/17 (0%) 0/16 (0%) 0/6 (0%) 0/17 (0%) 1/16 (6.3%) 0/41 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    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:
    NCT01024231
    Other Study ID Numbers:
    • CA209-004
    • (MDX1106-04)
    First Posted:
    Dec 2, 2009
    Last Update Posted:
    Mar 22, 2021
    Last Verified:
    Mar 1, 2021