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A Study of Two Different Dose Combinations of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT02714218
Collaborator
(none)
387
Enrollment
57
Locations
3
Arms
61.8
Actual Duration (Months)
6.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate two different dose combinations of nivolumab and ipilimumab in the treatment of melanoma.

Condition or Disease Intervention/Treatment Phase
  • Biological: Nivolumab 3 mg/kg IV
  • Biological: Ipilimumab 1 mg/kg IV
  • Biological: Nivolumab 1 mg/kg IV
  • Biological: Ipilimumab 3 mg/kg IV
  • Biological: Nivolumab 6 mg/kg IV
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
387 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination With Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination With Ipilimumab 3 mg/kg in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma
Actual Study Start Date :
Apr 4, 2016
Actual Primary Completion Date :
Apr 20, 2017
Actual Study Completion Date :
May 28, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV

Specified dose on specified days

Biological: Nivolumab 3 mg/kg IV
Followed by Nivolumab monotherapy

Biological: Ipilimumab 1 mg/kg IV
Followed by Nivolumab monotherapy
Experimental: Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV

Specified dose on specified days

Biological: Nivolumab 1 mg/kg IV

Biological: Ipilimumab 3 mg/kg IV
Experimental: Nivolumab 6 mg/kg IV + Ipilimumab 1 mg/kg

Specified dose on specified days

Biological: Ipilimumab 1 mg/kg IV
Followed by Nivolumab monotherapy

Biological: Nivolumab 6 mg/kg IV
A dose of 240mg is identical to a dose of 3mg/kg, therefore 6mg/kg is approximately equal to ~ 480mg.

Outcome Measures

Primary Outcome Measures

  1. The Percentage of Participants With Drug-Related Grade 3 - 5 Adverse Events (AEs) [From first dose of study treatment up to primary completion date 20-Apr-2017 (up to approximately 12 months)]

    The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria.

Secondary Outcome Measures

  1. Objective Response Rate (ORR) [From date of randomization to date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to approximately 5 years)]

    The percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). BOR is defined as the best response, as determined by the investigator, recorded between the date of randomization and the date of progression per RECIST 1.1 or the date of subsequent anticancer therapy, whichever occurred first. For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR assessment. Tumor assessments are scheduled at Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  2. Overall Survival (OS) [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up tp approximately 5 years)]

    The time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date. OS will be followed continuously while participants are on the study drug and every 3 months via in-person or phone contact after participants discontinue the study drug. Based on Kaplan-Meier Estimates.

  3. Progression Free Survival (PFS) [From randomization to the first date of documented progression or death due to any cause, whichever occurs first (up to approximately 5 years)]

    The time between the date of randomization and the first date of documented progression, determined by the investigator, or death due to any cause, whichever occurs first. Participants who die without a reported progression will be considered to have progressed on the date of their death. Those who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants without on study tumor assessments and who did not die will be censored on their date of randomization. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. Based on Kaplan-Meier Estimates. Progression is defined as at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).

  4. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Physical Functioning Scale [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Physical Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  5. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Role Functioning Scale [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Role Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  6. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Emotional Functioning Scale [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Emotional Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  7. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Cognitive Functioning Scale [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Cognitive Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  8. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Social Functioning Scale [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Social Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  9. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Global Health Status [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 comprises 6 functional scales (role function, physical functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.

  10. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Dyspnea [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Dyspnea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  11. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Insomnia [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Insomnia sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  12. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Appetite Loss [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Appetite loss sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  13. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Constipation [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Constipation sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points

  14. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Diarrhea [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Diarrhea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.

  15. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Financial Difficulties [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Financial difficulties sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points

  16. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Fatigue [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Fatigue sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points

  17. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Nausea and Vomiting [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Nausea and Vomiting sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points for the various scales of the EORTC QLQ-C30

  18. Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Pain [Weeks 7, 16, 20, 24, 28, 32, 36, 40]

    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Pain sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points

Eligibility Criteria

Criteria

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

For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

  • Subject must have been diagnosed with stage III or/and stage IV histologically confirmed melanoma [per American Joint Committee on Cancer (AJCC) staging system] that is unresectable or metastatic

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

  • Subject has not been treated by systemic anticancer therapy for unresectable or metastatic melanoma

Exclusion Criteria:

  • Subjects with active brain metastases or leptomeningeal metastases

  • Subjects with ocular melanoma

  • Subjects with active, known or suspected autoimmune disease

Other protocol defined inclusion/exclusion criteria could apply

Contacts and Locations

Locations

Site City State Country Postal Code
1 University Of Colorado Cancer Center Aurora Colorado United States 80045
2 H. Lee Moffitt Cancer Center Tampa Florida United States 33612
3 Allina Health Fridley Minnesota United States 55432
4 Washington University School Of Medicine Saint Louis Missouri United States 63110
5 Comprehensive Cancer Centers of Nevada Las Vegas Nevada United States 89148
6 Dartmouth-Hitchcock Medical Center Lebanon New Hampshire United States 03756
7 John Theurer Cancer Center at Hackensack University Medical Center Hackensack New Jersey United States 07601
8 Levine Cancer Institute Charlotte North Carolina United States 28204
9 Lehigh Valley Health Network Allentown Pennsylvania United States 18103
10 University Of Virginia Health System Charlottesville Virginia United States 22908
11 University of Washington - Seattle Cancer Care Alliance Seattle Washington United States 98109
12 Local Institution North Sydney New South Wales Australia 2060
13 Local Institution - 0045 Waratah New South Wales Australia 2298
14 Local Institution Greenslopes Queensland Australia 4120
15 Local Institution Melbourne Victoria Australia 3004
16 Local Institution - 0007 Edmonton Alberta Canada T6G 1Z2
17 Princess Margaret Cancer Centre Toronto Ontario Canada M5G 2M9
18 CHU de Quebec - Universite Laval Quebec Canada G1R 2J6
19 Local Institution - 0063 Aarhus N Denmark 8200
20 Local Institution - 0065 Herlev Denmark 2730
21 Local Institution - 0064 Odense Denmark 5000
22 Hopital Saint Andre Bordeaux France 33075
23 Chru De Lille Lille France 59037
24 Hopital De La Timone Marseille Cedex 5 France 13385
25 Hopital Hotel Dieu Nantes Cedex France 44093
26 Hopital Saint Louis Paris France 75475
27 Centre Hospitalier Lyon Sud Pierre Benite France 69310
28 Institut Claudius Regaud Toulouse Cedex 9 France 31059
29 Local Institution - 0019 Villejuif France 94805
30 Universitaetsklinikum Essen Essen Germany 45147
31 Universitaetsklinikum Heidelberg Heidelberg Germany 69120
32 Ludwig-Maximilians-Universitaet Muenchen Germany 80337
33 Universitaetsklinikum Tuebingen Tuebingen Germany 72076
34 Local Institution Ramat Gan Israel 5262100
35 Local Institution - 0039 Bergamo Italy 24127
36 Local Institution - 0042 Milano Italy 20133
37 Local Institution - 0040 Napoli Italy 80131
38 Istituto Oncologico Veneto IOV Padova Italy 35128
39 Local Institution - 0041 Siena Italy 53100
40 Ospedale San Vincenzo Taormina Italy 98039
41 Local Institution - 0052 Amsterdam Netherlands 1066 CX
42 Local Institution Amsterdam Netherlands 1081 HV
43 University Medical Center Groningen (Umcg) Groningen Netherlands 9700RB
44 Uniwersyteckie Centrum Kliniczne Klinika Onkologii I Radiote Gdansk Poland 80-214
45 Klinika Nowotworow Ukladowych i Uogolnionych Krakow Poland 31-115
46 Klinika Nowotworow Tkanek Miekkich, Kosci i Czerniakow Warszawa Poland 02-781
47 Local Institution Moscow Russian Federation 115478
48 Local Institution Badalona-barcelona Spain 08916
49 Local Institution - 0024 Barcelona Spain 08036
50 Local Institution Madrid Spain 28007
51 Local Institution - 0027 Madrid Spain 28034
52 Local Institution San Sabastian Gipuzkoa Spain 20014
53 Local Institution Valencia Spain 46014
54 Local Institution Manchester Greater Manchester United Kingdom M20 4XB
55 Local Institution Oxford Oxfordshire United Kingdom OX3 7LJ
56 Local Institution Guildford United Kingdom GU2 7XX
57 Local Institution London United Kingdom SW3 6JJ

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:
NCT02714218
Other Study ID Numbers:
  • CA209-511
First Posted:
Mar 21, 2016
Last Update Posted:
Jun 24, 2022
Last Verified:
Jun 1, 2022
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 387 participants were randomized, 385 were treated. Cohort C/N6I1 assessed for exploratory outcome measures not being reported in the Outcome Measures module. Safety data included with AE data.
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks nivolumab 6 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 480 mg Flat Dose 4 weeks later and repeated every 8 weeks
Period Title: Pre-Treatment Period
STARTED 180 180 27
COMPLETED 180 178 27
NOT COMPLETED 0 2 0
Period Title: Pre-Treatment Period
STARTED 180 178 27
COMPLETED 6 2 2
NOT COMPLETED 174 176 25

Baseline Characteristics

Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg Total
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks nivolumab 6 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 480 mg Flat Dose 4 weeks later and repeated every 8 weeks Total of all reporting groups
Overall Participants 180 180 27 387
Age, Customized (Count of Participants)
<65
115
63.9%
122
67.8%
17
63%
254
65.6%
>= 65 AND < 75
48
26.7%
43
23.9%
9
33.3%
100
25.8%
>= 75
17
9.4%
15
8.3%
1
3.7%
33
8.5%
Sex: Female, Male (Count of Participants)
Female
75
41.7%
77
42.8%
11
40.7%
163
42.1%
Male
105
58.3%
103
57.2%
16
59.3%
224
57.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
0
0%
Asian
1
0.6%
0
0%
1
3.7%
2
0.5%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
Black or African American
0
0%
2
1.1%
1
3.7%
3
0.8%
White
174
96.7%
170
94.4%
23
85.2%
367
94.8%
More than one race
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
5
2.8%
8
4.4%
2
7.4%
15
3.9%

Outcome Measures

1. Primary Outcome
Title The Percentage of Participants With Drug-Related Grade 3 - 5 Adverse Events (AEs)
Description The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria.
Time Frame From first dose of study treatment up to primary completion date 20-Apr-2017 (up to approximately 12 months)

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 180 178
Number (95% Confidence Interval) [Percentage of participants]
32.8
18.2%
45.5
25.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV, Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.0144
Comments
Method Cochran-Mantel-Haenszel
Comments Two-sided p-value CMH Test for comparison of odds ratio of NIVO 3 + IPI 1 over NIVO 1 + IPI 3
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.59
Confidence Interval (2-Sided) 95%
0.38 to 0.90
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV, Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Estimated Difference of rates
Estimated Value -12.7
Confidence Interval (2-Sided) 95%
-22.7 to -2.6
Parameter Dispersion Type:
Value:
Estimation Comments Estimate of NIVO 3 + IPI 1- NIVO 1 + IPI 3 is based on Cochran-Mantel-Haenszel (CMH) method of weighting, adjusting for PD-L1 expression and M stage at screening as entered into the IVRS
2. Post-Hoc Outcome
Title The Percentage of Participants With Drug-Related Grade 3 - 5 Adverse Events (AEs) - Extended Collection
Description The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until study completion date: 28-May-2021)
Time Frame From first dose of study treatment to 30 days after the last dose of study treatment (up to approximately 30 months)

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 180 178
Number (95% Confidence Interval) [Percentage of participants]
33.9
18.8%
48.3
26.8%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV, Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.0059
Comments
Method Cochran-Mantel-Haenszel
Comments Two-sided p-value CMH Test for comparison of odds ratio of NIVO 3 + IPI 1 over NIVO 1 + IPI 3
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.55
Confidence Interval (2-Sided) 95%
0.36 to 0.84
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV, Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Estimated Difference of rates
Estimated Value -14.4
Confidence Interval (2-Sided) 95%
-24.5 to -4.3
Parameter Dispersion Type:
Value:
Estimation Comments Estimate of NIVO 3 + IPI 1- NIVO 1 + IPI 3 is based on Cochran-Mantel-Haenszel (CMH) method of weighting, adjusting for PD-L1 expression and M stage at screening as entered into the IVRS
3. Secondary Outcome
Title Objective Response Rate (ORR)
Description The percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). BOR is defined as the best response, as determined by the investigator, recorded between the date of randomization and the date of progression per RECIST 1.1 or the date of subsequent anticancer therapy, whichever occurred first. For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR assessment. Tumor assessments are scheduled at Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame From date of randomization to date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to approximately 5 years)

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 180 178
Number (95% Confidence Interval) [Percentage of participants]
47.8
26.6%
53.4
29.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV, Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.2923
Comments
Method Cochran-Mantel-Haenszel
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.53 to 1.21
Parameter Dispersion Type:
Value:
Estimation Comments p-value from CMH Test for the comparison of the odds ratio of N3I1 over N1I3
4. Secondary Outcome
Title Overall Survival (OS)
Description The time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date. OS will be followed continuously while participants are on the study drug and every 3 months via in-person or phone contact after participants discontinue the study drug. Based on Kaplan-Meier Estimates.
Time Frame From date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up tp approximately 5 years)

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 180 178
Median (95% Confidence Interval) [Months]
NA
NA
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV, Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.08
Confidence Interval (2-Sided) 95%
0.79 to 1.47
Parameter Dispersion Type:
Value:
Estimation Comments Hazard Ratio is N3I1 over N1I3. (NIVO 3 + IPI 1 (N3I1) over NIVO 1 + IPI 3 (N1I3))
5. Secondary Outcome
Title Progression Free Survival (PFS)
Description The time between the date of randomization and the first date of documented progression, determined by the investigator, or death due to any cause, whichever occurs first. Participants who die without a reported progression will be considered to have progressed on the date of their death. Those who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants without on study tumor assessments and who did not die will be censored on their date of randomization. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. Based on Kaplan-Meier Estimates. Progression is defined as at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time Frame From randomization to the first date of documented progression or death due to any cause, whichever occurs first (up to approximately 5 years)

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 180 178
Median (95% Confidence Interval) [Months]
10.18
9.99
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV, Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.4512
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.12
Confidence Interval (2-Sided) 95%
0.84 to 1.48
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Physical Functioning Scale
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Physical Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
-2.1
(16.2)
-4.9
(16.5)
Week 16
-1.9
(15.3)
-2.7
(15.8)
Week 20
-1.4
(10.7)
-2.7
(13.7)
Week 24
-5.1
(15.6)
-5.7
(13.6)
Week 28
-2.5
(15.0)
-0.7
(14.8)
Week 32
-3.3
(16.5)
-3.5
(15.4)
Week 36
-4.0
(19.1)
-2.9
(14.8)
Week 40
-3.3
(17.3)
-3.4
(16.7)
7. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Role Functioning Scale
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Role Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
-2.5
(28.3)
-8.8
(25.6)
Week 16
-6.6
(30.3)
2.1
(25.6)
Week 20
-1.8
(19.9)
-5.2
(25.2)
Week 24
-3.9
(19.9)
-9.8
(29.3)
Week 28
-0.9
(23.4)
-1.3
(26.0)
Week 32
-3.6
(25.1)
-2.2
(29.3)
Week 36
-3.9
(26.4)
-2.9
(30.5)
Week 40
-4.0
(26.7)
-5.2
(34.2)
8. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Emotional Functioning Scale
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Emotional Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
4.5
(17.9)
4.4
(16.8)
Week 16
0.0
(21.7)
6.6
(20.1)
Week 20
3.9
(18.0)
4.5
(18.0)
Week 24
3.4
(18.4)
2.6
(23.3)
Week 28
5.9
(19.5)
5.6
(22.5)
Week 32
5.5
(17.3)
5.1
(21.6)
Week 36
3.0
(17.0)
4.7
(22.0)
Week 40
4.5
(21.4)
5.4
(19.9)
9. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Cognitive Functioning Scale
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Cognitive Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
-3.4
(15.0)
-1.9
(16.7)
Week 16
-2.6
(14.4)
-5.9
(22.4)
Week 20
-1.9
(16.9)
-6.0
(17.6)
Week 24
-2.7
(15.0)
-3.4
(14.9)
Week 28
-3.7
(17.7)
-3.7
(16.8)
Week 32
-1.5
(16.6)
-4.8
(16.9)
Week 36
-3.1
(18.5)
-8.8
(20.6)
Week 40
-2.6
(20.3)
-4.4
(15.2)
10. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Social Functioning Scale
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Social Functioning Scale sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 120 110
Week 7
-3.1
(22.8)
-6.1
(25.0)
Week 16
-6.3
(23.5)
-2.8
(26.7)
Week 20
-4.6
(21.0)
-3.2
(20.5)
Week 24
-1.6
(17.2)
-3.7
(20.0)
Week 28
1.4
(18.1)
-1.0
(22.2)
Week 32
0.3
(17.6)
-1.0
(19.6)
Week 36
0.5
(20.4)
0.3
(22.7)
Week 40
1.1
(22.0)
-4.1
(23.3)
11. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Global Health Status
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 comprises 6 functional scales (role function, physical functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 120 111
Week 7
0.5
(22.9)
-0.5
(19.0)
Week 16
0.0
(18.5)
5.0
(24.5)
Week 20
-1.5
(19.9)
0.0
(19.1)
Week 24
-0.5
(16.1)
-1.6
(24.9)
Week 28
0.7
(21.1)
6.3
(23.4)
Week 32
-0.5
(23.2)
5.4
(23.9)
Week 36
-2.9
(21.8)
2.6
(25.6)
Week 40
-0.8
(22.2)
3.7
(21.1)
12. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Dyspnea
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Dyspnea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
4.4
(21.5)
6.3
(23.0)
Week 16
5.8
(22.0)
2.1
(21.1)
Week 20
2.7
(22.7)
2.3
(22.4)
Week 24
2.3
(19.5)
2.3
(22.4)
Week 28
3.2
(25.7)
0.0
(23.3)
Week 32
2.6
(23.1)
2.6
(22.7)
Week 36
4.2
(21.8)
0.0
(21.1)
Week 40
3.7
(22.5)
2.2
(21.8)
13. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Insomnia
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Insomnia sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 120 112
Week 7
0.6
(28.7)
-1.5
(30.5)
Week 16
-0.5
(28.0)
-2.8
(29.0)
Week 20
-0.9
(28.5)
-6.3
(28.9)
Week 24
2.3
(28.0)
-7.5
(26.5)
Week 28
0.9
(25.6)
-7.3
(28.0)
Week 32
-3.1
(24.1)
-10.5
(29.4)
Week 36
0.5
(24.8)
-8.5
(30.4)
Week 40
-1.1
(18.9)
-14.1
(31.4)
14. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Appetite Loss
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Appetite loss sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
3.0
(24.7)
4.8
(28.6)
Week 16
2.1
(28.6)
-1.4
(31.5)
Week 20
1.4
(21.8)
-3.5
(25.7)
Week 24
-0.9
(22.9)
-2.9
(32.0)
Week 28
-0.9
(23.0)
-7.3
(26.3)
Week 32
1.0
(27.6)
-7.7
(23.4)
Week 36
-2.6
(24.7)
-9.2
(26.7)
Week 40
-2.6
(22.6)
-6.7
(31.5)
15. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Constipation
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Constipation sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
0.3
(26.4)
2.4
(26.7)
Week 16
5.3
(22.6)
-2.8
(32.1)
Week 20
3.7
(26.4)
1.1
(25.7)
Week 24
-0.5
(23.2)
-1.7
(26.8)
Week 28
3.2
(27.5)
1.4
(28.8)
Week 32
2.6
(23.1)
-5.1
(27.5)
Week 36
3.7
(23.3)
-0.7
(29.4)
Week 40
1.1
(21.6)
0.7
(29.7)
16. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Diarrhea
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Diarrhea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
1.4
(18.5)
1.2
(23.6)
Week 16
8.5
(22.4)
2.8
(30.6)
Week 20
2.3
(19.6)
-1.7
(22.0)
Week 24
1.8
(17.5)
1.1
(25.7)
Week 28
2.8
(19.2)
0.0
(19.4)
Week 32
0.5
(19.1)
-2.6
(21.7)
Week 36
3.6
(16.9)
-2.0
(20.5)
Week 40
-0.5
(18.4)
-3.7
(16.2)
17. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Financial Difficulties
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Financial difficulties sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 118 109
Week 7
2.0
(24.4)
2.4
(22.5)
Week 16
1.1
(19.8)
4.9
(21.7)
Week 20
2.8
(20.7)
5.3
(19.7)
Week 24
1.8
(22.8)
5.7
(17.8)
Week 28
2.8
(23.6)
6.8
(22.5)
Week 32
2.1
(22.7)
5.8
(22.6)
Week 36
3.6
(22.3)
8.5
(18.7)
Week 40
1.1
(23.9)
8.1
(19.0)
18. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Fatigue
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Fatigue sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
5.1
(23.3)
11.5
(23.2)
Week 16
9.2
(25.8)
5.1
(24.4)
Week 20
4.4
(20.6)
7.9
(20.5)
Week 24
5.4
(20.5)
6.9
(24.3)
Week 28
4.8
(22.9)
2.1
(19.5)
Week 32
5.5
(23.7)
3.2
(22.9)
Week 36
5.4
(27.1)
1.7
(21.2)
Week 40
5.8
(24.3)
0.7
(24.7)
19. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Nausea and Vomiting
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Nausea and Vomiting sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points for the various scales of the EORTC QLQ-C30
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 112
Week 7
1.5
(16.4)
4.9
(18.3)
Week 16
-0.3
(20.4)
3.1
(11.7)
Week 20
-2.3
(10.1)
1.1
(13.9)
Week 24
-0.5
(16.2)
4.0
(18.0)
Week 28
0.7
(13.5)
0.7
(14.3)
Week 32
-1.3
(14.2)
0.3
(15.7)
Week 36
0.0
(18.5)
1.6
(16.1)
Week 40
-1.3
(12.1)
0.7
(12.3)
20. Secondary Outcome
Title Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Pain
Description Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Pain sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points
Time Frame Weeks 7, 16, 20, 24, 28, 32, 36, 40

Outcome Measure Data

Analysis Population Description
All treated participants in cohorts A and B
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
Measure Participants 121 111
Week 7
-1.7
(28.0)
1.5
(25.6)
Week 16
-2.9
(22.9)
-2.8
(23.4)
Week 20
-5.7
(20.1)
1.7
(28.0)
Week 24
-2.9
(20.9)
0.9
(31.9)
Week 28
-3.0
(25.5)
-3.7
(30.9)
Week 32
-2.8
(27.1)
-4.5
(26.0)
Week 36
-2.6
(21.3)
-2.6
(29.9)
Week 40
0.3
(25.3)
-3.3
(27.2)

Adverse Events

Time Frame Adverse Events and Serious Adverse Events are collected from the first dose date until the last dose date + 30 days (Up to approximately 30 months) Participants were assessed for All Cause Mortality from their first dose until the study was completed (up to approximately 5 years)
Adverse Event Reporting Description The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication
Arm/Group Title Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
Arm/Group Description nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks. nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks nivolumab 6 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 480 mg Flat Dose 4 weeks later and repeated every 8 weeks
All Cause Mortality
Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 85/180 (47.2%) 78/180 (43.3%) 15/27 (55.6%)
Serious Adverse Events
Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 109/180 (60.6%) 127/178 (71.3%) 14/27 (51.9%)
Blood and lymphatic system disorders
Anaemia 2/180 (1.1%) 2/178 (1.1%) 0/27 (0%)
Eosinophilia 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Febrile neutropenia 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Haemolysis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Lymph node pain 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Cardiac disorders
Acute coronary syndrome 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Angina pectoris 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Atrial fibrillation 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Cardiac failure 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Cardiopulmonary failure 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Immune-mediated myocarditis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Myocardial infarction 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Myocarditis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Tachycardia 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Ear and labyrinth disorders
Vertigo 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Endocrine disorders
Adrenal insufficiency 1/180 (0.6%) 3/178 (1.7%) 1/27 (3.7%)
Adrenocortical insufficiency acute 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Adrenocorticotropic hormone deficiency 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Glucocorticoid deficiency 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hyperthyroidism 0/180 (0%) 3/178 (1.7%) 0/27 (0%)
Hypophysitis 2/180 (1.1%) 6/178 (3.4%) 1/27 (3.7%)
Hypopituitarism 0/180 (0%) 2/178 (1.1%) 0/27 (0%)
Thyroiditis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Eye disorders
Diplopia 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Dry eye 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Keratitis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Orbital myositis 0/180 (0%) 0/178 (0%) 1/27 (3.7%)
Vision blurred 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Gastrointestinal disorders
Abdominal pain 2/180 (1.1%) 2/178 (1.1%) 0/27 (0%)
Ascites 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Autoimmune colitis 0/180 (0%) 2/178 (1.1%) 0/27 (0%)
Colitis 6/180 (3.3%) 10/178 (5.6%) 1/27 (3.7%)
Colitis ulcerative 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Diarrhoea 5/180 (2.8%) 12/178 (6.7%) 0/27 (0%)
Dry mouth 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Dysphagia 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Gastric haemorrhage 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Gastritis 1/180 (0.6%) 2/178 (1.1%) 0/27 (0%)
Gastrointestinal necrosis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Gastrointestinal perforation 0/180 (0%) 2/178 (1.1%) 0/27 (0%)
Immune-mediated enterocolitis 2/180 (1.1%) 2/178 (1.1%) 0/27 (0%)
Intestinal obstruction 3/180 (1.7%) 0/178 (0%) 0/27 (0%)
Nausea 3/180 (1.7%) 3/178 (1.7%) 0/27 (0%)
Pancreatitis 3/180 (1.7%) 1/178 (0.6%) 0/27 (0%)
Small intestinal obstruction 0/180 (0%) 1/178 (0.6%) 1/27 (3.7%)
Vomiting 2/180 (1.1%) 4/178 (2.2%) 0/27 (0%)
General disorders
Chest discomfort 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Chest pain 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
General physical health deterioration 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Hyperthermia 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Inflammation 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Influenza like illness 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Pain 1/180 (0.6%) 3/178 (1.7%) 1/27 (3.7%)
Pyrexia 5/180 (2.8%) 11/178 (6.2%) 1/27 (3.7%)
Systemic inflammatory response syndrome 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hepatobiliary disorders
Autoimmune hepatitis 2/180 (1.1%) 5/178 (2.8%) 0/27 (0%)
Cholecystitis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Drug-induced liver injury 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hepatic cytolysis 0/180 (0%) 4/178 (2.2%) 1/27 (3.7%)
Hepatitis 0/180 (0%) 8/178 (4.5%) 0/27 (0%)
Hepatitis acute 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Hepatotoxicity 3/180 (1.7%) 1/178 (0.6%) 0/27 (0%)
Hypertransaminasaemia 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Immune-mediated hepatitis 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Immune system disorders
Cytokine release syndrome 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hypersensitivity 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Sarcoidosis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Infections and infestations
Arthritis bacterial 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Bronchitis 2/180 (1.1%) 1/178 (0.6%) 0/27 (0%)
Cellulitis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Chorioretinitis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Cytomegalovirus infection 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Diverticulitis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Diverticulitis intestinal perforated 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Endocarditis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Erysipelas 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Folliculitis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Infected cyst 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Influenza 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Lymph gland infection 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Meningoencephalitis viral 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Pneumonia 5/180 (2.8%) 4/178 (2.2%) 0/27 (0%)
Pneumonia bacterial 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Pneumonia pneumococcal 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Pneumonia respiratory syncytial viral 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Pyelonephritis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Respiratory tract infection 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Sepsis 2/180 (1.1%) 3/178 (1.7%) 0/27 (0%)
Septic shock 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Spinal cord infection 3/180 (1.7%) 0/178 (0%) 0/27 (0%)
Urinary tract infection 0/180 (0%) 1/178 (0.6%) 1/27 (3.7%)
Urosepsis 0/180 (0%) 0/178 (0%) 1/27 (3.7%)
Wound infection 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Injury, poisoning and procedural complications
Fall 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hip fracture 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Infusion related reaction 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Overdose 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Rib fracture 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Investigations
Alanine aminotransferase increased 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Antibiotic level below therapeutic 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Blood bilirubin increased 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
General physical condition abnormal 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hepatic enzyme increased 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Influenza A virus test positive 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Lipase increased 3/180 (1.7%) 0/178 (0%) 0/27 (0%)
Transaminases increased 0/180 (0%) 4/178 (2.2%) 0/27 (0%)
Metabolism and nutrition disorders
Decreased appetite 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Diabetic ketoacidosis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hypercalcaemia 0/180 (0%) 2/178 (1.1%) 0/27 (0%)
Hyperglycaemia 0/180 (0%) 1/178 (0.6%) 1/27 (3.7%)
Hypokalaemia 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Hyponatraemia 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Type 1 diabetes mellitus 2/180 (1.1%) 1/178 (0.6%) 0/27 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Back pain 1/180 (0.6%) 1/178 (0.6%) 1/27 (3.7%)
Bone pain 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Fasciitis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Musculoskeletal pain 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Myalgia 0/180 (0%) 2/178 (1.1%) 0/27 (0%)
Myositis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Pain in extremity 0/180 (0%) 2/178 (1.1%) 0/27 (0%)
Rhabdomyolysis 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Intracranial tumour haemorrhage 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Malignant neoplasm progression 23/180 (12.8%) 26/178 (14.6%) 3/27 (11.1%)
Metastases to central nervous system 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Metastases to lung 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Metastatic malignant melanoma 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Squamous cell carcinoma 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Tumour haemorrhage 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Tumour pain 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Nervous system disorders
Cerebrovascular accident 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Dystonia 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Epilepsy 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Haemorrhage intracranial 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Headache 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Hyperaesthesia 0/180 (0%) 0/178 (0%) 1/27 (3.7%)
Ischaemic stroke 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Loss of consciousness 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Meningism 0/180 (0%) 0/178 (0%) 1/27 (3.7%)
Meningoradiculitis 0/180 (0%) 3/178 (1.7%) 0/27 (0%)
Migraine 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Motor dysfunction 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Paraesthesia 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Partial seizures 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Peripheral sensory neuropathy 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Sciatica 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Seizure 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Spinal cord compression 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Status epilepticus 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Psychiatric disorders
Mania 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Mental status changes 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Renal and urinary disorders
Acute kidney injury 1/180 (0.6%) 1/178 (0.6%) 2/27 (7.4%)
Autoimmune nephritis 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Chronic kidney disease 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Nephritis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Renal failure 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Reproductive system and breast disorders
Ovarian cyst 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Pelvic pain 0/180 (0%) 0/178 (0%) 1/27 (3.7%)
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Chronic obstructive pulmonary disease 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Cough 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Dyspnoea 1/180 (0.6%) 2/178 (1.1%) 0/27 (0%)
Haemothorax 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Interstitial lung disease 2/180 (1.1%) 1/178 (0.6%) 0/27 (0%)
Lower respiratory tract congestion 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Lung disorder 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Organising pneumonia 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Pleural effusion 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Pleurisy 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Pneumonitis 7/180 (3.9%) 1/178 (0.6%) 0/27 (0%)
Pneumothorax 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Pulmonary embolism 0/180 (0%) 4/178 (2.2%) 0/27 (0%)
Pulmonary mass 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Pulmonary sarcoidosis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Respiratory distress 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Skin and subcutaneous tissue disorders
Pemphigoid 1/180 (0.6%) 1/178 (0.6%) 0/27 (0%)
Rash 0/180 (0%) 0/178 (0%) 1/27 (3.7%)
Toxic skin eruption 2/180 (1.1%) 0/178 (0%) 0/27 (0%)
Urticaria 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Vascular disorders
Aortic stenosis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Deep vein thrombosis 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Peripheral artery stenosis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Peripheral embolism 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Peripheral ischaemia 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Shock haemorrhagic 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Superior vena cava syndrome 0/180 (0%) 1/178 (0.6%) 0/27 (0%)
Vasculitis 1/180 (0.6%) 0/178 (0%) 0/27 (0%)
Other (Not Including Serious) Adverse Events
Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 169/180 (93.9%) 172/178 (96.6%) 26/27 (96.3%)
Blood and lymphatic system disorders
Anaemia 20/180 (11.1%) 17/178 (9.6%) 4/27 (14.8%)
Neutropenia 3/180 (1.7%) 3/178 (1.7%) 2/27 (7.4%)
Cardiac disorders
Bradycardia 0/180 (0%) 0/178 (0%) 2/27 (7.4%)
Ear and labyrinth disorders
Tinnitus 0/180 (0%) 1/178 (0.6%) 3/27 (11.1%)
Endocrine disorders
Adrenal insufficiency 4/180 (2.2%) 12/178 (6.7%) 1/27 (3.7%)
Hyperthyroidism 20/180 (11.1%) 31/178 (17.4%) 3/27 (11.1%)
Hypophysitis 10/180 (5.6%) 12/178 (6.7%) 3/27 (11.1%)
Hypothyroidism 27/180 (15%) 41/178 (23%) 2/27 (7.4%)
Eye disorders
Vision blurred 6/180 (3.3%) 9/178 (5.1%) 1/27 (3.7%)
Gastrointestinal disorders
Abdominal distension 4/180 (2.2%) 2/178 (1.1%) 2/27 (7.4%)
Abdominal pain 36/180 (20%) 25/178 (14%) 6/27 (22.2%)
Abdominal pain upper 12/180 (6.7%) 16/178 (9%) 2/27 (7.4%)
Constipation 25/180 (13.9%) 31/178 (17.4%) 3/27 (11.1%)
Diarrhoea 66/180 (36.7%) 73/178 (41%) 11/27 (40.7%)
Dry mouth 16/180 (8.9%) 28/178 (15.7%) 3/27 (11.1%)
Nausea 41/180 (22.8%) 49/178 (27.5%) 9/27 (33.3%)
Vomiting 28/180 (15.6%) 34/178 (19.1%) 4/27 (14.8%)
General disorders
Asthenia 49/180 (27.2%) 54/178 (30.3%) 8/27 (29.6%)
Chills 12/180 (6.7%) 10/178 (5.6%) 3/27 (11.1%)
Fatigue 66/180 (36.7%) 51/178 (28.7%) 8/27 (29.6%)
Influenza like illness 14/180 (7.8%) 15/178 (8.4%) 1/27 (3.7%)
Mucosal inflammation 2/180 (1.1%) 6/178 (3.4%) 2/27 (7.4%)
Oedema peripheral 18/180 (10%) 12/178 (6.7%) 2/27 (7.4%)
Pyrexia 39/180 (21.7%) 47/178 (26.4%) 6/27 (22.2%)
Hepatobiliary disorders
Cholestasis 1/180 (0.6%) 4/178 (2.2%) 2/27 (7.4%)
Hepatic cytolysis 6/180 (3.3%) 6/178 (3.4%) 3/27 (11.1%)
Infections and infestations
Nasopharyngitis 16/180 (8.9%) 16/178 (9%) 5/27 (18.5%)
Upper respiratory tract infection 14/180 (7.8%) 8/178 (4.5%) 1/27 (3.7%)
Urinary tract infection 5/180 (2.8%) 13/178 (7.3%) 1/27 (3.7%)
Investigations
Alanine aminotransferase increased 22/180 (12.2%) 36/178 (20.2%) 6/27 (22.2%)
Amylase increased 16/180 (8.9%) 14/178 (7.9%) 4/27 (14.8%)
Aspartate aminotransferase increased 18/180 (10%) 30/178 (16.9%) 5/27 (18.5%)
Blood alkaline phosphatase increased 10/180 (5.6%) 3/178 (1.7%) 2/27 (7.4%)
Blood cholesterol increased 1/180 (0.6%) 1/178 (0.6%) 2/27 (7.4%)
Blood creatine phosphokinase increased 7/180 (3.9%) 3/178 (1.7%) 3/27 (11.1%)
Blood creatinine increased 6/180 (3.3%) 12/178 (6.7%) 2/27 (7.4%)
Blood lactate dehydrogenase increased 3/180 (1.7%) 1/178 (0.6%) 2/27 (7.4%)
Blood magnesium decreased 0/180 (0%) 0/178 (0%) 2/27 (7.4%)
Blood thyroid stimulating hormone decreased 3/180 (1.7%) 5/178 (2.8%) 2/27 (7.4%)
Blood thyroid stimulating hormone increased 5/180 (2.8%) 2/178 (1.1%) 4/27 (14.8%)
Cortisol decreased 3/180 (1.7%) 0/178 (0%) 2/27 (7.4%)
Gamma-glutamyltransferase increased 13/180 (7.2%) 8/178 (4.5%) 1/27 (3.7%)
Haemoglobin decreased 1/180 (0.6%) 1/178 (0.6%) 2/27 (7.4%)
Lipase increased 17/180 (9.4%) 20/178 (11.2%) 3/27 (11.1%)
Neutrophil count decreased 1/180 (0.6%) 2/178 (1.1%) 2/27 (7.4%)
Protein total decreased 0/180 (0%) 1/178 (0.6%) 2/27 (7.4%)
Weight decreased 25/180 (13.9%) 29/178 (16.3%) 1/27 (3.7%)
Metabolism and nutrition disorders
Decreased appetite 37/180 (20.6%) 31/178 (17.4%) 4/27 (14.8%)
Dehydration 2/180 (1.1%) 5/178 (2.8%) 2/27 (7.4%)
Hypokalaemia 15/180 (8.3%) 17/178 (9.6%) 1/27 (3.7%)
Hyponatraemia 5/180 (2.8%) 9/178 (5.1%) 0/27 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 39/180 (21.7%) 36/178 (20.2%) 6/27 (22.2%)
Back pain 14/180 (7.8%) 23/178 (12.9%) 4/27 (14.8%)
Muscle spasms 7/180 (3.9%) 10/178 (5.6%) 0/27 (0%)
Muscular weakness 4/180 (2.2%) 7/178 (3.9%) 2/27 (7.4%)
Myalgia 23/180 (12.8%) 15/178 (8.4%) 3/27 (11.1%)
Pain in extremity 15/180 (8.3%) 16/178 (9%) 5/27 (18.5%)
Nervous system disorders
Dizziness 9/180 (5%) 9/178 (5.1%) 6/27 (22.2%)
Headache 38/180 (21.1%) 51/178 (28.7%) 4/27 (14.8%)
Paraesthesia 9/180 (5%) 16/178 (9%) 1/27 (3.7%)
Psychiatric disorders
Anxiety 7/180 (3.9%) 7/178 (3.9%) 2/27 (7.4%)
Insomnia 24/180 (13.3%) 18/178 (10.1%) 0/27 (0%)
Renal and urinary disorders
Haematuria 3/180 (1.7%) 1/178 (0.6%) 2/27 (7.4%)
Reproductive system and breast disorders
Vulvovaginal pruritus 0/180 (0%) 0/178 (0%) 2/27 (7.4%)
Respiratory, thoracic and mediastinal disorders
Cough 38/180 (21.1%) 35/178 (19.7%) 6/27 (22.2%)
Dyspnoea 33/180 (18.3%) 26/178 (14.6%) 1/27 (3.7%)
Rhinitis allergic 1/180 (0.6%) 1/178 (0.6%) 3/27 (11.1%)
Skin and subcutaneous tissue disorders
Dry skin 8/180 (4.4%) 11/178 (6.2%) 0/27 (0%)
Eczema 4/180 (2.2%) 3/178 (1.7%) 4/27 (14.8%)
Erythema 7/180 (3.9%) 5/178 (2.8%) 2/27 (7.4%)
Intertrigo 3/180 (1.7%) 1/178 (0.6%) 2/27 (7.4%)
Night sweats 4/180 (2.2%) 6/178 (3.4%) 2/27 (7.4%)
Pruritus 55/180 (30.6%) 60/178 (33.7%) 13/27 (48.1%)
Rash 42/180 (23.3%) 54/178 (30.3%) 0/27 (0%)
Rash erythematous 0/180 (0%) 0/178 (0%) 2/27 (7.4%)
Rash macular 7/180 (3.9%) 8/178 (4.5%) 2/27 (7.4%)
Rash maculo-papular 10/180 (5.6%) 17/178 (9.6%) 5/27 (18.5%)
Rash papular 2/180 (1.1%) 3/178 (1.7%) 2/27 (7.4%)
Skin hypopigmentation 2/180 (1.1%) 0/178 (0%) 2/27 (7.4%)
Vitiligo 21/180 (11.7%) 16/178 (9%) 3/27 (11.1%)
Vascular disorders
Hypertension 9/180 (5%) 6/178 (3.4%) 3/27 (11.1%)
Lymphoedema 5/180 (2.8%) 2/178 (1.1%) 2/27 (7.4%)

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:
NCT02714218
Other Study ID Numbers:
  • CA209-511
First Posted:
Mar 21, 2016
Last Update Posted:
Jun 24, 2022
Last Verified:
Jun 1, 2022