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Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma (CheckMate 064)

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ClinicalTrials.gov Identifier: NCT01783938
Recruitment Status : Active, not recruiting
First Posted : February 5, 2013
Results First Posted : April 11, 2016
Last Update Posted : August 2, 2018
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Advanced or Metastatic Melanoma
Interventions Biological: Nivolumab
Biological: Ipilimumab
Enrollment 177
Recruitment Details  
Pre-assignment Details 177 enrolled, 140 randomized (70 to each arm). Reasons for non-randomization=1 adverse event, 1 withdrew consent, 32 no longer met study criteria, 3 for other non-specified reasons. 138 treated (68 nivo-ipi, 70 ipi-nivo). Reasons for non-treatment=1 adverse event unrelated to study drugs, 1 no longer met study criteria. Two cohorts of participants
Arm/Group Title Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Hide Arm/Group Description Participants received nivolumab solution at 3 milligram/kilogram (mg/kg) intravenously every 2 weeks for up to 6 doses during Weeks 1 to 13 in Induction Period 1, followed by ipilimumab solution at 3 mg/kg intravenously every 3 weeks for up to 4 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period. Participants received ipilimumab solution at 3 milligram/kilogram (mg/kg) intravenously every 3 weeks for up to 4 doses during Weeks 1 to 13 in Induction Period 1, followed by nivolumab solution at 3 mg/kg intravenously every 2 weeks for up to 6 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Period Title: Overall Study
Started 68 70
Completed 21 [1] 17 [1]
Not Completed 47 53
Reason Not Completed
Disease Progression             18             39
Study Drug Toxicity             22             10
Adverse Event Unrelated to Study Drug             2             2
Request to Discontinue Study Treatment             1             2
Withdrew Consent             3             0
Not Specified             1             0
[1]
Completed=continuing treatment; did not permanently discontinue both study drugs in treatment period
Arm/Group Title Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab Total
Hide Arm/Group Description Participants received nivolumab solution at 3 milligram/kilogram (mg/kg) intravenously every 2 weeks for up to 6 doses during Weeks 1 to 13 in Induction Period 1, followed by ipilimumab solution at 3 mg/kg intravenously every 3 weeks for up to 4 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period. Participants received ipilimumab solution at 3 milligram/kilogram (mg/kg) intravenously every 3 weeks for up to 4 doses during Weeks 1 to 13 in Induction Period 1, followed by nivolumab solution at 3 mg/kg intravenously every 2 weeks for up to 6 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period. Total of all reporting groups
Overall Number of Baseline Participants 68 70 138
Hide Baseline Analysis Population Description
All treated participants; All participants who received at least one dose of any study therapy.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 68 participants 70 participants 138 participants
59.1  (14.08) 60.6  (15.17) 59.8  (14.61)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
Categorization I, <65 years 42 40 82
Categorization I, >=65 years 26 30 56
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
Categorization II, <65 years 42 40 82
Categorization II, >=65 and <75 years 19 18 37
Categorization II, >=75 years 7 12 19
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
Female
22
  32.4%
24
  34.3%
46
  33.3%
Male
46
  67.6%
46
  65.7%
92
  66.7%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
White 65 66 131
Black or African American 1 2 3
Asian 0 0 0
American Indian or Alaska Native 0 0 0
Native Hawaiian or Other Pacific Islander 0 0 0
Other 2 2 4
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 68 participants 70 participants 138 participants
68 70 138
Subtype of Disease  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
Mucosal 5 2 7
Cutaneous 52 55 107
Acral 1 4 5
Ocular/Uveal 6 6 12
Other 4 3 7
Baseline Lactate Dehydrogenase (LDH) Level  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
Upper limit of normal (ULN) or lower 45 41 86
Higher than ULN 23 29 52
Higher than 2*ULN 9 12 21
History of Brain Metastases  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
Yes 9 2 11
No 53 60 113
Not Reported 6 8 14
B-Raf proto-oncogene (BRAF) Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
Mutant 19 20 39
Wildtype 44 43 87
Not Reported 5 7 12
Eastern Cooperative Oncology Group (ECOG) Performance Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 68 participants 70 participants 138 participants
0 47 37 84
1 21 33 54
[1]
Measure Description: ECOG is a 6-item scale used to assess disease progression, daily functioning, appropriate treatment, and prognosis. Performance status is scored on a scale ranging from 0-5, with (best score) 0=fully active and able to carry on all pre-disease performance without restriction and (worst score) 5=death.
1.Primary Outcome
Title Percentage of Participants With Treatment-related Grade 3-5 Adverse Events (AEs) During the Induction Periods
Hide Description The rate or percentage of participants with treatment-related grade 3-5 AEs is defined as the number of participants who experienced at least 1 treatment related Grade 3 - 5 adverse event (AE) per NCI CTCAE version 4.0 criteria, any preferred term with an onset date after or on first day of Induction Period #1 and not later than discontinuation date from Induction Period #2, divided by the total number of treated participants. AEs with an onset date after start date of Continuation Period or start of subsequent anti-cancer therapy were not included. Adverse Event (AE)=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may or may not have a causal relationship with treatment. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Potentially Life-threatening or disabling, Gr 5=Death.
Time Frame Day 1 up to Week 25
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All treated participants; All participants who received at least one dose of any study therapy.
Arm/Group Title Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Hide Arm/Group Description:
Participants received nivolumab solution at 3 milligram/kilogram (mg/kg) intravenously every 2 weeks for up to 6 doses during Weeks 1 to 13 in Induction Period 1, followed by ipilimumab solution at 3 mg/kg intravenously every 3 weeks for up to 4 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Participants received ipilimumab solution at 3 milligram/kilogram (mg/kg) intravenously every 3 weeks for up to 4 doses during Weeks 1 to 13 in Induction Period 1, followed by nivolumab solution at 3 mg/kg intravenously every 2 weeks for up to 6 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Overall Number of Participants Analyzed 68 70
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
50.0
(37.6 to 62.4)
42.9
(31.1 to 55.3)
2.Secondary Outcome
Title Investigator-assessed Response Rate at Week 25
Hide Description Response rate is defined as the number of participants who have a complete response (CR) or partial response (PR) at Week 25 per modified RECIST 1.1 criteria, with confirmation on the scheduled scan at Week 33 (or any subsequent scan performed at least 4 weeks after the Week 25 scan), divided by the total number of treated participants. Results of the tumor assessment at Week 13 or any unscheduled tumor assessment obtained prior to Week 25, except for baseline/screening tumor assessment, were not considered in the assessment of response rate at Week 25. Any treated participant without an evaluable Week 25 time point response (per modified RECIST 1.1) was considered a non-responder for primary analysis of response rate at Week 25. Evaluations occurring after the dates of subsequent anticancer therapy were not included when determining or confirming response at Week 25. Confidence interval based on the Clopper and Pearson method.
Time Frame Week 25
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All treated participants; All participants who received at least one dose of any study therapy.
Arm/Group Title Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Hide Arm/Group Description:
Participants received nivolumab solution at 3 milligram/kilogram (mg/kg) intravenously every 2 weeks for up to 6 doses during Weeks 1 to 13 in Induction Period 1, followed by ipilimumab solution at 3 mg/kg intravenously every 3 weeks for up to 4 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Participants received ipilimumab solution at 3 milligram/kilogram (mg/kg) intravenously every 3 weeks for up to 4 doses during Weeks 1 to 13 in Induction Period 1, followed by nivolumab solution at 3 mg/kg intravenously every 2 weeks for up to 6 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Overall Number of Participants Analyzed 68 70
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
41.2
(29.4 to 53.8)
20.0
(11.4 to 31.3)
3.Secondary Outcome
Title Investigator-assessed Duration of Response (DOR)
Hide Description Duration of response (DOR) was performed to further characterize the response rate at Week 25. Duration of response is defined as the time between the Week 25 date of response and the date of objectively documented disease progression as defined by modified RECIST 1.1 criteria or death, whichever occurs first. DOR was assessed for participants with confirmed response at Week 25. Median computed using Kaplan-Meier product-limit method.
Time Frame Week 25 up to date of disease progression or death, up to approximately 2 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All treated participants with confirmed response at week 25; Participants were censored at their last assessment date if response was not changed.
Arm/Group Title Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Hide Arm/Group Description:
Participants received nivolumab solution at 3 milligram/kilogram (mg/kg) intravenously every 2 weeks for up to 6 doses during Weeks 1 to 13 in Induction Period 1, followed by ipilimumab solution at 3 mg/kg intravenously every 3 weeks for up to 4 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Participants received ipilimumab solution at 3 milligram/kilogram (mg/kg) intravenously every 3 weeks for up to 4 doses during Weeks 1 to 13 in Induction Period 1, followed by nivolumab solution at 3 mg/kg intravenously every 2 weeks for up to 6 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Overall Number of Participants Analyzed 28 14
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(14.49 to NA)
NA [1] 
(13.67 to NA)
[1]
N.A.: Not applicable: Median not yet reached, too few events to evaluate
4.Secondary Outcome
Title Investigator-assessed Rate of Progression
Hide Description The progression rate at a specific timepoint is defined as the number of participants who have Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at that specific timepoint divided by the total number of randomized participants. As specified by modified RECIST 1.1, the evaluation of PD at Week 13 and Week 25 used the baseline tumor assessment as reference. For purposes of the primary analysis of progression rates, if a treated participant were missing his/her tumor assessment at the specified study week, then the results of the previous tumor response evaluation were to be carried forward. Both clinical and radiological progressions were counted as a progression outcome. A participant who died without a reported prior progression was considered to have progressed on the date of his/her death. Deaths before or at Week 13 are counted as progression outcome. Confidence interval based on the Clopper and Pearson method.
Time Frame Week 13; Week 25
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All treated participants; All participants who received at least one dose of any study therapy.
Arm/Group Title Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Hide Arm/Group Description:
Participants received nivolumab solution at 3 milligram/kilogram (mg/kg) intravenously every 2 weeks for up to 6 doses during Weeks 1 to 13 in Induction Period 1, followed by ipilimumab solution at 3 mg/kg intravenously every 3 weeks for up to 4 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Participants received ipilimumab solution at 3 milligram/kilogram (mg/kg) intravenously every 3 weeks for up to 4 doses during Weeks 1 to 13 in Induction Period 1, followed by nivolumab solution at 3 mg/kg intravenously every 2 weeks for up to 6 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
Overall Number of Participants Analyzed 68 70
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Week 13
38.2
(26.7 to 50.8)
61.4
(49.0 to 72.8)
Week 25
38.2
(26.7 to 50.8)
60.0
(47.6 to 71.5)
Time Frame Day 1 to 30 days post last dose, up to April 2015 (approximately 2 years)
Adverse Event Reporting Description Study initiated: April 2013; Primary Endpoint Study Completion: April 2015; Study on-going
 
Arm/Group Title Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Hide Arm/Group Description Participants received nivolumab solution at 3 milligram/kilogram (mg/kg) intravenously every 2 weeks for up to 6 doses during Weeks 1 to 13 in Induction Period 1, followed by ipilimumab solution at 3 mg/kg intravenously every 3 weeks for up to 4 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period. Participants received ipilimumab solution at 3 milligram/kilogram (mg/kg) intravenously every 3 weeks for up to 4 doses during Weeks 1 to 13 in Induction Period 1, followed by nivolumab solution at 3 mg/kg intravenously every 2 weeks for up to 6 doses during Weeks 13 to 25 in Induction Period 2. Per protocol, a participant was allowed to permanently discontinue one agent and then receive the other agent. Participants received nivolumab solution at 3 mg/kg intravenously every 2 weeks, starting at week 25 in the continuation period, for a maximum of 2 years from 1st study treatment in Induction Period 1. At end of 2 years, participants who had investigator-assessed benefit and were tolerating therapy were allowed to continue nivolumab therapy in the Extension Period. Regimen followed until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment Period includes induction period 1, 2, continuation, and extension period.
All-Cause Mortality
Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Affected / at Risk (%) Affected / at Risk (%)
Total   51/68 (75.00%)   51/70 (72.86%) 
Blood and lymphatic system disorders     
Leukocytosis  1  1/68 (1.47%)  0/70 (0.00%) 
Anaemia  1  1/68 (1.47%)  3/70 (4.29%) 
Cardiac disorders     
Pericardial effusion  1  0/68 (0.00%)  1/70 (1.43%) 
Supraventricular tachycardia  1  0/68 (0.00%)  1/70 (1.43%) 
Atrial fibrillation  1  2/68 (2.94%)  0/70 (0.00%) 
Myocardial infarction  1  0/68 (0.00%)  1/70 (1.43%) 
Cardiac failure  1  1/68 (1.47%)  1/70 (1.43%) 
Cardiac failure congestive  1  1/68 (1.47%)  0/70 (0.00%) 
Acute coronary syndrome  1  1/68 (1.47%)  0/70 (0.00%) 
Angina pectoris  1  1/68 (1.47%)  0/70 (0.00%) 
Ear and labyrinth disorders     
Hearing impaired  1  1/68 (1.47%)  0/70 (0.00%) 
Endocrine disorders     
Adrenal insufficiency  1  4/68 (5.88%)  0/70 (0.00%) 
Hypophysitis  1  1/68 (1.47%)  2/70 (2.86%) 
Addison's disease  1  1/68 (1.47%)  0/70 (0.00%) 
Inappropriate antidiuretic hormone secretion  1  1/68 (1.47%)  0/70 (0.00%) 
Eye disorders     
Macular oedema  1  0/68 (0.00%)  1/70 (1.43%) 
Gastrointestinal disorders     
Enterocolitis  1  0/68 (0.00%)  1/70 (1.43%) 
Stomatitis  1  0/68 (0.00%)  1/70 (1.43%) 
Enteritis  1  0/68 (0.00%)  1/70 (1.43%) 
Gastritis  1  2/68 (2.94%)  0/70 (0.00%) 
Pancreatitis acute  1  0/68 (0.00%)  2/70 (2.86%) 
Autoimmune colitis  1  0/68 (0.00%)  1/70 (1.43%) 
Diarrhoea  1  6/68 (8.82%)  4/70 (5.71%) 
Diarrhoea haemorrhagic  1  0/68 (0.00%)  1/70 (1.43%) 
Abdominal pain  1  3/68 (4.41%)  3/70 (4.29%) 
Gastrointestinal haemorrhage  1  0/68 (0.00%)  1/70 (1.43%) 
Crohn's disease  1  1/68 (1.47%)  0/70 (0.00%) 
Nausea  1  3/68 (4.41%)  1/70 (1.43%) 
Vomiting  1  3/68 (4.41%)  1/70 (1.43%) 
Colitis  1  9/68 (13.24%)  14/70 (20.00%) 
General disorders     
Asthenia  1  1/68 (1.47%)  3/70 (4.29%) 
Fatigue  1  1/68 (1.47%)  9/70 (12.86%) 
Gait disturbance  1  0/68 (0.00%)  1/70 (1.43%) 
Malaise  1  0/68 (0.00%)  1/70 (1.43%) 
Pain  1  0/68 (0.00%)  2/70 (2.86%) 
Systemic inflammatory response syndrome  1  1/68 (1.47%)  0/70 (0.00%) 
Oedema peripheral  1  1/68 (1.47%)  0/70 (0.00%) 
Pyrexia  1  4/68 (5.88%)  4/70 (5.71%) 
Hepatobiliary disorders     
Hepatitis  1  3/68 (4.41%)  0/70 (0.00%) 
Hyperbilirubinaemia  1  0/68 (0.00%)  1/70 (1.43%) 
Hepatic failure  1  1/68 (1.47%)  0/70 (0.00%) 
Cholecystitis  1  0/68 (0.00%)  1/70 (1.43%) 
Immune system disorders     
Autoimmune disorder  1  1/68 (1.47%)  0/70 (0.00%) 
Infections and infestations     
Sinusitis  1  1/68 (1.47%)  0/70 (0.00%) 
Wound infection  1  2/68 (2.94%)  0/70 (0.00%) 
Appendicitis  1  1/68 (1.47%)  1/70 (1.43%) 
Cellulitis  1  0/68 (0.00%)  1/70 (1.43%) 
Clostridium difficile colitis  1  0/68 (0.00%)  1/70 (1.43%) 
Mucosal infection  1  0/68 (0.00%)  1/70 (1.43%) 
Bacterial infection  1  1/68 (1.47%)  0/70 (0.00%) 
Diverticulitis  1  1/68 (1.47%)  0/70 (0.00%) 
Encephalitis  1  1/68 (1.47%)  0/70 (0.00%) 
Influenza  1  1/68 (1.47%)  0/70 (0.00%) 
Clostridium difficile infection  1  0/68 (0.00%)  1/70 (1.43%) 
Lung infection  1  2/68 (2.94%)  3/70 (4.29%) 
Pneumonia  1  1/68 (1.47%)  0/70 (0.00%) 
Urinary tract infection  1  0/68 (0.00%)  4/70 (5.71%) 
Infected cyst  1  0/68 (0.00%)  1/70 (1.43%) 
Pneumocystis jirovecii pneumonia  1  1/68 (1.47%)  0/70 (0.00%) 
Injury, poisoning and procedural complications     
Spinal fracture  1  0/68 (0.00%)  1/70 (1.43%) 
Cervical vertebral fracture  1  0/68 (0.00%)  1/70 (1.43%) 
Investigations     
International normalised ratio increased  1  0/68 (0.00%)  1/70 (1.43%) 
Lipase increased  1  1/68 (1.47%)  0/70 (0.00%) 
Aspartate aminotransferase increased  1  1/68 (1.47%)  2/70 (2.86%) 
Alanine aminotransferase increased  1  1/68 (1.47%)  2/70 (2.86%) 
Hepatic enzyme increased  1  1/68 (1.47%)  0/70 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  2/68 (2.94%)  5/70 (7.14%) 
Hyperglycaemia  1  1/68 (1.47%)  1/70 (1.43%) 
Polydipsia  1  0/68 (0.00%)  1/70 (1.43%) 
Decreased appetite  1  0/68 (0.00%)  1/70 (1.43%) 
Hypokalaemia  1  0/68 (0.00%)  2/70 (2.86%) 
Metabolic acidosis  1  0/68 (0.00%)  1/70 (1.43%) 
Hyponatraemia  1  1/68 (1.47%)  1/70 (1.43%) 
Musculoskeletal and connective tissue disorders     
Pain in extremity  1  1/68 (1.47%)  0/70 (0.00%) 
Back pain  1  2/68 (2.94%)  0/70 (0.00%) 
Groin pain  1  1/68 (1.47%)  0/70 (0.00%) 
Musculoskeletal pain  1  0/68 (0.00%)  1/70 (1.43%) 
Arthralgia  1  2/68 (2.94%)  0/70 (0.00%) 
Bone pain  1  0/68 (0.00%)  1/70 (1.43%) 
Muscular weakness  1  0/68 (0.00%)  1/70 (1.43%) 
Musculoskeletal chest pain  1  0/68 (0.00%)  1/70 (1.43%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant neoplasm progression  1  2/68 (2.94%)  7/70 (10.00%) 
Metastatic pain  1  0/68 (0.00%)  1/70 (1.43%) 
Tumour haemorrhage  1  1/68 (1.47%)  0/70 (0.00%) 
Metastases to central nervous system  1  1/68 (1.47%)  1/70 (1.43%) 
Nervous system disorders     
Demyelinating polyneuropathy  1  1/68 (1.47%)  0/70 (0.00%) 
Meningitis noninfective  1  1/68 (1.47%)  0/70 (0.00%) 
Ataxia  1  0/68 (0.00%)  1/70 (1.43%) 
Brain oedema  1  1/68 (1.47%)  0/70 (0.00%) 
Haemorrhage intracranial  1  0/68 (0.00%)  1/70 (1.43%) 
Myasthenia gravis  1  1/68 (1.47%)  0/70 (0.00%) 
Headache  1  2/68 (2.94%)  1/70 (1.43%) 
Syncope  1  1/68 (1.47%)  0/70 (0.00%) 
Vasogenic cerebral oedema  1  0/68 (0.00%)  1/70 (1.43%) 
Psychiatric disorders     
Mental status changes  1  0/68 (0.00%)  1/70 (1.43%) 
Renal and urinary disorders     
Acute kidney injury  1  2/68 (2.94%)  2/70 (2.86%) 
Renal failure  1  1/68 (1.47%)  1/70 (1.43%) 
Respiratory, thoracic and mediastinal disorders     
Pleural effusion  1  0/68 (0.00%)  2/70 (2.86%) 
Pneumonitis  1  3/68 (4.41%)  0/70 (0.00%) 
Respiratory failure  1  1/68 (1.47%)  1/70 (1.43%) 
Pulmonary embolism  1  1/68 (1.47%)  1/70 (1.43%) 
Chronic obstructive pulmonary disease  1  1/68 (1.47%)  0/70 (0.00%) 
Dyspnoea  1  1/68 (1.47%)  2/70 (2.86%) 
Skin and subcutaneous tissue disorders     
Rash maculo-papular  1  0/68 (0.00%)  1/70 (1.43%) 
Rash  1  0/68 (0.00%)  2/70 (2.86%) 
Pain of skin  1  0/68 (0.00%)  1/70 (1.43%) 
Vascular disorders     
Jugular vein thrombosis  1  1/68 (1.47%)  0/70 (0.00%) 
Embolism  1  0/68 (0.00%)  2/70 (2.86%) 
Hypotension  1  2/68 (2.94%)  1/70 (1.43%) 
Thrombosis  1  0/68 (0.00%)  1/70 (1.43%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Nivolumab Followed by Ipilimumab Ipilimumab Followed by Nivolumab
Affected / at Risk (%) Affected / at Risk (%)
Total   68/68 (100.00%)   67/70 (95.71%) 
Blood and lymphatic system disorders     
Anaemia  1  19/68 (27.94%)  22/70 (31.43%) 
Endocrine disorders     
Adrenal insufficiency  1  4/68 (5.88%)  3/70 (4.29%) 
Hypothyroidism  1  16/68 (23.53%)  16/70 (22.86%) 
Hypophysitis  1  5/68 (7.35%)  3/70 (4.29%) 
Eye disorders     
Photophobia  1  4/68 (5.88%)  1/70 (1.43%) 
Vision blurred  1  9/68 (13.24%)  9/70 (12.86%) 
Dry eye  1  2/68 (2.94%)  5/70 (7.14%) 
Gastrointestinal disorders     
Dry mouth  1  8/68 (11.76%)  6/70 (8.57%) 
Abdominal pain upper  1  4/68 (5.88%)  6/70 (8.57%) 
Constipation  1  23/68 (33.82%)  27/70 (38.57%) 
Abdominal distension  1  6/68 (8.82%)  6/70 (8.57%) 
Diarrhoea  1  40/68 (58.82%)  33/70 (47.14%) 
Abdominal pain  1  15/68 (22.06%)  20/70 (28.57%) 
Flatulence  1  2/68 (2.94%)  4/70 (5.71%) 
Nausea  1  39/68 (57.35%)  36/70 (51.43%) 
Vomiting  1  20/68 (29.41%)  27/70 (38.57%) 
Colitis  1  6/68 (8.82%)  8/70 (11.43%) 
General disorders     
Asthenia  1  6/68 (8.82%)  6/70 (8.57%) 
Fatigue  1  53/68 (77.94%)  57/70 (81.43%) 
Malaise  1  3/68 (4.41%)  5/70 (7.14%) 
Pain  1  5/68 (7.35%)  7/70 (10.00%) 
Non-cardiac chest pain  1  3/68 (4.41%)  5/70 (7.14%) 
ADVERSE EVENT  1  4/68 (5.88%)  0/70 (0.00%) 
Oedema peripheral  1  13/68 (19.12%)  12/70 (17.14%) 
Influenza like illness  1  10/68 (14.71%)  2/70 (2.86%) 
Pyrexia  1  27/68 (39.71%)  18/70 (25.71%) 
Chills  1  18/68 (26.47%)  13/70 (18.57%) 
Infections and infestations     
Sinusitis  1  4/68 (5.88%)  3/70 (4.29%) 
Upper respiratory tract infection  1  11/68 (16.18%)  7/70 (10.00%) 
Nasopharyngitis  1  6/68 (8.82%)  5/70 (7.14%) 
Skin infection  1  5/68 (7.35%)  2/70 (2.86%) 
Urinary tract infection  1  6/68 (8.82%)  7/70 (10.00%) 
Injury, poisoning and procedural complications     
Infusion related reaction  1  5/68 (7.35%)  4/70 (5.71%) 
Fall  1  4/68 (5.88%)  2/70 (2.86%) 
Investigations     
Platelet count decreased  1  6/68 (8.82%)  3/70 (4.29%) 
Weight decreased  1  12/68 (17.65%)  20/70 (28.57%) 
Blood bilirubin increased  1  8/68 (11.76%)  1/70 (1.43%) 
Lipase increased  1  26/68 (38.24%)  22/70 (31.43%) 
Aspartate aminotransferase increased  1  28/68 (41.18%)  17/70 (24.29%) 
Alanine aminotransferase increased  1  29/68 (42.65%)  21/70 (30.00%) 
Blood creatinine increased  1  2/68 (2.94%)  8/70 (11.43%) 
Lymphocyte count decreased  1  7/68 (10.29%)  5/70 (7.14%) 
Blood alkaline phosphatase increased  1  15/68 (22.06%)  12/70 (17.14%) 
Amylase increased  1  17/68 (25.00%)  13/70 (18.57%) 
Blood thyroid stimulating hormone increased  1  4/68 (5.88%)  5/70 (7.14%) 
White blood cell count decreased  1  4/68 (5.88%)  1/70 (1.43%) 
Metabolism and nutrition disorders     
Dehydration  1  15/68 (22.06%)  15/70 (21.43%) 
Hypoalbuminaemia  1  6/68 (8.82%)  5/70 (7.14%) 
Hyperglycaemia  1  15/68 (22.06%)  6/70 (8.57%) 
Decreased appetite  1  31/68 (45.59%)  29/70 (41.43%) 
Hypokalaemia  1  8/68 (11.76%)  14/70 (20.00%) 
Hypoglycaemia  1  4/68 (5.88%)  0/70 (0.00%) 
Hypocalcaemia  1  6/68 (8.82%)  3/70 (4.29%) 
Hypermagnesaemia  1  5/68 (7.35%)  3/70 (4.29%) 
Hyperkalaemia  1  8/68 (11.76%)  7/70 (10.00%) 
Hypercalcaemia  1  4/68 (5.88%)  7/70 (10.00%) 
Hypomagnesaemia  1  7/68 (10.29%)  5/70 (7.14%) 
Hyponatraemia  1  20/68 (29.41%)  19/70 (27.14%) 
Musculoskeletal and connective tissue disorders     
Pain in extremity  1  12/68 (17.65%)  5/70 (7.14%) 
Back pain  1  16/68 (23.53%)  13/70 (18.57%) 
Muscle spasms  1  4/68 (5.88%)  0/70 (0.00%) 
Neck pain  1  5/68 (7.35%)  4/70 (5.71%) 
Musculoskeletal pain  1  10/68 (14.71%)  2/70 (2.86%) 
Myalgia  1  13/68 (19.12%)  4/70 (5.71%) 
Arthralgia  1  28/68 (41.18%)  18/70 (25.71%) 
Arthritis  1  4/68 (5.88%)  0/70 (0.00%) 
Muscular weakness  1  16/68 (23.53%)  13/70 (18.57%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Tumour pain  1  4/68 (5.88%)  2/70 (2.86%) 
Nervous system disorders     
Paraesthesia  1  7/68 (10.29%)  3/70 (4.29%) 
Dizziness  1  12/68 (17.65%)  5/70 (7.14%) 
Sinus headache  1  5/68 (7.35%)  1/70 (1.43%) 
Dysgeusia  1  7/68 (10.29%)  5/70 (7.14%) 
Headache  1  29/68 (42.65%)  14/70 (20.00%) 
Psychiatric disorders     
Anxiety  1  9/68 (13.24%)  8/70 (11.43%) 
Insomnia  1  18/68 (26.47%)  12/70 (17.14%) 
Depression  1  7/68 (10.29%)  3/70 (4.29%) 
Confusional state  1  4/68 (5.88%)  2/70 (2.86%) 
Renal and urinary disorders     
Nocturia  1  0/68 (0.00%)  4/70 (5.71%) 
Urinary tract pain  1  4/68 (5.88%)  0/70 (0.00%) 
Haematuria  1  6/68 (8.82%)  3/70 (4.29%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  27/68 (39.71%)  26/70 (37.14%) 
Productive cough  1  8/68 (11.76%)  8/70 (11.43%) 
Nasal congestion  1  7/68 (10.29%)  4/70 (5.71%) 
Sinus congestion  1  1/68 (1.47%)  4/70 (5.71%) 
Dysphonia  1  5/68 (7.35%)  2/70 (2.86%) 
Oropharyngeal pain  1  6/68 (8.82%)  3/70 (4.29%) 
Pneumonitis  1  4/68 (5.88%)  2/70 (2.86%) 
Rhinorrhoea  1  4/68 (5.88%)  1/70 (1.43%) 
Dyspnoea  1  14/68 (20.59%)  13/70 (18.57%) 
Upper-airway cough syndrome  1  6/68 (8.82%)  6/70 (8.57%) 
Skin and subcutaneous tissue disorders     
Dermatitis acneiform  1  6/68 (8.82%)  1/70 (1.43%) 
Dry skin  1  7/68 (10.29%)  7/70 (10.00%) 
Vitiligo  1  11/68 (16.18%)  12/70 (17.14%) 
Rash maculo-papular  1  15/68 (22.06%)  10/70 (14.29%) 
Alopecia  1  4/68 (5.88%)  2/70 (2.86%) 
Hyperhidrosis  1  5/68 (7.35%)  4/70 (5.71%) 
Rash  1  30/68 (44.12%)  25/70 (35.71%) 
Rash pruritic  1  1/68 (1.47%)  7/70 (10.00%) 
Night sweats  1  4/68 (5.88%)  4/70 (5.71%) 
Pruritus  1  31/68 (45.59%)  32/70 (45.71%) 
Vascular disorders     
Hypertension  1  6/68 (8.82%)  2/70 (2.86%) 
Hypotension  1  4/68 (5.88%)  5/70 (7.14%) 
Hot flush  1  2/68 (2.94%)  4/70 (5.71%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01783938     History of Changes
Other Study ID Numbers: CA209-064
First Submitted: February 1, 2013
First Posted: February 5, 2013
Results First Submitted: March 11, 2016
Results First Posted: April 11, 2016
Last Update Posted: August 2, 2018