CheckMate204: An Investigational Immuno-therapy Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain, Treated With Nivolumab in Combination With Ipilimumab, Followed by Nivolumab by Itself

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02320058
• Collaborator: (none)
• Enrollment: 119
• Locations: 36
• Arm: 1
• Actual Duration (Months): 66.2
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a study of Nivolumab combined with Ipilimumab followed by Nivolumab by itself for the treatment of patients with Melanoma that has spread to the brain. Patients with histologically confirmed Malignant Melanoma and asymptomatic brain metastases are eligible for the study.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Ipilimumab; Drug: Nivolumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 119 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center Phase 2 Open-Label Study to Evaluate Safety and Efficacy in Subjects With Melanoma Metastatic to the Brain Treated With Nivolumab in Combination With Ipilimumab Followed by Nivolumab Monotherapy
• Actual Study Start Date: Mar 5, 2015
• Actual Primary Completion Date: Sep 8, 2020
• Actual Study Completion Date: Sep 8, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nivolumab and Ipilimumab Induction Phase: Nivolumab + Ipilimumab infusion intravenously Maintenance Phase: Nivolumab infusion intravenously	Drug: Ipilimumab; Other Names: Yervoy ; Drug: Nivolumab; Other Names: Opdivo BMS-936558

Outcome Measures

Primary Outcome Measures

1. Intracranial Clinical Benefit Rate (CBR) [Up to 66 months]

   Intracranial Clinical Benefit Rate (CBR) is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months, as determined by modified RECIST 1.1 criteria for index intracranial lesions based on investigator review.

Secondary Outcome Measures

1. Intracranial Objective Response Rate (ORR) [Up to 66 months]

   Investigator-Assessed Intracranial Objective Response Rate (ORR) per modified RECIST 1.1 criteria is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants.

2. Intracranial Progression Free Survival (PFS) [Up to 66 months]

   Intracranial progression-free survival (PFS) per modified RECIST 1.1 criteria is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. 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.

3. Extracranial Clinical Benefit Rate (CBR) [Up to 66 months]

   Extracranial Clinical Benefit Rate (CBR) is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months, as determined by RECIST 1.1 criteria for index extracranial lesions based on investigator review.

4. Extracranial Objective Response Rate (ORR) [Up to 66 months]

   Extracranial Objective Response Rate (ORR) per RECIST 1.1 criteria is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants.

5. Extracranial Progression Free Survival (PFS) [Up to 66 months]

   Extracranial progression-free survival (PFS) per RECIST 1.1 criteria is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. 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.

6. Global Clinical Benefit Rate (CBR) [Up to 66 months]

   Investigator-assessed global (intracranial + extracranial) clinical benefit rate (CBR) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months

7. Global Objective Response Rate (ORR) [Up to 66 months]

   Investigator-assessed global objective response rate (ORR) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants.

8. Global Progression Free Survival (PFS) [Up to 66 months]

   Investigator-assessed global progression free survival (PFS) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. 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.

9. Overall Survival (OS) [Up to 66 months]

   Overall Survival (OS) is defined as the time from the date of the start of treatment until the date of death. For participants who have not died, OS will be censored at the recorded last date of participant contact, and participants with a missing recorded last date of contact will be censored at the last date the participant was known to be alive.

10. Number of Participants With Adverse Events (AEs) [From first dose to 30 days post last dose (Up to 66 months)]

    Number of participants with any grade of adverse events (AEs) and any grade of serious adverse events (SAEs) graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v4.0)

11. Number of Participants Deaths [Up to 66 months]

    Number of participants who died due to any cause.

12. Number of Participants With Laboratory Abnormalities in Specific Liver Tests [From first dose to 30 days post last dose (Up to 66 months)]

    Number of participants with laboratory abnormalities in specific liver tests based on US conventional units to determine the safety and tolerability of Nivolumab and Daratumumab. The number of participants with the following laboratory abnormalities from on-treatment evaluations will be summarized: ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN Total bilirubin > 2 x ULN Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN

13. Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests [From first dose to 30 days post last dose (Up to 66 months)]

    Number of participants with laboratory abnormalities in specific thyroid tests based on US conventional units to determine the safety and tolerability of Nivolumab and Daratumumab. The number of subjects with the following laboratory abnormalities from on-treatment evaluations will be summarized: TSH value > ULN and with baseline TSH value <= ULN with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH test with all FT3/FT4 test values >= LLN within 2-week window after the abnormal TSH test with FT3/FT4 missing within 2-week window after the abnormal TSH test. TSH < LLN and with baseline TSH value >= LLN with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal TSH test with all FT3/FT4 test values <= ULN within 2-week window after the abnormal TSH test with FT3/FT4 missing within 2-week window after the abnormal TSH test

Eligibility Criteria

Criteria

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

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

Inclusion Criteria:

1. Target Population

2. Histologically confirmed malignant melanoma with measurable metastases in the brain. Both asymptomatic and symptomatic patients.

3. Cohort A (asymptomatic patients): At least 1 measurable brain metastasis ≥ 0.5 cm in and ≤ 3 cm in longest diameter that has not been previously irradiated. No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy

Cohort B (symptomatic patients): Subjects with neurologic signs and symptoms related to metastatic brain lesions are eligibile. Subjects must have at least 1 measurable brain metastasis ≥ 0.5 cm in and ≤ 3 cm in longest diameter that has not been previously irradiated. No immediate requirement (within 3 weeks prior to first treatment) for local intervention (surgery, radiosurgery, corticosteroid therapy). Steroid use is permitted as defined in the protocol.

1. Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain metastases is permitted if there has been complete recovery, with no neurologic sequelae, and measurable lesions remain. Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable. lesions or prior excision must have occurred ≥ 3 weeks before the start of dosing for this study

2. Must have tumor tissue available for biomarker analysis. Biopsy should be excisional, incisional, punch, or core needle

3. Cohort A (asymptomatic): Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy within 10 days prior to first treatment.

Cohort B (symptomatic): Subjects with neurologic signs and symptoms related to metastatic brain lesions are eligible per Amendment 02. Subjects with neurologic signs and symptoms may be treated with a total daily dose of no more than 4 mg of dexamethasone that is stable or tapering for 10 days prior to first treatment. Subjects with neurologic signs and symptoms who are not being treated with steroids are eligible for Cohort B and should have no experience of seizure within 10 days prior to first treatment.

1. Allowable prior therapy:

2. Approved adjuvant therapies, which may include molecularly-targeted agents, IFN α, and ipilimumab. Patients who received ipilimumab as adjuvant therapy must have a 6 month washout before receiving any dosing on this study

3. For advanced disease, interleukin-2 at any dose and/or IFN-α (any formulation, no washout required); MEK and BRAF inhibitors: washout for at least 4 weeks prior to the start of dosing in this study

4. Steroids for physiological replacement are allowed.

5. Cohort A (asymptomatic): ECOG performance status ≤1 Cohort B (symptomatic): ECOG performance status ≤2

Exclusion Criteria:

1. Target Disease Exceptions

2. History of known leptomeningeal involvement (lumbar puncture not required)

3. Previous stereotactic or highly conformal radiotherapy within 3 weeks before the start of dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion(s)

4. Brain lesions >3 lesions which were previously treated with SRT

5. Brain lesion size > 3cm 3. Medical History and Concurrent Diseases

1. History of whole brain irradiation b) Subjects with an active, known or suspected autoimmune disease c) Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled d) Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. For any prior invasive malignancy, at least 5 years must have elapsed since curative therapy and patients must have no residual sequelae of prior therapy e) Cohort A (asymptomatic): The use of corticosteroids is not allowed within 10 days prior to first treatment (based upon 5 times the expected half life of dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has been used, consultation with the sponsor Medical Monitor is required to determine the washout period prior to initiating study treatment Cohort B (symptomatic): Subjects with neurologic sign and symptoms related to brain metastases who are being treated with a total daily dose of higher than 4 mg dexamethasone or equivalent within 10 prior to the start of treatment with study drug are excluded.

1. Physical and Laboratory Test Findings

2. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection

3. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART-due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV

4. Allergies and Adverse Drug Reaction

1. History of allergy to study drug components b) History of severe hypersensitivity reaction to any monoclonal antibody

1. Other Exclusion Criteria

2. Prisoners or subjects who are involuntarily incarcerated

3. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria

Other protocol defined inclusion/exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Angeles Clinic and Research Institute	Los Angeles	California	United States	90025
3	UCLA Medical Hematology and Oncology	Los Angeles	California	United States	90095
4	Stanford University	Palo Alto	California	United States	94304
5	The California Pacific Medical Research Institute	San Francisco	California	United States	94115
6	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94158
7	University of Colorado - Cancer Center - PPDS	Aurora	Colorado	United States	80045
8	Washington Cancer Inst at MedStar Washington Hospital Ctr	Washington	District of Columbia	United States	20007
9	Weinberg Cancer Institute At Franklin Square	Washington	District of Columbia	United States	20007
10	Georgetown University Medical Center	Washington	District of Columbia	United States	20057
11	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
12	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
13	The Cleveland Clinic Foundation	Weston	Florida	United States	33331
14	Winship Cancer Institute, Emory University	Atlanta	Georgia	United States	30322-1013
15	University of Chicago	Chicago	Illinois	United States	60637
16	Loyola University Medical Center	Maywood	Illinois	United States	60153
17	Dana Farber Cancer Institute.	Boston	Massachusetts	United States	02215
18	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
19	Massachusetts General Hospital	Boston	Massachusetts	United States	02215
20	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
21	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
22	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
23	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
24	NYU Langone Medical Center	New York	New York	United States	10016
25	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
26	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
27	Duke University Medical Center	Durham	North Carolina	United States	27710
28	Case School of Medicine University Hospitals of Cleveland	Cleveland	Ohio	United States	44106-5055
29	Lehigh Valley Health Network	Allentown	Pennsylvania	United States	18105
30	St Luke's Health Network	Easton	Pennsylvania	United States	18045
31	Abramson Cancer Center of The University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
32	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
33	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
34	MD Anderson Cancer Center	Houston	Texas	United States	77030
35	University of Utah - Huntsman Cancer Institute - PPDS	Salt Lake City	Utah	United States	84112
36	Inova Melanoma and Skin Cancer Center	Fairfax	Virginia	United States	55905

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Nov 13, 2017
• Statistical Analysis Plan - Dec 3, 2020

More Information

Additional Information:

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02320058
• Other Study ID Numbers: CA209-204
• First Posted: Dec 19, 2014
• Last Update Posted: Oct 5, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Melanoma; Nivolumab; Ipilimumab

Study Results

Participant Flow

Pre-assignment Detail	119 participants treated

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Period Title: Overall Study
STARTED	101	18
COMPLETED	59	5
NOT COMPLETED	42	13

Baseline Characteristics

Arm/Group Title	Cohort A	Cohort B	Total
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Total of all reporting groups
Overall Participants	101	18	119
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.0 (12.29)	58.2 (13.24)	58.0 (12.38)
Sex: Female, Male (Count of Participants)
Female	33 32.7%	5 27.8%	38 31.9%
Male	68 67.3%	13 72.2%	81 68.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2%	3 16.7%	5 4.2%
Not Hispanic or Latino	99 98%	15 83.3%	114 95.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Number) [Number]
White	99 98%	17 94.4%	116 97.5%
Black or African American	0 0%	0 0%	0 0%
Asian	1 1%	0 0%	1 0.8%
American Indian or Alaska Native	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Other	1 1%	1 5.6%	2 1.7%

Outcome Measures

1. Primary Outcome

Title	Intracranial Clinical Benefit Rate (CBR)
Description	Intracranial Clinical Benefit Rate (CBR) is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months, as determined by modified RECIST 1.1 criteria for index intracranial lesions based on investigator review.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Number (95% Confidence Interval) [Percentage of Participants]	57.4 56.8%	16.7 92.8%

2. Secondary Outcome

Title	Intracranial Objective Response Rate (ORR)
Description	Investigator-Assessed Intracranial Objective Response Rate (ORR) per modified RECIST 1.1 criteria is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Number (95% Confidence Interval) [Percentage of Participants]	53.5 53%	16.7 92.8%

3. Secondary Outcome

Title	Intracranial Progression Free Survival (PFS)
Description	Intracranial progression-free survival (PFS) per modified RECIST 1.1 criteria is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. 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.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Median (95% Confidence Interval) [Months]	NA	1.18

4. Secondary Outcome

Title	Extracranial Clinical Benefit Rate (CBR)
Description	Extracranial Clinical Benefit Rate (CBR) is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months, as determined by RECIST 1.1 criteria for index extracranial lesions based on investigator review.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Number (95% Confidence Interval) [Percentage of Participants]	53.5 53%	22.2 123.3%

5. Secondary Outcome

Title	Extracranial Objective Response Rate (ORR)
Description	Extracranial Objective Response Rate (ORR) per RECIST 1.1 criteria is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Number (95% Confidence Interval) [Percentage of Participants]	48.5 48%	22.2 123.3%

6. Secondary Outcome

Title	Extracranial Progression Free Survival (PFS)
Description	Extracranial progression-free survival (PFS) per RECIST 1.1 criteria is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. 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.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Median (95% Confidence Interval) [Months]	39.29	1.77

7. Secondary Outcome

Title	Global Clinical Benefit Rate (CBR)
Description	Investigator-assessed global (intracranial + extracranial) clinical benefit rate (CBR) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of >6 months
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Number (95% Confidence Interval) [Percentage of participants]	55.4 54.9%	22.2 123.3%

8. Secondary Outcome

Title	Global Objective Response Rate (ORR)
Description	Investigator-assessed global objective response rate (ORR) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of treated participants.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Number (95% Confidence Interval) [Percentage of participants]	51.5 51%	22.2 123.3%

9. Secondary Outcome

Title	Global Progression Free Survival (PFS)
Description	Investigator-assessed global progression free survival (PFS) per a combination of modified RECIST 1.1 criteria for intracranial lesions and RECIST 1.1 for extracranial disease is defined as the time between the date of first dose of study drug and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Participant who die without a reported progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date of first dose of study drug. 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.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Median (95% Confidence Interval) [Months]	29.54	1.18

10. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) is defined as the time from the date of the start of treatment until the date of death. For participants who have not died, OS will be censored at the recorded last date of participant contact, and participants with a missing recorded last date of contact will be censored at the last date the participant was known to be alive.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Median (95% Confidence Interval) [Months]	45.80	8.77

11. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	Number of participants with any grade of adverse events (AEs) and any grade of serious adverse events (SAEs) graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Time Frame	From first dose to 30 days post last dose (Up to 66 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Adverse Events (AEs)	98 97%	18 100%
Serious Adverse Events (SAEs)	44 43.6%	11 61.1%

12. Secondary Outcome

Title	Number of Participants Deaths
Description	Number of participants who died due to any cause.
Time Frame	Up to 66 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
Count of Participants [Participants]	29 28.7%	10 55.6%

13. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities in Specific Liver Tests
Description	Number of participants with laboratory abnormalities in specific liver tests based on US conventional units to determine the safety and tolerability of Nivolumab and Daratumumab. The number of participants with the following laboratory abnormalities from on-treatment evaluations will be summarized: ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN Total bilirubin > 2 x ULN Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
Time Frame	From first dose to 30 days post last dose (Up to 66 months)

Outcome Measure Data

Analysis Population Description

All treated participants with at least one on-treatment measurement of the corresponding laboratory parameter

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	96	15
ALT OR AST > 3XULN	25 24.8%	1 5.6%
ALT OR AST > 5XULN	16 15.8%	0 0%
ALT OR AST > 10XULN	7 6.9%	0 0%
ALT OR AST > 20XULN	2 2%	0 0%
TOTAL BILIRUBIN > 2XULN	3 3%	0 0%
CONCURRENT ALT OR AST ELEVATION > 3XULN WITH TOTAL BILIRUBIN > 2XULN WITHIN ONE DAY	1 1%	0 0%
CONCURRENT ALT OR AST ELEVATION > 3XULN WITH TOTAL BILIRUBIN > 2XULN WITHIN 30 DAYS	1 1%	0 0%

14. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests
Description	Number of participants with laboratory abnormalities in specific thyroid tests based on US conventional units to determine the safety and tolerability of Nivolumab and Daratumumab. The number of subjects with the following laboratory abnormalities from on-treatment evaluations will be summarized: TSH value > ULN and with baseline TSH value <= ULN with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH test with all FT3/FT4 test values >= LLN within 2-week window after the abnormal TSH test with FT3/FT4 missing within 2-week window after the abnormal TSH test. TSH < LLN and with baseline TSH value >= LLN with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal TSH test with all FT3/FT4 test values <= ULN within 2-week window after the abnormal TSH test with FT3/FT4 missing within 2-week window after the abnormal TSH test
Time Frame	From first dose to 30 days post last dose (Up to 66 months)

Outcome Measure Data

Analysis Population Description

All treated participants with at least one on-treatment TSH measurement

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.	Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
Measure Participants	101	18
TSH > ULN	33 32.7%	2 11.1%
TSH > ULN WITH TSH <= ULN AT BASELINE	26 25.7%	2 11.1%
TSH > ULN WITH AT LEAST ONE FT3/FT4 TEST VALUE < LLN	10 9.9%	0 0%
TSH > ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN	4 4%	0 0%
TSH > ULN WITH FT3/FT4 TEST MISSING	23 22.8%	0 0%
TSH < LLN	38 37.6%	5 27.8%
TSH < LLN WITH TSH >= LLN AT BASELINE	37 36.6%	4 22.2%
TSH < LLN WITH AT LEAST ONE FT3/FT4 TEST VALUE > ULN	7 6.9%	0 0%
TSH < LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN	2 2%	1 5.6%
TSH < LLN WITH FT3/FT4 TEST MISSING	15 14.9%	2 11.1%

Adverse Events

Time Frame	From first dose to 100 days post last dose (Up to 68 months)
Arm/Group Title	Cohort A		Cohort B
Arm/Group Description	Asymptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.		Symptomatic patients treated with Nivolumab IV 1 mg/kg Q3W + Ipilimumab IV 3 mg/kg Q3W for a total of 4 doses of the combination therapy followed by Nivolumab IV 3 mg/kg BID for a maximum of 24 months or until progression or until unacceptable toxicity.
All Cause Mortality
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/101 (28.7%)		10/18 (55.6%)
Serious Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/101 (49.5%)		14/18 (77.8%)
Blood and lymphatic system disorders
WARM TYPE HAEMOLYTIC ANAEMIA	1/101 (1%)		0/18 (0%)
Cardiac disorders
ACUTE CORONARY SYNDROME	2/101 (2%)		0/18 (0%)
ANGINA PECTORIS	1/101 (1%)		0/18 (0%)
ATRIAL FIBRILLATION	3/101 (3%)		0/18 (0%)
MYOCARDITIS	1/101 (1%)		0/18 (0%)
Endocrine disorders
ADRENAL INSUFFICIENCY	4/101 (4%)		0/18 (0%)
HYPERTHYROIDISM	3/101 (3%)		0/18 (0%)
HYPOPHYSITIS	6/101 (5.9%)		0/18 (0%)
Eye disorders
VISION BLURRED	2/101 (2%)		0/18 (0%)
Gastrointestinal disorders
ABDOMINAL PAIN	1/101 (1%)		0/18 (0%)
COLITIS	5/101 (5%)		1/18 (5.6%)
DIARRHOEA	6/101 (5.9%)		1/18 (5.6%)
DUODENITIS	1/101 (1%)		0/18 (0%)
GASTRITIS	1/101 (1%)		0/18 (0%)
GASTROINTESTINAL HAEMORRHAGE	1/101 (1%)		0/18 (0%)
IMMUNE-MEDIATED PANCREATITIS	1/101 (1%)		0/18 (0%)
NAUSEA	3/101 (3%)		1/18 (5.6%)
PANCREATITIS	1/101 (1%)		0/18 (0%)
SMALL INTESTINAL OBSTRUCTION	0/101 (0%)		1/18 (5.6%)
STOMATITIS	0/101 (0%)		1/18 (5.6%)
VOMITING	4/101 (4%)		1/18 (5.6%)
General disorders
DEATH	1/101 (1%)		0/18 (0%)
FATIGUE	2/101 (2%)		0/18 (0%)
INFLUENZA LIKE ILLNESS	2/101 (2%)		0/18 (0%)
MUCOSAL INFLAMMATION	0/101 (0%)		1/18 (5.6%)
OEDEMA PERIPHERAL	1/101 (1%)		0/18 (0%)
PYREXIA	4/101 (4%)		1/18 (5.6%)
Hepatobiliary disorders
CHOLECYSTITIS	1/101 (1%)		0/18 (0%)
CHOLELITHIASIS	1/101 (1%)		0/18 (0%)
HEPATITIS ACUTE	1/101 (1%)		0/18 (0%)
Immune system disorders
CYTOKINE RELEASE SYNDROME	1/101 (1%)		0/18 (0%)
Infections and infestations
BACILLUS INFECTION	0/101 (0%)		1/18 (5.6%)
CELLULITIS ORBITAL	0/101 (0%)		1/18 (5.6%)
CLOSTRIDIUM DIFFICILE INFECTION	1/101 (1%)		0/18 (0%)
GASTROENTERITIS	0/101 (0%)		1/18 (5.6%)
MENINGITIS BACTERIAL	0/101 (0%)		1/18 (5.6%)
ORBITAL INFECTION	0/101 (0%)		1/18 (5.6%)
PNEUMONIA	2/101 (2%)		1/18 (5.6%)
RASH PUSTULAR	0/101 (0%)		1/18 (5.6%)
SEPSIS	0/101 (0%)		1/18 (5.6%)
SEPTIC SHOCK	1/101 (1%)		0/18 (0%)
SKIN INFECTION	1/101 (1%)		0/18 (0%)
SOFT TISSUE INFECTION	1/101 (1%)		0/18 (0%)
STAPHYLOCOCCAL SEPSIS	0/101 (0%)		1/18 (5.6%)
UPPER RESPIRATORY TRACT INFECTION	0/101 (0%)		1/18 (5.6%)
URINARY TRACT INFECTION	1/101 (1%)		1/18 (5.6%)
Injury, poisoning and procedural complications
HIP FRACTURE	1/101 (1%)		0/18 (0%)
SYNOVIAL RUPTURE	1/101 (1%)		0/18 (0%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	7/101 (6.9%)		0/18 (0%)
AMYLASE INCREASED	1/101 (1%)		0/18 (0%)
ASPARTATE AMINOTRANSFERASE INCREASED	6/101 (5.9%)		0/18 (0%)
LIPASE INCREASED	1/101 (1%)		0/18 (0%)
Metabolism and nutrition disorders
DEHYDRATION	1/101 (1%)		0/18 (0%)
HYPONATRAEMIA	1/101 (1%)		0/18 (0%)
TYPE 1 DIABETES MELLITUS	1/101 (1%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
BACK PAIN	1/101 (1%)		0/18 (0%)
MUSCULAR WEAKNESS	1/101 (1%)		0/18 (0%)
MYOSITIS	1/101 (1%)		0/18 (0%)
RHABDOMYOLYSIS	1/101 (1%)		0/18 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
INTRACRANIAL TUMOUR HAEMORRHAGE	0/101 (0%)		1/18 (5.6%)
MALIGNANT NEOPLASM PROGRESSION	6/101 (5.9%)		9/18 (50%)
TUMOUR PSEUDOPROGRESSION	0/101 (0%)		1/18 (5.6%)
Nervous system disorders
BRAIN OEDEMA	3/101 (3%)		0/18 (0%)
CEREBRAL HAEMORRHAGE	1/101 (1%)		0/18 (0%)
DYSAESTHESIA	1/101 (1%)		0/18 (0%)
HAEMORRHAGE INTRACRANIAL	3/101 (3%)		0/18 (0%)
HEADACHE	1/101 (1%)		0/18 (0%)
HEMIPARESIS	1/101 (1%)		0/18 (0%)
ISCHAEMIC STROKE	1/101 (1%)		0/18 (0%)
LACUNAR INFARCTION	1/101 (1%)		0/18 (0%)
METABOLIC ENCEPHALOPATHY	1/101 (1%)		0/18 (0%)
PARAESTHESIA	1/101 (1%)		0/18 (0%)
PARTIAL SEIZURES	0/101 (0%)		1/18 (5.6%)
PERIPHERAL MOTOR NEUROPATHY	1/101 (1%)		0/18 (0%)
PERIPHERAL SENSORY NEUROPATHY	2/101 (2%)		0/18 (0%)
PRESYNCOPE	1/101 (1%)		0/18 (0%)
SEIZURE	3/101 (3%)		1/18 (5.6%)
SYNCOPE	1/101 (1%)		0/18 (0%)
Renal and urinary disorders
ACUTE KIDNEY INJURY	3/101 (3%)		0/18 (0%)
IMMUNE-MEDIATED NEPHRITIS	1/101 (1%)		0/18 (0%)
NEPHRITIS	1/101 (1%)		0/18 (0%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	2/101 (2%)		0/18 (0%)
GRANULOMATOUS PNEUMONITIS	1/101 (1%)		0/18 (0%)
LUNG DISORDER	0/101 (0%)		1/18 (5.6%)
PLEURAL EFFUSION	0/101 (0%)		1/18 (5.6%)
PNEUMONITIS	4/101 (4%)		1/18 (5.6%)
PULMONARY EMBOLISM	3/101 (3%)		1/18 (5.6%)
Skin and subcutaneous tissue disorders
RASH MACULO-PAPULAR	1/101 (1%)		0/18 (0%)
Vascular disorders
EMBOLISM	1/101 (1%)		0/18 (0%)
HYPOTENSION	3/101 (3%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	97/101 (96%)		18/18 (100%)
Blood and lymphatic system disorders
ANAEMIA	16/101 (15.8%)		1/18 (5.6%)
Cardiac disorders
ATRIAL FIBRILLATION	2/101 (2%)		1/18 (5.6%)
SINUS TACHYCARDIA	6/101 (5.9%)		1/18 (5.6%)
TACHYCARDIA	4/101 (4%)		1/18 (5.6%)
Ear and labyrinth disorders
EAR PAIN	1/101 (1%)		2/18 (11.1%)
TINNITUS	3/101 (3%)		1/18 (5.6%)
Endocrine disorders
ADRENAL INSUFFICIENCY	10/101 (9.9%)		0/18 (0%)
HYPERTHYROIDISM	14/101 (13.9%)		0/18 (0%)
HYPOGONADISM	0/101 (0%)		1/18 (5.6%)
HYPOPHYSITIS	11/101 (10.9%)		2/18 (11.1%)
HYPOTHYROIDISM	26/101 (25.7%)		1/18 (5.6%)
THYROIDITIS	4/101 (4%)		1/18 (5.6%)
Eye disorders
IRITIS	0/101 (0%)		2/18 (11.1%)
OCULAR HYPERAEMIA	2/101 (2%)		1/18 (5.6%)
PHOTOPHOBIA	2/101 (2%)		1/18 (5.6%)
PHOTOPSIA	2/101 (2%)		2/18 (11.1%)
VISION BLURRED	14/101 (13.9%)		5/18 (27.8%)
VISUAL ACUITY REDUCED	0/101 (0%)		1/18 (5.6%)
VISUAL IMPAIRMENT	4/101 (4%)		1/18 (5.6%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	5/101 (5%)		2/18 (11.1%)
ABDOMINAL PAIN	19/101 (18.8%)		3/18 (16.7%)
ABDOMINAL PAIN UPPER	8/101 (7.9%)		0/18 (0%)
ABDOMINAL TENDERNESS	2/101 (2%)		1/18 (5.6%)
APHTHOUS ULCER	0/101 (0%)		1/18 (5.6%)
ASCITES	1/101 (1%)		1/18 (5.6%)
CONSTIPATION	14/101 (13.9%)		3/18 (16.7%)
DIARRHOEA	51/101 (50.5%)		8/18 (44.4%)
DRY MOUTH	9/101 (8.9%)		1/18 (5.6%)
DYSPEPSIA	8/101 (7.9%)		0/18 (0%)
FLATULENCE	4/101 (4%)		2/18 (11.1%)
GASTROOESOPHAGEAL REFLUX DISEASE	2/101 (2%)		1/18 (5.6%)
NAUSEA	53/101 (52.5%)		10/18 (55.6%)
ORAL DISORDER	0/101 (0%)		1/18 (5.6%)
STOMATITIS	5/101 (5%)		2/18 (11.1%)
VOMITING	28/101 (27.7%)		6/18 (33.3%)
General disorders
ASTHENIA	2/101 (2%)		1/18 (5.6%)
CHILLS	15/101 (14.9%)		3/18 (16.7%)
DISEASE PROGRESSION	0/101 (0%)		1/18 (5.6%)
FATIGUE	69/101 (68.3%)		8/18 (44.4%)
GAIT DISTURBANCE	2/101 (2%)		2/18 (11.1%)
INFLUENZA LIKE ILLNESS	13/101 (12.9%)		1/18 (5.6%)
LOCALISED OEDEMA	1/101 (1%)		1/18 (5.6%)
MALAISE	4/101 (4%)		1/18 (5.6%)
NON-CARDIAC CHEST PAIN	3/101 (3%)		1/18 (5.6%)
OEDEMA	0/101 (0%)		1/18 (5.6%)
OEDEMA PERIPHERAL	18/101 (17.8%)		3/18 (16.7%)
PAIN	5/101 (5%)		1/18 (5.6%)
PYREXIA	28/101 (27.7%)		4/18 (22.2%)
Immune system disorders
CYTOKINE RELEASE SYNDROME	0/101 (0%)		1/18 (5.6%)
HYPERSENSITIVITY	2/101 (2%)		1/18 (5.6%)
Infections and infestations
CRYPTOCOCCAL FUNGAEMIA	0/101 (0%)		1/18 (5.6%)
IMPETIGO	0/101 (0%)		1/18 (5.6%)
ORAL CANDIDIASIS	6/101 (5.9%)		1/18 (5.6%)
SINUSITIS	8/101 (7.9%)		1/18 (5.6%)
TINEA CRURIS	1/101 (1%)		1/18 (5.6%)
UPPER RESPIRATORY TRACT INFECTION	11/101 (10.9%)		1/18 (5.6%)
URINARY TRACT INFECTION	8/101 (7.9%)		1/18 (5.6%)
Injury, poisoning and procedural complications
ESCHAR	0/101 (0%)		1/18 (5.6%)
FALL	3/101 (3%)		1/18 (5.6%)
PROCEDURAL PAIN	2/101 (2%)		1/18 (5.6%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	41/101 (40.6%)		6/18 (33.3%)
AMYLASE INCREASED	17/101 (16.8%)		1/18 (5.6%)
ASPARTATE AMINOTRANSFERASE INCREASED	39/101 (38.6%)		3/18 (16.7%)
BLOOD ALKALINE PHOSPHATASE INCREASED	12/101 (11.9%)		2/18 (11.1%)
BLOOD BILIRUBIN INCREASED	7/101 (6.9%)		1/18 (5.6%)
BLOOD CREATININE INCREASED	7/101 (6.9%)		2/18 (11.1%)
LIPASE INCREASED	25/101 (24.8%)		1/18 (5.6%)
LIVER FUNCTION TEST INCREASED	2/101 (2%)		1/18 (5.6%)
LYMPHOCYTE COUNT DECREASED	8/101 (7.9%)		1/18 (5.6%)
PLATELET COUNT DECREASED	9/101 (8.9%)		0/18 (0%)
WEIGHT DECREASED	15/101 (14.9%)		2/18 (11.1%)
WEIGHT INCREASED	7/101 (6.9%)		0/18 (0%)
WHITE BLOOD CELL COUNT DECREASED	6/101 (5.9%)		0/18 (0%)
Metabolism and nutrition disorders
DECREASED APPETITE	30/101 (29.7%)		4/18 (22.2%)
DEHYDRATION	11/101 (10.9%)		3/18 (16.7%)
HYPERGLYCAEMIA	11/101 (10.9%)		2/18 (11.1%)
HYPERKALAEMIA	9/101 (8.9%)		1/18 (5.6%)
HYPOALBUMINAEMIA	7/101 (6.9%)		0/18 (0%)
HYPOGLYCAEMIA	1/101 (1%)		1/18 (5.6%)
HYPOKALAEMIA	15/101 (14.9%)		1/18 (5.6%)
HYPOMAGNESAEMIA	9/101 (8.9%)		3/18 (16.7%)
HYPONATRAEMIA	14/101 (13.9%)		4/18 (22.2%)
HYPOPHOSPHATAEMIA	5/101 (5%)		1/18 (5.6%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	36/101 (35.6%)		1/18 (5.6%)
BACK PAIN	19/101 (18.8%)		4/18 (22.2%)
GROIN PAIN	1/101 (1%)		1/18 (5.6%)
MUSCLE SPASMS	5/101 (5%)		1/18 (5.6%)
MUSCULAR WEAKNESS	11/101 (10.9%)		3/18 (16.7%)
MYALGIA	17/101 (16.8%)		0/18 (0%)
NECK PAIN	3/101 (3%)		1/18 (5.6%)
PAIN IN EXTREMITY	11/101 (10.9%)		2/18 (11.1%)
PAIN IN JAW	0/101 (0%)		1/18 (5.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR PSEUDOPROGRESSION	0/101 (0%)		1/18 (5.6%)
Nervous system disorders
AMNESIA	1/101 (1%)		1/18 (5.6%)
APHASIA	6/101 (5.9%)		3/18 (16.7%)
ATAXIA	2/101 (2%)		1/18 (5.6%)
BALANCE DISORDER	0/101 (0%)		1/18 (5.6%)
COORDINATION ABNORMAL	1/101 (1%)		1/18 (5.6%)
DIZZINESS	18/101 (17.8%)		4/18 (22.2%)
DYSARTHRIA	0/101 (0%)		1/18 (5.6%)
DYSGEUSIA	7/101 (6.9%)		0/18 (0%)
HAEMORRHAGE INTRACRANIAL	4/101 (4%)		1/18 (5.6%)
HEADACHE	52/101 (51.5%)		8/18 (44.4%)
HYPOAESTHESIA	4/101 (4%)		1/18 (5.6%)
LETHARGY	1/101 (1%)		1/18 (5.6%)
MEMORY IMPAIRMENT	2/101 (2%)		1/18 (5.6%)
PARAESTHESIA	11/101 (10.9%)		1/18 (5.6%)
PAROSMIA	0/101 (0%)		1/18 (5.6%)
PERIPHERAL MOTOR NEUROPATHY	0/101 (0%)		1/18 (5.6%)
PERIPHERAL SENSORY NEUROPATHY	7/101 (6.9%)		1/18 (5.6%)
PRESYNCOPE	1/101 (1%)		1/18 (5.6%)
SEIZURE	3/101 (3%)		2/18 (11.1%)
SYNCOPE	4/101 (4%)		2/18 (11.1%)
Psychiatric disorders
ANXIETY	5/101 (5%)		2/18 (11.1%)
CONFUSIONAL STATE	7/101 (6.9%)		3/18 (16.7%)
DEPRESSION	6/101 (5.9%)		1/18 (5.6%)
INSOMNIA	23/101 (22.8%)		5/18 (27.8%)
Renal and urinary disorders
ACUTE KIDNEY INJURY	2/101 (2%)		1/18 (5.6%)
NEPHRITIS	0/101 (0%)		1/18 (5.6%)
NOCTURIA	2/101 (2%)		1/18 (5.6%)
URINARY RETENTION	0/101 (0%)		1/18 (5.6%)
Reproductive system and breast disorders
VULVOVAGINAL DRYNESS	0/101 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
COUGH	33/101 (32.7%)		6/18 (33.3%)
DYSPHONIA	1/101 (1%)		1/18 (5.6%)
DYSPNOEA	17/101 (16.8%)		3/18 (16.7%)
DYSPNOEA EXERTIONAL	4/101 (4%)		1/18 (5.6%)
HYPOXIA	2/101 (2%)		1/18 (5.6%)
INCREASED BRONCHIAL SECRETION	0/101 (0%)		1/18 (5.6%)
NASAL CONGESTION	15/101 (14.9%)		2/18 (11.1%)
OROPHARYNGEAL PAIN	6/101 (5.9%)		3/18 (16.7%)
PLEURAL EFFUSION	0/101 (0%)		1/18 (5.6%)
PNEUMONITIS	9/101 (8.9%)		1/18 (5.6%)
PRODUCTIVE COUGH	3/101 (3%)		1/18 (5.6%)
TACHYPNOEA	1/101 (1%)		1/18 (5.6%)
WHEEZING	2/101 (2%)		2/18 (11.1%)
Skin and subcutaneous tissue disorders
ALOPECIA	4/101 (4%)		1/18 (5.6%)
DERMATITIS ACNEIFORM	5/101 (5%)		2/18 (11.1%)
DRY SKIN	10/101 (9.9%)		3/18 (16.7%)
HYPERHIDROSIS	6/101 (5.9%)		1/18 (5.6%)
MACULE	0/101 (0%)		1/18 (5.6%)
NIGHT SWEATS	6/101 (5.9%)		0/18 (0%)
ONYCHOMADESIS	0/101 (0%)		1/18 (5.6%)
PHOTOSENSITIVITY REACTION	1/101 (1%)		1/18 (5.6%)
PRURITUS	42/101 (41.6%)		4/18 (22.2%)
RASH	14/101 (13.9%)		3/18 (16.7%)
RASH MACULAR	3/101 (3%)		1/18 (5.6%)
RASH MACULO-PAPULAR	42/101 (41.6%)		5/18 (27.8%)
RASH PRURITIC	5/101 (5%)		2/18 (11.1%)
SKIN HYPOPIGMENTATION	10/101 (9.9%)		1/18 (5.6%)
VITILIGO	7/101 (6.9%)		0/18 (0%)
Vascular disorders
HOT FLUSH	5/101 (5%)		1/18 (5.6%)
HYPERTENSION	13/101 (12.9%)		0/18 (0%)
HYPOTENSION	9/101 (8.9%)		1/18 (5.6%)

Limitations/Caveats

[Not Specified]

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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.