CHECKMATE 920: A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02982954
• Collaborator: (none)
• Enrollment: 211
• Locations: 61
• Arms: 4
• Actual Duration (Months): 56.6
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To investigate the safety of Nivolumab in combination with Ipilimumab in subjects with previously untreated advanced or metastatic Renal Cell Cancer.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Nivolumab; Drug: Ipilimumab	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 211 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 3b/4 Safety Trial of Nivolumab Combined With Ipilimumab in Subjects With Previously Untreated, Advanced or Metastatic RCC (CheckMate 920: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 920)
• Actual Study Start Date: Jan 16, 2017
• Actual Primary Completion Date: May 11, 2020
• Actual Study Completion Date: Oct 6, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ccRCC KPS ≥ 70% Clear-Cell Renal Cell Carcinoma (ccRCC) with Karnofsky Performance Status (KPS) ≥ 70%	Drug: Nivolumab; Specified dose on specified day; Other Names: BMS-936558 Opdivo ; Drug: Ipilimumab; Specified Dose on Specified Day; Other Names: Yervoy BMS-734016
Experimental: Non-ccRCC, KPS ≥ 70% Non Clear-Cell Renal Cell Carcinoma (nccRCC) with KPS ≥ 70%	Drug: Nivolumab; Specified dose on specified day; Other Names: BMS-936558 Opdivo ; Drug: Ipilimumab; Specified Dose on Specified Day; Other Names: Yervoy BMS-734016
Experimental: RCC with non-active Brain Mets, KPS ≥70% Renal Cell Carcinoma (RCC) with non-active Brain Metastases, with KPS ≥70%	Drug: Nivolumab; Specified dose on specified day; Other Names: BMS-936558 Opdivo ; Drug: Ipilimumab; Specified Dose on Specified Day; Other Names: Yervoy BMS-734016
Experimental: any RCC with KPS 50%-60% Renal Cell Carcinoma (RCC), regardless of any histology or existing non-active brain metastasis, with KPS 50%-60%	Drug: Nivolumab; Specified dose on specified day; Other Names: BMS-936558 Opdivo ; Drug: Ipilimumab; Specified Dose on Specified Day; Other Names: Yervoy BMS-734016

Outcome Measures

Primary Outcome Measures

1. Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs) [Approximately 39 Months]

   Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity

2. Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs) [Approximately 39 Months]

   Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity

Secondary Outcome Measures

1. Time to Onset of Grade 3-5 IMAEs [Approximately 39 Months]

   Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity

2. Time to Resolution of Grade 3-5 IMAEs [Approximately 39 Months]

   Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity

3. Percentage of Participants Who Received Immune Modulating Medication for High Grade (Grade 3-5) IMAEs. [Approximately 39 Months]

   Percentage of participants who immune modulating medication with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity

4. Percentage of Participants Who Received Hormone Replacement Therapy for High Grade (Grade 3-5) IMAEs [Approximately 39 Months]

   Percentage of participants who received Hormone Replacement Therapy for grade 3-5 IMAEs

5. Percentage of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grade 3-5) IMAEs of Interest [Approximately 39 Months]

   Percentage of Participants who received ≥ 40mg of prednisone for high grade (grade 3-5) IMAEs of interest

6. Median Progression Free Survival (PFS) [Approximately 24 Months]

   defined as the time from first dose to the date of the first documented PD as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause whichever occur first.

7. Objective Response Rate [Approximately 42 Months]

   defined as the percentage of participants with a best overall response (BOR) of CR or PR divided by the number of response evaluable participants.

8. Time to Response Rate (TRR) [Approximately 42 Months]

   defined as the median percentage of participants with a best overall response (BOR) of CR or PR divided by the number of response evaluable participants.

9. Duration of Response (DOR) [Approximately 42 Months]

   defined as the time between the date of first confirmed response to the date of the first documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs first.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Type of Participant and Target Disease Characteristics

2. Advanced or metastatic RCC

3. Histologically confirmed, previously untreated (treatment-naive) RCC

4. No prior systemic therapy for RCC except for one prior adjuvant or neoadjuvant therapy for completely resectable RCC

5. Measurable disease as per RECIST 1.1. Subject must have extracranial metastasis as measurable disease

6. Karnofsky Performance Status (KPS) of at least 70% for Cohort 1, 2, and 3; KPS of 50-60% for Cohort 4

7. Tumor tissue need be received by the central vendor (block or unstained slides). Note: Fine Needle Aspiration (FNA)and bone metastases samples are not acceptable for submission.

Exclusion Criteria:

1. Medical Conditions

2. Subjects with any active autoimmune disease or a history of known autoimmune disease

3. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured

4. Known HIV or AIDS-related illness

5. Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.

6. Prior/Concomitant Therapy

7. Prior systemic treatment in the metastatic setting with Vascular epithelial growth factor(VEGF) or VEGF receptor targeted therapy

8. Prior treatment with an anti-Programmed Death (PD) -1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation 137 (CD137), or anti-cytotoxic T-lymphocyte-associated antigen 4(CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. This includes the utilization of these agents in the neo-adjuvant or adjuvant setting.

9. Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.

Other protocol defined inclusion/exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwest Alabama Cancer Center, Pc	Muscle Shoals	Alabama	United States	35661
2	Alaska Urological Institute dba Alaska Clinical Research Center	Anchorage	Alaska	United States	99503
3	Ironwood Cancer And Research Centers, Pc	Chandler	Arizona	United States	85224
4	Highlands Oncology Group, P.A.	Fayetteville	Arkansas	United States	72703
5	eCare	Encinitas	California	United States	92024
6	Pacific Shores Medical Group	Long Beach	California	United States	90813
7	Los Angeles Cancer Network	Los Angeles	California	United States	90017
8	UCLA Hematology Oncology	Los Angeles	California	United States	90095
9	Torrance Health Association	Redondo Beach	California	United States	90277
10	Kaiser Permanente Medical Group - Southern California	Riverside	California	United States	92505
11	Sharp Memorial Hospital	San Diego	California	United States	92123
12	Coastal Integrative Cancer Care	San Luis Obispo	California	United States	93401
13	Central Coast Med Oncology	Santa Maria	California	United States	93454
14	Florida Cancer Specialists S.	Fort Myers	Florida	United States	33901
15	University Of Miami/Sylvester Cancer Center	Miami	Florida	United States	33136
16	UF Health Cancer Center at Orlando Health	Orlando	Florida	United States	32806
17	Florida Cancer Specialists	Saint Petersburg	Florida	United States	33705
18	Emory University - Winship Cancer Institute	Atlanta	Georgia	United States	30322
19	Illinois Cancer Specialists	Niles	Illinois	United States	60714
20	Ft. Wayne Med Onco-Hema Inc	Fort Wayne	Indiana	United States	46845
21	Cancer Center Of Kansas	Wichita	Kansas	United States	67214
22	Norton Cancer Institute	Louisville	Kentucky	United States	40202
23	Southdale Cancer Clinic	Burnsville	Minnesota	United States	55337
24	Minnesota Oncology Hematology	Coon Rapids	Minnesota	United States	55433
25	Park Nicollet Clinic Cancer Center	Minneapolis	Minnesota	United States	55416
26	Hattiesburg Clinic	Hattiesburg	Mississippi	United States	39401
27	Jackson Oncology Associates, Pllc	Jackson	Mississippi	United States	39202
28	HCA Midwest Division	Kansas City	Missouri	United States	64132
29	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89148
30	John Theurer Cancer Center	Hackensack	New Jersey	United States	07601
31	University Of New Mexico	Albuquerque	New Mexico	United States	87106
32	Montefiore Medical Center	Bronx	New York	United States	10461
33	Maimonides Medical Center	Brooklyn	New York	United States	11220
34	St. Francis Cancer Treatment Center	Grand Island	New York	United States	68803
35	Broome Oncology	Johnson City	New York	United States	13790
36	Laura & Isaac Perlmutter Cancer Center	New York	New York	United States	10016
37	Weill Cornell Medical College	New York	New York	United States	10021
38	SUNY Upstate Medical University	Syracuse	New York	United States	13210
39	Duke University Medical Center	Durham	North Carolina	United States	27710
40	Southeastern Medical Oncology Center	Goldsboro	North Carolina	United States	27534
41	Oklahoma Cancer Specialists and Research Institute, LLC-Clinical Research	Tulsa	Oklahoma	United States	74146
42	Va Medical Center Pittsburgh Healthcare System	Pittsburgh	Pennsylvania	United States	15240
43	Charleston Hematology Oncology Associates, Pa	Charleston	South Carolina	United States	29414
44	Hollings Cancer Center	Charleston	South Carolina	United States	29425
45	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
46	Tennessee Oncology, PLLC - SCRI - PPDS	Chattanooga	Tennessee	United States	37404
47	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
48	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232-6307
49	Texas Oncology	Austin	Texas	United States	78731
50	Texas Oncology	Dallas	Texas	United States	75246
51	Texas Oncology-Fort Worth 12th Ave	Fort Worth	Texas	United States	76104
52	Texas Oncology-Midland Allison Cancer Center	Midland	Texas	United States	79701
53	Texas Oncology	San Antonio	Texas	United States	78217
54	University of Virginia Health System	Charlottesville	Virginia	United States	22936
55	Inova Research Center	Fairfax	Virginia	United States	22031
56	Bon Secours St Francis Hospital	Midlothian	Virginia	United States	23114
57	Virginia Cancer Institute	Richmond	Virginia	United States	23226
58	University of Washington - Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
59	Medical Oncology Associates	Spokane	Washington	United States	99208
60	Yakima Valley Memorial Hospital/North Star Lodge	Yakima	Washington	United States	98902
61	University of Wisconsin Clinical Science Center	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Dec 18, 2019
• Statistical Analysis Plan - May 26, 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: NCT02982954
• Other Study ID Numbers: CA209-920
• First Posted: Dec 6, 2016
• Last Update Posted: May 12, 2022
• Last Verified: Apr 1, 2022

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

Study Results

Participant Flow

Pre-assignment Detail	211 participants treated. 211 participants did not complete treatment and 95 continued in the study

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Period Title: Treatment Period
STARTED	106	52	28	25
COMPLETED	0	0	0	0
NOT COMPLETED	106	52	28	25
Period Title: Treatment Period
STARTED	106	52	28	25
COMPLETED	52	19	17	7
NOT COMPLETED	54	33	11	18

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Total
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	Total of all reporting groups
Overall Participants	106	52	28	25	211
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.8 (9.43)	60.1 (14.09)	61.3 (11.06)	65.2 (12.54)	62.2 (11.3)
Sex: Female, Male (Count of Participants)
Female	20 18.9%	16 30.8%	4 14.3%	6 24%	46 21.8%
Male	86 81.1%	36 69.2%	24 85.7%	19 76%	165 78.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 4.7%	3 5.8%	1 3.6%	1 4%	10 4.7%
Not Hispanic or Latino	101 95.3%	48 92.3%	27 96.4%	24 96%	200 94.8%
Unknown or Not Reported	0 0%	1 1.9%	0 0%	0 0%	1 0.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.9%	0 0%	0 0%	1 0.5%
Asian	0 0%	1 1.9%	1 3.6%	0 0%	2 0.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 0.9%	6 11.5%	1 3.6%	1 4%	9 4.3%
White	104 98.1%	40 76.9%	26 92.9%	24 96%	194 91.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.9%	4 7.7%	0 0%	0 0%	5 2.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With High Grade (Grade 3-4) Immune Mediated Adverse Events (IMAEs)
Description	Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity
Time Frame	Approximately 39 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Pneumonitis	1 0.9%	0 0%	0 0%	0 0%
Diarrhoea/Colitis	8 7.5%	4 7.7%	3 10.7%	0 0%
Hepatitis	3 2.8%	1 1.9%	1 3.6%	1 4%
Nephritis and Renal Dysfunction	0 0%	2 3.8%	0 0%	0 0%
Rash	7 6.6%	3 5.8%	1 3.6%	0 0%
Hypersensitivity	0 0%	0 0%	0 0%	0 0%
Adrenal Insufficiency	3 2.8%	1 1.9%	0 0%	1 4%
Hypothyroidism and Thyroiditis	0 0%	0 0%	0 0%	1 4%
Diabetes Mellitus	4 3.8%	0 0%	1 3.6%	0 0%
Hyperthyroidism	0 0%	0 0%	0 0%	0 0%
Hypophysitis	0 0%	1 1.9%	1 3.6%	0 0%

2. Primary Outcome

Title	Number of Participants With High Grade (Grade 5) Immune Mediated Adverse Events (IMAEs)
Description	Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity
Time Frame	Approximately 39 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Pneumonitis	0 0%	0 0%	0 0%	0 0%
Diarrhoea/Colitis	0 0%	0 0%	0 0%	0 0%
Hepatitis	0 0%	0 0%	0 0%	0 0%
Nephritis and Renal Dysfunction	0 0%	0 0%	0 0%	0 0%
Rash	0 0%	0 0%	0 0%	0 0%
Hypersensitivity	0 0%	0 0%	0 0%	0 0%
Adrenal Insufficiency	0 0%	0 0%	0 0%	0 0%
Hypothyroidism and Thyroiditis	0 0%	0 0%	0 0%	0 0%
Diabetes Mellitus	0 0%	0 0%	0 0%	0 0%
Hyperthyroidism	0 0%	0 0%	0 0%	0 0%
Hypophysitis	0 0%	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Time to Onset of Grade 3-5 IMAEs
Description	Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity
Time Frame	Approximately 39 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants Who Experienced at Least 1 IMAE Where Immune-modulating Medication was Initiated

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Pneumonitis	12.7
Diarrhoea/Colitis	21.79	10.43	11.0
Hepatitis	8.43	9.4	11.6	10.1
Nephritis and Renal Dysfunction	9.43
Rash	4.00	6.14	8.3
Adrenal Insufficiency	51.43	12.7	14.9
Hypothyroidism and Thyroiditis	14.9
Diabetes Mellitus	13.57	2.00
Hypophysitis	18.7

4. Secondary Outcome

Title	Time to Resolution of Grade 3-5 IMAEs
Description	Number of participants with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity
Time Frame	Approximately 39 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants Who Experienced at Least 1 IMAE Where Immune-modulating Medication was Initiated

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Pneumonitis	0.9
Diarrhoea/Colitis	2.71	5.93	1.14
Hepatitis	7.71	3.00	2.1
Nephritis and Renal Dysfunction	7.79
Rash	5.29	8.00	5.3
Adrenal Insufficiency	0.71	6.0
Diabetes Mellitus	NA	1.1
Hypophysitis	7.6

5. Secondary Outcome

Title	Percentage of Participants Who Received Immune Modulating Medication for High Grade (Grade 3-5) IMAEs.
Description	Percentage of participants who immune modulating medication with IMAEs in the following categories: Skin, Endocrine, Gastrointestinal, Hepatic, Renal, Pulmonary and Hypersensitivity
Time Frame	Approximately 39 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Pneumonitis	100 94.3%
Diarrhoea/Colitis	100 94.3%	100 192.3%	100 357.1%
Hepatitis	100 94.3%	100 192.3%	100 357.1%	100 400%
Nephritis and Renal Dysfunction	100 94.3%
Rash	100 94.3%	100 192.3%	100 357.1%
Adrenal Insufficiency	66.7 62.9%	100 192.3%	100 357.1%
Hypothyroidism and Thyroiditis	0 0%
Diabetes Mellitus	0 0%	100 192.3%
Hypophysitis	100 94.3%	0 0%

6. Secondary Outcome

Title	Percentage of Participants Who Received Hormone Replacement Therapy for High Grade (Grade 3-5) IMAEs
Description	Percentage of participants who received Hormone Replacement Therapy for grade 3-5 IMAEs
Time Frame	Approximately 39 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Pneumonitis	100 94.3%
Diarrhoea/Colitis	100 94.3%	75.0 144.2%	100 357.1%
Hepatitis	100 94.3%	100 192.3%	100 357.1%	100 400%
Nephritis and Renal Dysfunction	100 94.3%
Rash	100 94.3%	100 192.3%	100 357.1%
Adrenal Insufficiency	66.7 62.9%	100 192.3%	100 357.1%
Hypothyroidism and Thyroiditis	0 0%
Diabetes Mellitus	0 0%	100 192.3%
Hypophysitis	100 94.3%	0 0%

7. Secondary Outcome

Title	Percentage of Participants Who Received ≥ 40mg of Prednisone for High Grade (Grade 3-5) IMAEs of Interest
Description	Percentage of Participants who received ≥ 40mg of prednisone for high grade (grade 3-5) IMAEs of interest
Time Frame	Approximately 39 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Pneumonitis	100 94.3%
Diarrhoea/Colitis	100 94.3%	75.0 144.2%	100 357.1%
Hepatitis	100 94.3%	100 192.3%	100 357.1%	100 400%
Nephritis and Renal Dysfunction	100 94.3%
Rash	85.7 80.8%	66.7 128.3%	100 357.1%
Adrenal Insufficiency	66.7 62.9%	0 0%	100 357.1%
Hypothyroidism and Thyroiditis	NA NaN
Diabetes Mellitus	NA NaN	100 192.3%
Hypophysitis	100 94.3%	0 0%

8. Secondary Outcome

Title	Median Progression Free Survival (PFS)
Description	defined as the time from first dose to the date of the first documented PD as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause whichever occur first.
Time Frame	Approximately 24 Months

Outcome Measure Data

Analysis Population Description

All Treated Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	106	52	28	25
Median (95% Confidence Interval) [Months]	4.8	3.7	9.0	4.6

9. Secondary Outcome

Title	Objective Response Rate
Description	defined as the percentage of participants with a best overall response (BOR) of CR or PR divided by the number of response evaluable participants.
Time Frame	Approximately 42 Months

Outcome Measure Data

Analysis Population Description

All Response Evaluable Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	96	46	25	18
Number (95% Confidence Interval) [Percentage of Participants]	34.4 32.5%	19.6 37.7%	32.0 114.3%	33.3 133.2%

10. Secondary Outcome

Title	Time to Response Rate (TRR)
Description	defined as the median percentage of participants with a best overall response (BOR) of CR or PR divided by the number of response evaluable participants.
Time Frame	Approximately 42 Months

Outcome Measure Data

Analysis Population Description

All Response Evaluable Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	96	46	25	18
Mean (Full Range) [Months]	6.1	4.2	2.8	7.5

11. Secondary Outcome

Title	Duration of Response (DOR)
Description	defined as the time between the date of first confirmed response to the date of the first documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs first.
Time Frame	Approximately 42 Months

Outcome Measure Data

Analysis Population Description

All Response Evaluable Participants

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses	nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
Measure Participants	96	46	25	18
Median (95% Confidence Interval) [Months]	9.20	NA	23.95	20.57

Adverse Events

Time Frame	Approximately 42 months
Arm/Group Title	COHORT 1		COHORT 2		COHORT 3		COHORT 4
Arm/Group Description	nivolumab 6mg/kg IV plus, ipilimumab 1mg/kg IV Q8 weeks alternating with nivolumab 480 mg IV Q8 weeks, staggered Q 4 weeks		nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q3 weeks for 4 doses		nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses		nivolumab 3mg/kg IV combined with ipilimumab 1mg/kg IV Q 3 weeks for 4 doses
All Cause Mortality
	COHORT 1		COHORT 2		COHORT 3		COHORT 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/106 (41.5%)		27/52 (51.9%)		10/28 (35.7%)		17/25 (68%)
Serious Adverse Events
	COHORT 1		COHORT 2		COHORT 3		COHORT 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/106 (53.8%)		21/52 (40.4%)		12/28 (42.9%)		16/25 (64%)
Blood and lymphatic system disorders
Anaemia	0/106 (0%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Anaemia of chronic disease	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Leukocytosis	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Splenic infarction	0/106 (0%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Cardiac disorders
Acute coronary syndrome	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Acute myocardial infarction	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Atrial fibrillation	4/106 (3.8%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Atrioventricular block complete	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Ischaemic cardiomyopathy	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Myocardial infarction	1/106 (0.9%)		1/52 (1.9%)		0/28 (0%)		1/25 (4%)
Pericarditis	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Endocrine disorders
Adrenal insufficiency	3/106 (2.8%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Hypophysitis	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Gastrointestinal disorders
Ascites	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Colitis	5/106 (4.7%)		2/52 (3.8%)		1/28 (3.6%)		0/25 (0%)
Diarrhoea	3/106 (2.8%)		1/52 (1.9%)		1/28 (3.6%)		0/25 (0%)
Diverticular perforation	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Duodenal ulcer haemorrhage	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Dysphagia	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Faecaloma	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Incarcerated inguinal hernia	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Intussusception	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Lower gastrointestinal haemorrhage	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Nausea	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Pancreatitis	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Retroperitoneal haematoma	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Small intestinal obstruction	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Stomatitis	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Upper gastrointestinal haemorrhage	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Vomiting	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
General disorders
Fatigue	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Non-cardiac chest pain	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Pyrexia	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Systemic inflammatory response syndrome	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Hepatobiliary disorders
Autoimmune hepatitis	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Cholelithiasis	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Drug-induced liver injury	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Immune-mediated hepatitis	0/106 (0%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Immune system disorders
Anaphylactic reaction	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Infections and infestations
Cholecystitis infective	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Clostridium difficile infection	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Cryptosporidiosis infection	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Device related infection	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Diverticulitis	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Encephalitis	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Influenza	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Meningitis aseptic	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Pneumonia	3/106 (2.8%)		2/52 (3.8%)		1/28 (3.6%)		0/25 (0%)
Postoperative wound infection	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Sepsis	1/106 (0.9%)		1/52 (1.9%)		1/28 (3.6%)		0/25 (0%)
Septic shock	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Staphylococcal sepsis	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Urinary tract infection	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Viral infection	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Injury, poisoning and procedural complications
Acetabulum fracture	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Clavicle fracture	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Femoral neck fracture	1/106 (0.9%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Femur fracture	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Subdural haematoma	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Toxicity to various agents	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Investigations
Aspartate aminotransferase increased	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Blood creatinine increased	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Body temperature increased	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
CSF white blood cell count increased	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Hepatic enzyme increased	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Lipase increased	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Metabolism and nutrition disorders
Acidosis	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Dehydration	3/106 (2.8%)		0/52 (0%)		2/28 (7.1%)		0/25 (0%)
Diabetic ketoacidosis	2/106 (1.9%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Hypercalcaemia	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Hyperglycaemia	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Hyperglycaemic hyperosmolar nonketotic syndrome	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Hyperkalaemia	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Hypokalaemia	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Hyponatraemia	2/106 (1.9%)		2/52 (3.8%)		0/28 (0%)		0/25 (0%)
Hypovolaemia	0/106 (0%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/106 (0%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Flank pain	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Pathological fracture	1/106 (0.9%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Cancer pain	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Malignant neoplasm progression	9/106 (8.5%)		4/52 (7.7%)		3/28 (10.7%)		4/25 (16%)
Malignant pleural effusion	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Metastases to central nervous system	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Metastatic renal cell carcinoma	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Respiratory tract neoplasm	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Nervous system disorders
Cerebellar infarction	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Dysarthria	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Encephalopathy	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Facial paralysis	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Haemorrhage intracranial	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Hypoxic-ischaemic encephalopathy	0/106 (0%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Myasthenia gravis	1/106 (0.9%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Seizure	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Syncope	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Vasogenic cerebral oedema	0/106 (0%)		0/52 (0%)		1/28 (3.6%)		0/25 (0%)
Psychiatric disorders
Mental status changes	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Renal and urinary disorders
Acute kidney injury	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Haematuria	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Nephritis	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Nephrolithiasis	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/106 (1.9%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Chronic obstructive pulmonary disease	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Dyspnoea	2/106 (1.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Haemoptysis	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Hypoxia	0/106 (0%)		1/52 (1.9%)		0/28 (0%)		1/25 (4%)
Pleural effusion	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		2/25 (8%)
Pneumonitis	3/106 (2.8%)		1/52 (1.9%)		0/28 (0%)		1/25 (4%)
Pulmonary embolism	1/106 (0.9%)		1/52 (1.9%)		0/28 (0%)		0/25 (0%)
Respiratory arrest	0/106 (0%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Vascular disorders
Hypotension	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		1/25 (4%)
Lymphoedema	1/106 (0.9%)		0/52 (0%)		0/28 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	COHORT 1		COHORT 2		COHORT 3		COHORT 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	103/106 (97.2%)		50/52 (96.2%)		27/28 (96.4%)		24/25 (96%)
Blood and lymphatic system disorders
Anaemia	19/106 (17.9%)		5/52 (9.6%)		9/28 (32.1%)		3/25 (12%)
Iron deficiency anaemia	2/106 (1.9%)		0/52 (0%)		1/28 (3.6%)		2/25 (8%)
Leukocytosis	0/106 (0%)		0/52 (0%)		0/28 (0%)		2/25 (8%)
Cardiac disorders
Palpitations	2/106 (1.9%)		0/52 (0%)		1/28 (3.6%)		2/25 (8%)
Endocrine disorders
Hyperthyroidism	7/106 (6.6%)		2/52 (3.8%)		3/28 (10.7%)		3/25 (12%)
Hypothyroidism	18/106 (17%)		4/52 (7.7%)		8/28 (28.6%)		7/25 (28%)
Eye disorders
Vision blurred	7/106 (6.6%)		2/52 (3.8%)		2/28 (7.1%)		1/25 (4%)
Gastrointestinal disorders
Abdominal distension	5/106 (4.7%)		3/52 (5.8%)		0/28 (0%)		2/25 (8%)
Abdominal pain	17/106 (16%)		7/52 (13.5%)		6/28 (21.4%)		7/25 (28%)
Abdominal pain lower	2/106 (1.9%)		3/52 (5.8%)		0/28 (0%)		0/25 (0%)
Constipation	24/106 (22.6%)		11/52 (21.2%)		4/28 (14.3%)		7/25 (28%)
Diarrhoea	43/106 (40.6%)		19/52 (36.5%)		11/28 (39.3%)		9/25 (36%)
Dry mouth	10/106 (9.4%)		4/52 (7.7%)		3/28 (10.7%)		1/25 (4%)
Dyspepsia	9/106 (8.5%)		1/52 (1.9%)		0/28 (0%)		2/25 (8%)
Gastrooesophageal reflux disease	6/106 (5.7%)		1/52 (1.9%)		1/28 (3.6%)		0/25 (0%)
Nausea	37/106 (34.9%)		18/52 (34.6%)		12/28 (42.9%)		4/25 (16%)
Stomatitis	6/106 (5.7%)		4/52 (7.7%)		1/28 (3.6%)		1/25 (4%)
Vomiting	23/106 (21.7%)		12/52 (23.1%)		3/28 (10.7%)		1/25 (4%)
General disorders
Asthenia	11/106 (10.4%)		4/52 (7.7%)		4/28 (14.3%)		1/25 (4%)
Chills	8/106 (7.5%)		5/52 (9.6%)		3/28 (10.7%)		0/25 (0%)
Fatigue	62/106 (58.5%)		31/52 (59.6%)		14/28 (50%)		2/25 (8%)
Localised oedema	0/106 (0%)		0/52 (0%)		0/28 (0%)		2/25 (8%)
Non-cardiac chest pain	3/106 (2.8%)		3/52 (5.8%)		0/28 (0%)		2/25 (8%)
Oedema peripheral	20/106 (18.9%)		8/52 (15.4%)		6/28 (21.4%)		3/25 (12%)
Pain	4/106 (3.8%)		3/52 (5.8%)		0/28 (0%)		0/25 (0%)
Peripheral swelling	4/106 (3.8%)		0/52 (0%)		2/28 (7.1%)		0/25 (0%)
Pyrexia	12/106 (11.3%)		9/52 (17.3%)		3/28 (10.7%)		1/25 (4%)
Immune system disorders
Seasonal allergy	6/106 (5.7%)		0/52 (0%)		2/28 (7.1%)		0/25 (0%)
Infections and infestations
Diverticulitis	2/106 (1.9%)		0/52 (0%)		2/28 (7.1%)		0/25 (0%)
Oral candidiasis	4/106 (3.8%)		3/52 (5.8%)		2/28 (7.1%)		0/25 (0%)
Pneumonia	5/106 (4.7%)		2/52 (3.8%)		1/28 (3.6%)		2/25 (8%)
Sinusitis	3/106 (2.8%)		3/52 (5.8%)		1/28 (3.6%)		1/25 (4%)
Upper respiratory tract infection	10/106 (9.4%)		3/52 (5.8%)		2/28 (7.1%)		2/25 (8%)
Urinary tract infection	7/106 (6.6%)		2/52 (3.8%)		4/28 (14.3%)		2/25 (8%)
Injury, poisoning and procedural complications
Fall	8/106 (7.5%)		2/52 (3.8%)		1/28 (3.6%)		3/25 (12%)
Infusion related reaction	8/106 (7.5%)		1/52 (1.9%)		0/28 (0%)		3/25 (12%)
Investigations
Alanine aminotransferase increased	14/106 (13.2%)		3/52 (5.8%)		1/28 (3.6%)		1/25 (4%)
Amylase increased	13/106 (12.3%)		6/52 (11.5%)		5/28 (17.9%)		3/25 (12%)
Aspartate aminotransferase increased	14/106 (13.2%)		6/52 (11.5%)		1/28 (3.6%)		2/25 (8%)
Blood alkaline phosphatase increased	9/106 (8.5%)		0/52 (0%)		1/28 (3.6%)		1/25 (4%)
Blood creatinine increased	20/106 (18.9%)		3/52 (5.8%)		5/28 (17.9%)		7/25 (28%)
Blood thyroid stimulating hormone decreased	3/106 (2.8%)		3/52 (5.8%)		0/28 (0%)		0/25 (0%)
Lipase increased	21/106 (19.8%)		8/52 (15.4%)		6/28 (21.4%)		5/25 (20%)
Weight decreased	11/106 (10.4%)		10/52 (19.2%)		8/28 (28.6%)		6/25 (24%)
Weight increased	7/106 (6.6%)		2/52 (3.8%)		1/28 (3.6%)		0/25 (0%)
Metabolism and nutrition disorders
Decreased appetite	25/106 (23.6%)		12/52 (23.1%)		5/28 (17.9%)		5/25 (20%)
Dehydration	14/106 (13.2%)		9/52 (17.3%)		6/28 (21.4%)		3/25 (12%)
Hypercalcaemia	5/106 (4.7%)		1/52 (1.9%)		1/28 (3.6%)		2/25 (8%)
Hyperglycaemia	12/106 (11.3%)		3/52 (5.8%)		2/28 (7.1%)		2/25 (8%)
Hyperkalaemia	6/106 (5.7%)		6/52 (11.5%)		0/28 (0%)		4/25 (16%)
Hypoalbuminaemia	10/106 (9.4%)		1/52 (1.9%)		3/28 (10.7%)		3/25 (12%)
Hypocalcaemia	6/106 (5.7%)		1/52 (1.9%)		1/28 (3.6%)		2/25 (8%)
Hypoglycaemia	3/106 (2.8%)		0/52 (0%)		2/28 (7.1%)		0/25 (0%)
Hypokalaemia	10/106 (9.4%)		3/52 (5.8%)		2/28 (7.1%)		1/25 (4%)
Hypomagnesaemia	13/106 (12.3%)		0/52 (0%)		5/28 (17.9%)		3/25 (12%)
Hyponatraemia	16/106 (15.1%)		7/52 (13.5%)		4/28 (14.3%)		2/25 (8%)
Hypophosphataemia	6/106 (5.7%)		0/52 (0%)		1/28 (3.6%)		1/25 (4%)
Musculoskeletal and connective tissue disorders
Arthralgia	22/106 (20.8%)		9/52 (17.3%)		5/28 (17.9%)		3/25 (12%)
Back pain	16/106 (15.1%)		9/52 (17.3%)		3/28 (10.7%)		3/25 (12%)
Flank pain	6/106 (5.7%)		7/52 (13.5%)		1/28 (3.6%)		1/25 (4%)
Muscle spasms	4/106 (3.8%)		2/52 (3.8%)		4/28 (14.3%)		1/25 (4%)
Muscular weakness	10/106 (9.4%)		7/52 (13.5%)		2/28 (7.1%)		1/25 (4%)
Musculoskeletal chest pain	1/106 (0.9%)		3/52 (5.8%)		0/28 (0%)		3/25 (12%)
Musculoskeletal discomfort	0/106 (0%)		1/52 (1.9%)		2/28 (7.1%)		0/25 (0%)
Musculoskeletal pain	10/106 (9.4%)		4/52 (7.7%)		2/28 (7.1%)		0/25 (0%)
Myalgia	6/106 (5.7%)		4/52 (7.7%)		3/28 (10.7%)		0/25 (0%)
Neck pain	8/106 (7.5%)		1/52 (1.9%)		0/28 (0%)		1/25 (4%)
Pain in extremity	13/106 (12.3%)		3/52 (5.8%)		4/28 (14.3%)		2/25 (8%)
Nervous system disorders
Dizziness	19/106 (17.9%)		7/52 (13.5%)		1/28 (3.6%)		0/25 (0%)
Headache	18/106 (17%)		11/52 (21.2%)		3/28 (10.7%)		2/25 (8%)
Paraesthesia	6/106 (5.7%)		1/52 (1.9%)		0/28 (0%)		2/25 (8%)
Peripheral sensory neuropathy	7/106 (6.6%)		1/52 (1.9%)		1/28 (3.6%)		0/25 (0%)
Tremor	2/106 (1.9%)		3/52 (5.8%)		0/28 (0%)		1/25 (4%)
Psychiatric disorders
Anxiety	12/106 (11.3%)		6/52 (11.5%)		4/28 (14.3%)		4/25 (16%)
Confusional state	3/106 (2.8%)		2/52 (3.8%)		4/28 (14.3%)		1/25 (4%)
Depression	6/106 (5.7%)		5/52 (9.6%)		2/28 (7.1%)		3/25 (12%)
Insomnia	18/106 (17%)		7/52 (13.5%)		4/28 (14.3%)		2/25 (8%)
Renal and urinary disorders
Acute kidney injury	2/106 (1.9%)		2/52 (3.8%)		4/28 (14.3%)		3/25 (12%)
Proteinuria	1/106 (0.9%)		0/52 (0%)		1/28 (3.6%)		2/25 (8%)
Respiratory, thoracic and mediastinal disorders
Cough	30/106 (28.3%)		9/52 (17.3%)		7/28 (25%)		5/25 (20%)
Dyspnoea	21/106 (19.8%)		8/52 (15.4%)		3/28 (10.7%)		5/25 (20%)
Dyspnoea exertional	5/106 (4.7%)		5/52 (9.6%)		2/28 (7.1%)		0/25 (0%)
Haemoptysis	3/106 (2.8%)		0/52 (0%)		0/28 (0%)		2/25 (8%)
Hiccups	3/106 (2.8%)		1/52 (1.9%)		3/28 (10.7%)		0/25 (0%)
Nasal congestion	6/106 (5.7%)		1/52 (1.9%)		2/28 (7.1%)		0/25 (0%)
Oropharyngeal pain	9/106 (8.5%)		1/52 (1.9%)		0/28 (0%)		2/25 (8%)
Productive cough	2/106 (1.9%)		3/52 (5.8%)		1/28 (3.6%)		2/25 (8%)
Pulmonary embolism	1/106 (0.9%)		3/52 (5.8%)		0/28 (0%)		0/25 (0%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	6/106 (5.7%)		3/52 (5.8%)		1/28 (3.6%)		1/25 (4%)
Dry skin	10/106 (9.4%)		2/52 (3.8%)		1/28 (3.6%)		0/25 (0%)
Hyperhidrosis	1/106 (0.9%)		2/52 (3.8%)		2/28 (7.1%)		0/25 (0%)
Pruritus	32/106 (30.2%)		10/52 (19.2%)		9/28 (32.1%)		5/25 (20%)
Rash	8/106 (7.5%)		3/52 (5.8%)		2/28 (7.1%)		5/25 (20%)
Rash macular	6/106 (5.7%)		0/52 (0%)		2/28 (7.1%)		0/25 (0%)
Rash maculo-papular	12/106 (11.3%)		9/52 (17.3%)		6/28 (21.4%)		7/25 (28%)
Rash papular	3/106 (2.8%)		1/52 (1.9%)		0/28 (0%)		2/25 (8%)
Rash pruritic	10/106 (9.4%)		4/52 (7.7%)		3/28 (10.7%)		1/25 (4%)
Vascular disorders
Hypertension	7/106 (6.6%)		4/52 (7.7%)		1/28 (3.6%)		1/25 (4%)
Hypotension	10/106 (9.4%)		5/52 (9.6%)		4/28 (14.3%)		3/25 (12%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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