A Randomized Phase 3 Open Label Study of Nivolumab Versus Bevacizumab and Multiple Phase 1 Safety Cohorts of Nivolumab or Nivolumab in Combination With Ipilimumab Across Different Lines of Glioblastoma
Phase: PHASE3
Conditions: Recurrent Glioblastoma
Sponsor: Bristol-Myers Squibb

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Revised Protocol No.: 07
Date: 16-Nov-2016
6
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Revised Protocol No.: 07
Date: 16-Nov-2016
10
Approved
8.0
v
Approved
1.0
v

TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Summary of Investigational Agents ......................................................... 
1.1.2 Background Information .......................................................................... 
1.1.3 Summary of Results from the Ipilimumab and Nivolumab Programs ..... 
1.1.3.1 Preclinical Summary of Nivolumab Combined with Ipilimumab ... 
1.1.3.2 Summary of Safety ........................................................................... 
1.1.3.3 Summary of Clinical Activity .......................................................... 
1.1.3.4 Summary of Clinical Trial Experience with Ipilimumab in Brain 
Metastases ............................................................................................. 
1.1.4 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab .................................................................................................. 
1.1.5 Rationale for Permitting Continued Treatment in Cases of Suspected 
Progressive Disease .................................................................................... 
1.1.8 Rationale for Investigational Treatment Arm for Cohort 2 ..................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives (Cohort 2) ............................................................. 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Safety Evaluation of Cohort 1 and 1b ...................................................... 
3.1.1.1 Evaluation of Risk/Benefit for a Treatment Arm that does not meet 
Tolerability Criteria .............................................................................. 
3.1.2 Review of Safety ....................................................................................... 
3.1.3 Treatment beyond progression ................................................................ 
3.1.4 Dose reductions ....................................................................................... 
3.1.6 Study Phases ............................................................................................ 
3.1.7 Total Study Duration................................................................................ 
3.2 Post Study Access to Therapy ........................................................................... 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 07
Date: 16-Nov-2016
11
Approved
8.0
v
Approved
1.0
v

3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 Permitted Therapy ................................................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.6 Post Treatment Study Follow up....................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 TREATMENTS ......................................................................................................... 
4.1 Study Treatments .............................................................................................. 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Non-investigational Product .................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.1.3.1 Nivolumab (BMS-936558) .............................................................. 
4.1.3.2 Ipilimumab ...................................................................................... 
4.1.3.3 Bevacizumab ................................................................................... 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Antiemetic Premedications ...................................................................... 
4.3.2 Dose Delay Criteria ................................................................................. 
4.3.2.1 Management Algorithms for Immuno-Oncology Agents ................ 
4.3.3 Dose Modifications .................................................................................. 
4.3.4 Criteria to Resume Treatment .................................................................. 
4.3.5 Discontinuation Criteria .......................................................................... 
4.3.6 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...... 
4.3.7 Treatment Beyond Initial Radiological Assessment of Disease 
Progression ................................................................................................. 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Head Magnetic Resonance Imaging (MRI) ............................................. 
5.4.2 Efficacy Assessments ................................................................................ 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 07
Date: 16-Nov-2016
12
Approved
8.0
v
Approved
1.0
v

5.6.7 Tumor Samples......................................................................................... 
5.6.7.1 Tumor-Based Biomarker Measures ................................................ 
5.6.8 Tumor sample collection details .............................................................. 
5.9 Results of Central Radiologic Assessments ...................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) (Cohort 2) ........................................................... 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Analyses of Primary Endpoint ........................................................ 
8.4.2.2 Analyses of Secondary Endpoints ................................................... 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 07
Date: 16-Nov-2016
13
Approved
8.0
v
Approved
1.0
v

8.4.3 Safety Analyses......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 KARNOFSKY PERFORMANCE SCALES ........................................ 
APPENDIX 2 MANAGEMENT ALGORITHMS ....................................................... 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 07
Date: 16-Nov-2016
14
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
15
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
16
Approved
8.0
v
Approved
1.0
v

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1.1.2
Background Information 
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Revised Protocol No.: 07
Date: 16-Nov-2016
17
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
18
Approved
8.0
v
Approved
1.0
v

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1.1.3
Summary of Results from the Ipilimumab and Nivolumab Programs
1.1.3.1
Preclinical Summary of Nivolumab Combined with Ipilimumab
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Revised Protocol No.: 07
Date: 16-Nov-2016
19
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
20
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Revised Protocol No.: 07
Date: 16-Nov-2016
21
Approved
8.0
v
Approved
1.0
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Revised Protocol No.: 07
Date: 16-Nov-2016
22
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
23
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
24
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Date: 16-Nov-2016
25
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Revised Protocol No.: 07
Date: 16-Nov-2016
26
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Revised Protocol No.: 07
Date: 16-Nov-2016
27
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Revised Protocol No.: 07
Date: 16-Nov-2016
28
Approved
8.0
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1.0
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Revised Protocol No.: 07
Date: 16-Nov-2016
29
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8.0
v
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Revised Protocol No.: 07
Date: 16-Nov-2016
30
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
31
Approved
8.0
v
Approved
1.0
v

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1.1.4
Rationale to Support Dose/Schedule of Nivolumab Combined with 
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Revised Protocol No.: 07
Date: 16-Nov-2016
32
Approved
8.0
v
Approved
1.0
v

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1.1.5
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Progressive Disease
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Revised Protocol No.: 07
Date: 16-Nov-2016
33
Approved
8.0
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Revised Protocol No.: 07
Date: 16-Nov-2016
34
Approved
8.0
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1.0
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Revised Protocol No.: 07
Date: 16-Nov-2016
35
Approved
8.0
v
Approved
1.0
v

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1.3.2
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Revised Protocol No.: 07
Date: 16-Nov-2016
36
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
37
Approved
8.0
v
Approved
1.0
v

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Date: 16-Nov-2016
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Revised Protocol No.: 07
Date: 16-Nov-2016
41
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
42
Approved
8.0
v
Approved
1.0
v

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Revised Protocol No.: 07
Date: 16-Nov-2016
43
Approved
8.0
v
Approved
1.0
v

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3.1.1
Safety Evaluation of Cohort 1 and 1b
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Revised Protocol No.: 07
Date: 16-Nov-2016
44
Approved
8.0
v
Approved
1.0
v

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3.1.1.1
Evaluation of Risk/Benefit for a Treatment Arm that does not meet 
Tolerability Criteria
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Revised Protocol No.: 07
Date: 16-Nov-2016
45
Approved
8.0
v
Approved
1.0
v

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3.1.2
Review of Safety
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3.1.3
Treatment beyond progression
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3.1.4
Dose reductions
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Revised Protocol No.: 07
Date: 16-Nov-2016
46
Approved
8.0
v
Approved
1.0
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Revised Protocol No.: 07
Date: 16-Nov-2016
47
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Revised Protocol No.: 07
Date: 16-Nov-2016
48
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8.0
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Revised Protocol No.: 07
Date: 16-Nov-2016
49
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8.0
v
Approved
1.0
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Revised Protocol No.: 07
Date: 16-Nov-2016
50
Approved
8.0
v
Approved
1.0
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Date: 16-Nov-2016
61
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Date: 16-Nov-2016
63
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Revised Protocol No.: 07
Date: 16-Nov-2016
64
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8.0
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Date: 16-Nov-2016
65
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Date: 16-Nov-2016
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Date: 16-Nov-2016
77
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Revised Protocol No.: 07
Date: 16-Nov-2016
82
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8.3.1
Primary Endpoint(s)
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DQGWKHGDWHRIGHDWKGXHWRDQ\FDXVH$VXEMHFWZKRKDVQRWGLHGZLOOEHFHQVRUHGDWWKHODVW
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8.3.2
Secondary Endpoint(s) (Cohort 2)
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UDWHDWPRQWKVIURP.DSODQ0HLHUFXUYHRI26
7KHVHFRQGVHFRQGDU\REMHFWLYHFRPSDULQJ3)6EHWZHHQDUP1DQGDUP%ZLOOEHPHDVXUHG
E\WKHHQGSRLQWRI3)63)6LVGHILQHG DVWKHWLPHIURPUDQGRPL]DWLRQWRWKHGDWHRIWKHILUVW
GRFXPHQWHGWXPRUSURJUHVVLRQRUGHDWKGXHWRDQ\FDXVH6XEMHFWVZKRGLHZLWKRXWDUHSRUWHG
SULRUSURJUHVVLRQZLOOEHFRQVLGHUHGWRKDYHSURJUHVVHGRQWKHGDWHRIGHDWK6XEMHFWVZKRGLG
QRW KDYH GLVHDVH SURJUHVVLRQ RU GLH ZLOO EH FHQVRUHG DW WKH GDWH RI ODVW WXPRU DVVHVVPHQW
6XEMHFWVZKRGLGQRWKDYHDQ\RQVWXG\WXPRUDVVHVVPHQWDQGGLGQRWGLHZLOOEHFHQVRUHGDWWKH
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Revised Protocol No.: 07
Date: 16-Nov-2016
103
Approved
8.0
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GLIIHUHQWLDWLQJ UDGLRORJLF SURJUHVVLRQ IURP SVHXGRSURJUHVVLRQ DQG WXPRU SDWKRORJ\ GRHV QRW
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GRFXPHQWHG. 6XEMHFWV ZLWK QRQPHDVXUHDEOH GLVHDVH DW EDVHOLQH ZLOO EH FRQVLGHUHG WR KDYH
SURJUHVVHG LI WKHUH LV DQ DSSHDUDQFH RI QHZ OHVLRQV FRQVLVWHQW ZLWK WXPRU DQ\ XQHTXLYRFDO
LQFUHDVH LQ EDVHOLQH HQKDQFLQJ GLVHDVH WKH XQHTXLYRFDO DSSHDUDQFH RI QHZ WXPRU JURZWK RU
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7KHODVWVHFRQGDU\REMHFWLYHFRPSDULQJ255EHWZHHQDUP1DQGDUP%ZLOOEHPHDVXUHGE\
WKHHQGSRLQWRI255255 LVGHILQHGDVWKHQXPEHURI VXEMHFWVZKRVH EHVWRYHUDOOUHVSRQVH
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DVWKHEHVWUHVSRQVHGHVLJQDWLRQDVGHWHUPLQHGE\LQYHVWLJDWRUVUHFRUGHGEHWZHHQWKHGDWHRI
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DYDLODEOHUHVSRQVHGHVLJQDWLRQVZLOOFRQWULEXWHWRWKH%25DVVHVVPHQWV%25ZLOOEHGHWHUPLQHG
E\LQYHVWLJDWRUUHSRUWHGUHVSRQVHEDVHGRQ5$12FULWHULD
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VXEVHTXHQWWKHUDS\ SULRU WRWKH ZHHNWXPRU DVVHVVPHQWWKLV VXEMHFWZLOO EHFRXQWHG LQWKH
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8.3.3
Exploratory Endpoint(s) 
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E\WKHHQGSRLQWVGXUDWLRQRIUHVSRQVH'25DQGWLPHWRUHVSRQVH775'25LVGHILQHGDVWKH
WLPHEHWZHHQWKHGDWHRIILUVWGRFXPHQWHGUHVSRQVH&5RU35WRWKHGDWHRIILUVWGRFXPHQWHG
WXPRUSURJUHVVLRQSHU5$12FULWHULDDVVHVVHGE\WKHLQYHVWLJDWRURUGHDWKGXHWRDQ\FDXVH
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WLPHWKH\ZLOOEHFHQVRUHGIRUWKHSULPDU\GHILQLWLRQRI3)6775LVGHILQHGDVWKHWLPHIURP
UDQGRPL]DWLRQWRWKHGDWHRIWKHILUVWGRFXPHQWHG&5RU35SHULQYHVWLJDWRUUHSRUWHG5$12
FULWHULD6HFWLRQ'25DQG775ZLOOEHHYDOXDWHGIRUUHVSRQGHUV&5RU35RQO\
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HYHQWVGHDWKVDQGODERUDWRU\DEQRUPDOLWLHV
Revised Protocol No.: 07
Date: 16-Nov-2016
104
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8.4.1
Demographics and Baseline Characteristics
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JURXS DVWUHDWHGIRU &RKRUW  DQGE DQG LQDOOUDQGRPL]HGVXEMHFWV E\WUHDWPHQWJURXS DV
UDQGRPL]HGIRU&RKRUWXVLQJGHVFULSWLYHVWDWLVWLFV
8.4.2
Efficacy Analyses
7KH DQDO\VHV RI SULPDU\ DQG VHFRQGDU\ HQGSRLQWV ZLOO RQO\ LQFOXGH VXEMHFWV ZKR HQUROOHG LQ
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LQ 26 LV GHPRQVWUDWHG D KLHUDUFKLFDO K\SRWKHVLV WHVWLQJ DSSURDFK IRU WKH NH\ VHFRQGDU\
HQGSRLQWV ZLOO EH XVHG WR SUHVHUYH D VWXG\ZLVH W\SH , HUURU UDWH DW 7KH NH\ VHFRQGDU\
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8.4.2.1
Analyses of Primary Endpoint 
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Revised Protocol No.: 07
Date: 16-Nov-2016
105
Approved
8.0
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Approved
1.0
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8.4.2.2
Analyses of Secondary Endpoints 
7KHFRPSDULVRQRI26ZLOOEHEDVHGRQDWZRVLGHG=WHVW7KHFRPSDULVRQRI3)6ZLOOEH
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WKHWHVWLQJSURFHGXUHEDVHGZLOOEHVSHFLILHGLQWKHVWDWLVWLFDODQDO\VLVSODQ
8.4.3
Safety Analyses
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6$(VDQGWUHDWPHQWUHODWHG6$(VZLOOEHWDEXODWHGXVLQJZRUVWJUDGHSHU1&,&7&$(Y
FULWHULD E\ V\VWHP RUJDQ FODVV DQG SUHIHUUHG WHUP 2QVWXG\ ODE SDUDPHWHUV LQFOXGLQJ
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Revised Protocol No.: 07
Date: 16-Nov-2016
106
Approved
8.0
v
Approved
1.0
v

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9.1.1
Compliance with the Protocol and Protocol Revisions 
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PXVWEHGLVFXVVHGZLWKDQGEHSUHSDUHGE\%067KHLQYHVWLJDWRUVKRXOGQRWLPSOHPHQWDQ\
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Revised Protocol No.: 07
Date: 16-Nov-2016
107
Approved
8.0
v
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1.0
v

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9.1.2
Monitoring
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9.1.3
Investigational Site Training
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9.2.1
Records Retention
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Date: 16-Nov-2016
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Revised Protocol No.: 04e
Date: 16-Nov-2016
9
6.0
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Revised Protocol No.: 04e
Date: 16-Nov-2016
10
6.0
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Revised Protocol No.: 04e
Date: 16-Nov-2016
11
6.0
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Date: 16-Nov-2016
12
6.0
Approved v
Approved
1.0
v

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Date: 16-Nov-2016
13
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
14
6.0
Approved v
Approved
1.0
v

TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Summary of Investigational Agents ......................................................... 
1.1.2 Background Information .......................................................................... 
1.1.3 Summary of Results from the Ipilimumab and Nivolumab Programs ..... 
1.1.3.1 Preclinical Summary of Nivolumab Combined with Ipilimumab ... 
1.1.3.2 Preclinical Summary of Nivolumab Combined with Radiation 
Therapy for GBM .................................................................................. 
1.1.3.3 Summary of Clinical Safety ............................................................. 
1.1.3.4 Summary of Clinical Activity .......................................................... 
1.1.3.5 Summary of Clinical Trial Experience with Ipilimumab in Brain 
Metastases ............................................................................................. 
1.1.4 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Ipilimumab .................................................................................................. 
1.1.5 Rationale for Permitting Continued Treatment in Cases of Suspected 
Progressive Disease .................................................................................... 
1.1.8 Rationale for Investigational Treatment Arm for Cohort 2 ..................... 
1.1.9 Rationale for Expansion of Cohorts 1C and 1D (Part B) ........................ 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives(s) ..................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Safety Evaluation of Safety Cohorts ........................................................ 
3.1.1.1 Safety Evaluation of Cohorts 1 and 1b ........................................... 
3.1.1.2 Safety Evaluation of Cohorts 1c and 1d ......................................... 
3.1.1.3 Evaluation of Risk/Benefit for a Treatment Arm that does not meet 
Tolerability Criteria .............................................................................. 
3.1.2 Review of Safety ....................................................................................... 
3.1.3 Treatment beyond progression ................................................................ 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 04e
Date: 16-Nov-2016
15
6.0
Approved v
Approved
1.0
v

3.1.4 Dose reductions ....................................................................................... 
3.1.6 Study Phases ............................................................................................ 
3.1.7 Total Study Duration................................................................................ 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 Permitted Therapy ................................................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.6 Post Treatment Study Follow up....................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 TREATMENTS ......................................................................................................... 
4.1 Study Drugs ...................................................................................................... 
4.1.1 Investigational Product ............................................................................ 
4.1.2 Non-investigational Product .................................................................... 
4.1.3 Handling and Dispensing ........................................................................ 
4.1.3.1 Nivolumab (BMS-936558) .............................................................. 
4.1.3.2 Ipilimumab ...................................................................................... 
4.1.3.3 Bevacizumab ................................................................................... 
4.2 Method of Assigning Subject Identification ..................................................... 
4.3 Selection and Timing of Dose for Each Subject ............................................... 
4.3.1 Premedications ........................................................................................ 
4.3.2 Dose Delay Criteria ................................................................................. 
4.3.2.1 Management Algorithms for Immuno-Oncology Agents ................ 
4.3.3 Dose Modifications .................................................................................. 
4.3.4 Criteria to Resume Treatment .................................................................. 
4.3.5 Discontinuation Criteria .......................................................................... 
4.3.6 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ...... 
4.3.7 Treatment Beyond Initial Radiological Assessment of Disease 
Progression ................................................................................................. 
4.4 Blinding/Unblinding ......................................................................................... 
4.5 Treatment Compliance ...................................................................................... 
4.6 Destruction and Return of Study Drug ............................................................. 
4.6.1 Destruction of Study Drug ....................................................................... 
4.6.2 Return of Study Drug ............................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 04e
Date: 16-Nov-2016
16
6.0
Approved v
Approved
1.0
v

5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Head Magnetic Resonance Imaging (MRI) ............................................. 
5.4.2 Efficacy Assessments ................................................................................ 
5.6.7 Tumor Samples......................................................................................... 
5.6.7.1 Tumor-Based Biomarker Measures ................................................ 
5.6.8 Tumor sample collection details .............................................................. 
5.9 Results of Central Radiologic Assessments ...................................................... 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) (Cohort 2) ........................................................... 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 04e
Date: 16-Nov-2016
17
6.0
Approved v
Approved
1.0
v

8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Analyses of Primary Endpoint ........................................................ 
8.4.2.2 Analyses of Secondary Endpoints ................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 KARNOFSKY PERFORMANCE SCALES ........................................ 
APPENDIX 2 MANAGEMENT ALGORITHMS ....................................................... 
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Clinical Protocol
BMS-936558
CA209143
nivolumab
Revised Protocol No.: 04e
Date: 16-Nov-2016
18
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
19
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
20
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
21
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
22
6.0
Approved v
Approved
1.0
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Revised Protocol No.: 04e
Date: 16-Nov-2016
23
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
24
6.0
Approved v
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Revised Protocol No.: 04e
Date: 16-Nov-2016
25
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
26
6.0
Approved v
Approved
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v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
27
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
28
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
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Revised Protocol No.: 04e
Date: 16-Nov-2016
30
6.0
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Revised Protocol No.: 04e
Date: 16-Nov-2016
31
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Revised Protocol No.: 04e
Date: 16-Nov-2016
32
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Revised Protocol No.: 04e
Date: 16-Nov-2016
33
6.0
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Revised Protocol No.: 04e
Date: 16-Nov-2016
34
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
35
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
36
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
37
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
38
6.0
Approved v
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Revised Protocol No.: 04e
Date: 16-Nov-2016
39
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
40
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
41
6.0
Approved v
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1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
42
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
43
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
44
6.0
Approved v
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1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
45
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
46
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
47
6.0
Approved v
Approved
1.0
v

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Secondary Objectives
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Revised Protocol No.: 04e
Date: 16-Nov-2016
48
6.0
Approved v
Approved
1.0
v

&OLQLFDO3URWRFRO
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Revised Protocol No.: 04e
Date: 16-Nov-2016
49
6.0
Approved v
Approved
1.0
v

&OLQLFDO3URWRFRO
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Date: 16-Nov-2016
56
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Revised Protocol No.: 04e
Date: 16-Nov-2016
57
6.0
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Revised Protocol No.: 04e
Date: 16-Nov-2016
58
6.0
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59
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3.1.1.2
Safety Evaluation of Cohorts 1c and 1d
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GLDJQRVHG XQPHWK\ODWHG 0*07 *%0 &RKRUW G ZLOO EH HQUROOHG WR UHFHLYH QLYROXPDE
PRQRWKHUDS\
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SULRUWRFRPSOHWLQJIRXUGRVHV+RZHYHUWROHUDELOLW\EH\RQGIRXUGRVHVPD\DOVREHWDNHQLQWR
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HQUROOPHQWLQHDFK WUHDWPHQWDUPLVEDVHGRQGUXJUHODWHGDGYHUVHHYHQWVOHDGLQJWRSHUPDQHQW
GLVFRQWLQXDWLRQ LQ WKH VDIHW\ OHDGLQ FRKRUWV OLVWHG LQ 6HFWLRQ  DQG DELOLW\ WR WROHUDWH
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•
1RPRUHWKDQRQHWKLUGRIWKHILUVWVXEMHFWVLQDFRKRUW &RKRUWVFRU G SHUPDQHQWO\
GLVFRQWLQXHVWXG\GUXJSULRUWRFRPSOHWLQJIRXUGRVHV GXHWRWUHDWPHQWUHODWHG DGYHUVHHYHQWV
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1R PRUHWKDQRQHWKLUG RI WKHVXEMHFWV LQDJLYHQFRKRUW &RKRUWVFRU GSHUPDQHQWO\
GLVFRQWLQXH VWDQGDUG RI FDUH FKHPRUDGLDWLRQ ZLWK WHPR]RORPLGH &RKRUW F RU UDGLDWLRQ
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Revised Protocol No.: 04e
Date: 16-Nov-2016
60
6.0
Approved v
Approved
1.0
v

&OLQLFDO3URWRFRO
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FRPSOHWLQJ IRXU GRVHV GXH WR WUHDWPHQWUHODWHG DGYHUVH HYHQWV LQFOXGLQJ GXULQJ WKH LQLWLDO
 VXEMHFW VDIHW\OHDGLQIXUWKHUDFFUXDOZLOOEHLPPHGLDWHO\LQWHUUXSWHGZKLOHWKHVDIHW\DQG
WROHUDELOLW\RIWKDWFRKRUW LV UHYLHZHGZLWKWKH'0&6HFWLRQ$GHFLVLRQZLOOEHPDGH
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3.1.1.3
Evaluation of Risk/Benefit for a Treatment Arm that does not meet 
Tolerability Criteria
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GHWHUPLQHZKHWKHURUQRWWRDGYDQFHWKDWDUP,QWKLVHYHQWWKH'0&ZLOOUHYLHZDOODYDLODEOH
FRKRUW GDWD&RKRUWV EFRU GDQGUHFRPPHQGFRQWLQXDWLRQPRGLILFDWLRQRUWHUPLQDWLRQ
RIWKHWUHDWPHQWDUP7KHUDWLRQDOHIRUIXUWKHUHYDOXDWLRQZLWKWKH'0&LVWKDWWKHPRVWIUHTXHQW
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•
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PRQLWRUDEOHYLDURXWLQHEORRGGUDZV
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PHHWLQJ WKH µQRW WROHUDEOH¶ FULWHULD DERYH WKHQ WKH '0& DQG (&,5%V PXVW EH QRWLILHG
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3.1.2
Review of Safety
7KHVXEMHFWV¶VDIHW\ZLOOEHPRQLWRUHGRQDQRQJRLQJEDVLVDVGHVFULEHGIXOO\LQ6HFWLRQ6DIHW\
FRQIHUHQFHFDOOVZLWKLQYHVWLJDWRUVDQGUHSUHVHQWDWLYHVRIWKHVSRQVRUZLOOEHKHOG DV QHFHVVDU\
$Q LQGHSHQGHQW 'DWD 0RQLWRULQJ &RPPLWWHH '0& ZLOO SURYLGH VDIHW\ UHYLHZV HYHU\ VL[
PRQWKV RU DV GHILQHG LQ WKH '0& &KDUWHU 'HFLVLRQV UHJDUGLQJ VDIHW\ ZLOO EH PDGH E\ WKH
VSRQVRULQFRQMXQFWLRQZLWKIHHGEDFNIURPWKHLQYHVWLJDWRUV DQGWKH'0&,QDGGLWLRQD%06
PHGLFDO VDIHW\ WHDP 067 ZLOO URXWLQHO\ UHYLHZV VDIHW\ VLJQDOV DFURVV WKH HQWLUH QLYROXPDE
SURJUDPLQFOXGLQJFRPELQDWLRQVWXGLHVZLWKLSLOLPXPDE 7KH'0&ZLOOPHHWRQDUHJXODUEDVLV
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Revised Protocol No.: 04e
Date: 16-Nov-2016
61
6.0
Approved v
Approved
1.0
v

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3.1.3
Treatment beyond progression
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3.1.4
Dose reductions
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3.1.6
Study Phases
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Revised Protocol No.: 04e
Date: 16-Nov-2016
62
6.0
Approved v
Approved
1.0
v

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Revised Protocol No.: 04e
Date: 16-Nov-2016
63
6.0
Approved v
Approved
1.0
v

&OLQLFDO3URWRFRO
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3.1.7
Total Study Duration
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Revised Protocol No.: 04e
Date: 16-Nov-2016
77
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Date: 16-Nov-2016
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Date: 16-Nov-2016
81
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Date: 16-Nov-2016
102
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Date: 16-Nov-2016
103
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Revised Protocol No.: 04e
Date: 16-Nov-2016
121
6.0
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Date: 16-Nov-2016
122
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Revised Protocol No.: 04e
Date: 16-Nov-2016
123
6.0
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Revised Protocol No.: 04e
Date: 16-Nov-2016
124
6.0
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8.3.3
Exploratory Endpoint(s) 
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Revised Protocol No.: 04e
Date: 16-Nov-2016
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8.4.1
Demographics and Baseline Characteristics
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8.4.2
Efficacy Analyses
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8.4.2.1
Analyses of Primary Endpoint 
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8.4.2.2
Analyses of Secondary Endpoints 
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8.4.3
Safety Analyses
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Revised Protocol No.: 04e
Date: 16-Nov-2016
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Date: 16-Nov-2016
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9.1.1
Compliance with the Protocol and Protocol Revisions 
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9.1.2
Monitoring
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Revised Protocol No.: 04e
Date: 16-Nov-2016
128
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Investigational Site Training
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9.2.1
Records Retention
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9.2.2
Study Drug Records 
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Revised Protocol No.: 04e
Date: 16-Nov-2016
129
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Case Report Forms
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