Conditions: Solid Tumor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether the combination of Ulocuplumab and Nivolumab is safe and effective in the treatment of pancreatic cancer and small cell lung cancer.

Detailed description:
* Intervention model: Single group for Stage 1 DLT, then Parallel
* Data Monitoring Committee: No (Stage 1) Yes (Stage 2 Randomized Ph2)

Arms:
arm 1: Small cell lung cancer (SCLC) arm 2: Pancreatic cancer (PAC)

Interventions: intervention 1: Ulocuplumab intervention 2: Nivolumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_001.pdf: 
Page:
1
Protocol Number:
CA212115
IND Number:
125564
Ex-US
Non-IND
EUDRACT Number
2015-000136-15
Date:
23-Mar-2015
Revised Date:
13-Jan-2016
Clinical Protocol CA212115
A Phase 1/2 Study of the Safety and Efficacy of Ulocuplumab Combined with Nivolumab in 
Subjects with Advanced or Metastatic Solid Tumors
(CXCessoR4: Clinical trial of the anti-CXCR4 antibody ulocuplumab in malignant tumors)
Revised Protocol Number: 03
Incorporates Amendment: 04
Study Director
Medical Monitor
Glenn Kroog, MD
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
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CA212115
BMS-936564/BMS-936558
ulocuplumab/nivolumab
Revised Protocol No.: 03
Date: 13-Jan-2016
2
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Clinical Protocol
CA212115
BMS-936564/BMS-936558
ulocuplumab/nivolumab
Revised Protocol No.: 03
Date: 13-Jan-2016
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised Protocol 
03
13-Jan-2016
Incorporates Amendment 04
Amendment 04
13-Jan-2016
This amendment changes DLT, dose delay, dose modification and 
dose discontinuation criteria to align with nivolumab program 
standard language. Additional changes have been made to platelet 
inclusion criteria and prohibited medications. Chest x-rays were added 
to monitor for pulmonary toxicity. Administrative edits and 
clarifications are also incorporated.
Revised Protocol 
02
16-Sep-2015
Incorporates Amendment 03
Amendment 03
16-Sep-2015
This 
amendment 
changes 
dose 
delay, 
dose 
modification, 
discontinuation and dose limiting toxicity (DLT) criteria to account 
for the known toxicity profiles of ulocuplumab and nivolumab and 
correct internal inconsistencies in the management of toxicity. The 
major change is to remove the requirement to discontinue study 
therapy for grade 3 platelets > 7 days and replace it with the 
recommendation to hold study therapy for grade 3 platelets > 7 days.
Revised Protocol 
01
20-May-2015
Incorporates Amendment 02
Amendment 02
20-May-2015
This amendment adds a sentinel 400 mg weekly ulocuplumab dose 
level in the dose evaluation phase at the request of regulatory 
authorities. It also incorporates administrative edits and minor 
clarifications to the study procedures.
This amendment applies to all subjects and is to be implemented after 
IRB/IEC/HA review.
Original Protocol
23-Mar-2015
Not applicable
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CA212115
BMS-936564/BMS-936558
ulocuplumab/nivolumab
SYNOPSIS
Clinical Protocol CA212115
Protocol Title: A Phase 1/2 Study of the Safety and Efficacy of Ulocuplumab Combined with Nivolumab in 
Subjects with Advanced or Metastatic Solid Tumors
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):

Ulocuplumab 200 mg, 400 mg, 800 mg or 1600 mg administered IV over 60 minutes every week combined 
with nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks until progression

Ulocuplumab 1600 mg administered IV over 60 minutes every 2 weeks combined with nivolumab administered 
IV over 60 minutes at 3 mg/kg every 2 weeks until progression
Study Phase: 1/2
Research Hypothesis: Treatment with ulocuplumab plus nivolumab will be safe, tolerable and demonstrate a 
clinically meaningful efficacy in subjects with advanced or metastatic solid tumors.
Objectives:
Primary Objective:

Stage 1: To identify the recommended dose and schedule of ulocuplumab, based on safety and efficacy, in 
combination with nivolumab in subjects with advanced or metastatic tumors

Stage 2: To evaluate the efficacy, separately by tumor type, based on objective response rate (ORR) or overall 
survival (OS; randomized Phase 2 study in pancreatic adenocarcinoma (PAC) only), of ulocuplumab combined 
with nivolumab in subjects with advanced or metastatic tumors
Secondary Objectives:

To assess the safety and tolerability of ulocuplumab combined with nivolumab, in subjects with advanced or 
metastatic tumors

To assess progression-free survival (PFS) with ulocuplumab combined with nivolumab, separately by tumor 
type, in subjects with advanced or metastatic tumors
Exploratory Objectives:

 
 
 
 
 
 
Study Design: This is an open-label, multicenter phase 1/2 study to evaluate safety and efficacy of ulocuplumab in 
combination with nivolumab in subjects with small cell lung cancer (SCLC) and PAC. The study design allows for 
the testing of different doses and schedules of ulocuplumab in the Dose Evaluation Phase. In addition, the protocol 
Revised Protocol No.: 03
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Clinical Protocol
CA212115
BMS-936564/BMS-936558
ulocuplumab/nivolumab
incorporates a flexible design to permit the initiation of a randomized Phase 2 study with comparative arm in the 
Dose Expansion Phase if high efficacy is observed. If high efficacy is not observed, the study continues as a single 
arm study for the Dose Expansion Phase.
Dose Evaluation Phase (Stage 1)
Dose Expansion Phase (Stage2)
Study Population: Subjects with pathologically confirmed locally advanced or metastatic SCLC and PAC that have 
failed at least one prior line of chemotherapy are eligible. Subjects must have an ECOG score of 0-1. Subjects with 
active brain metastases are excluded.
Study Drug:
Study Drug for CA212115
Medication 
Potency 
IP/Non-IP 
Ulocuplumab (BMS-936564)
100 mg (10 mg/mL)
IP
Nivolumab (BMS-936558 )
100 mg (10 mg/mL)
IP
U=ulocuplumab
N=nivolumab
DLT evaluation 
(n=3-6 pts @ 6 wks)
=
Stage 1 safety and efficacy evaluation per 
tumor type @ 3 mos
=
unacceptable 
toxicity/DLTs 
DL 2 
U 800 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
unacceptable 
toxicity/DLTs 
DL 2
U 800 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3A
U 1600 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3B
U 1600 mg q2wk + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 1
U 400 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 2
U 800 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3A
U 1600 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
acceptable 
toxicity
acceptable 
toxicity
randomization
DL 1 
U 400 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC or PAC
DL -1
U 200 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL -1
U 200 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
unacceptable 
toxicity/DLTs 
acceptable 
toxicity
acceptable 
toxicity
Simon 2-stage (per tumor type):
Randomized Phase 2 (per tumor type):. 
DLX (recommended dose from Stage 1)
Nivo Mono (for SCLC) or Inv Choice (for PAC)
DLX  (recommended dose from Stage 1)
n=25 SCLC and 20 PAC
OR
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CA212115
BMS-936564/BMS-936558
ulocuplumab/nivolumab
Study Assessments: Radiographic tumor assessments will be performed at baseline, at 6 weeks from first dose and 
continue every 6 weeks for the first 24 weeks and every 12 weeks thereafter until disease progression or treatment 
discontinuation.
Statistical Considerations:
Sample Size: The sample size will start at dose level 1 (DL1) with a minimum of 3 treated subjects with either PAC 
or SCLC using a Rolling Six design for evaluation of dose limiting toxicity (DLT). Then, the sample size will be 
increased by the number of subjects separately by tumor type needed to continue the DLT evaluation at each dose 
level followed by the number of subjects separately by tumor type needed for one or three randomized cohort(s) to 
complete the Dose Evaluation Phase. Finally, the sample size will be increased by the number of subjects needed for 
the Dose Expansion Phase selected for each tumor type.
For SCLC, up to approximately 175 treated subjects may be needed. This sample size considers 3-18 subjects for the 
DLT evaluation and 19 subjects per cohort (57 subjects for three randomized cohorts) of the Dose Evaluation Phase. 
The Dose Expansion Phase in the form of a second stage of a Simon 2-stage like design would require an additional 
25 subjects OR in the form of a randomized Phase 2 study with a comparative arm would require an additional 
50 subjects per arm (ie. 100 subjects for the two arms). 
For PAC, up to approximately 331 treated subjects may be needed. This sample size considers 3-18 subjects for the 
DLT evaluation and 21 subjects per cohort (63 subjects for three randomized cohorts) for the Dose Evaluation 
Phase. The Dose Expansion Phase in the form of a second stage of a Simon 2-stage like design would require an 
additional 20 subjects OR in the form of a randomized Phase 2 study with a comparative arm would require an 
additional 125 subjects per arm (ie. 250 subjects for the two arms). 
Endpoints: The primary efficacy endpoint will be ORR, as determined by the investigators, for the Dose Evaluation 
Phase and if a Simon 2-stage like design is continued for the Dose Expansion Phase. If a randomized Phase 2 study 
with a comparative arm is selected for the Dose Expansion Phase, the primary efficacy endpoint will be ORR for 
SCLC and OS for PAC. Secondary efficacy endpoints will consist of safety, tolerability and PFS. Safety and 
tolerability endpoints will consist of the incidence of DLT (primary safety endpoint during the DLT evaluation 
phase), adverse events (AE), serious adverse events (SAE) and specific laboratory abnormalities (worst grade). 
Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0
Analyses: All analyses will be presented separately by tumor type. Within a tumor type, the Dose Evaluation Phase 
analyses will be presented by cohort. If a Simon 2-stage like design is completed, analyses of the Dose Evaluation 
Phase and the Dose Expansion Phase will be pooled and presented by cohort. If a randomized Phase 2 study with 
comparator arm is initiated, the analyses of this design will be presented by treatment arm.
Baseline characteristics and efficacy analyses will be summarized for the All Dose Evaluation Randomized Treated 
Subjects (primary population) and the All Treated Subjects population by cohort (and, if a randomized two-arm 
Phase 2 study is initiated, for the All Dose Expansion Randomized Subjects population by randomized treatment 
arm). ORR will be summarized by a binomial response rate and corresponding two-sided 95% exact CI using the 
Clopper and Pearson method. If a randomized Phase 2 study is initiated, ORR will be compared between the 
treatment arms using a one-sided alpha level of 0.10 with Cochran-Mantel-Haenszel (CMH) test stratified by the 
stratification factors defined for each tumor type. The primary analysis of OS as primary endpoint for PAC will be a 
comparison of the OS of subjects randomized to ulocuplumab plus nivolumab to that of subjects randomized to the 
investigator’s choice chemotherapy using a one-sided alpha level of 0.10 log-rank test stratified by the stratification 
factors defined for each tumor type. PFS and OS will be summarized using the Kaplan-Meier (KM) product-limit 
method.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Unmet Medical Need in Small Cell Lung Cancer (SCLC) ...................... 
1.1.2 Rationale for Ulocuplumab in Combination with Nivolumab in SCLC .. 
1.1.3 Unmet Medical Need in Pancreatic Adenocarcinoma (PAC) ................. 
1.1.4 Rationale for Ulocuplumab in Combination with Nivolumab in PAC .... 
1.1.5 Preclinical Rationale for the Dual Inhibition of CXCR4 and PD-1 ........ 
1.1.6 Rationale for Study Design ...................................................................... 
1.1.7 Rationale for Dose Selection of Ulocuplumab......................................... 
1.1.8 Rationale for Dose Selection of Nivolumab ............................................. 
1.1.9 Rationale for Biomarker Analysis ............................................................ 
1.1.10 Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease .................................................................................... 
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 ................................................................... 
1.4.1 Ulocuplumab ............................................................................................ 
1.4.1.1 Ulocuplumab Safety ........................................................................ 
1.4.1.2 Ulocuplumab Clinical Activity ........................................................ 
1.4.2 Nivolumab ................................................................................................ 
1.4.2.1 Nivolumab Safety ............................................................................ 
1.4.2.2 Nivolumab Clinical Activity ............................................................ 
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 Dose Evaluation Phase (Stage 1) ............................................................ 
3.1.2 Decision Rules to Proceed with Dose Expansion Phase ......................... 
3.1.3 Dose Expansion Phase (Stage 2) ............................................................. 
3.1.4 Dose Limiting Toxicity ............................................................................. 
3.2 Post Study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
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ulocuplumab/nivolumab
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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 ......................................................... 
3.4.2.1 Palliative Radiation Therapy .......................................................... 
3.4.2.2 Surgical Resection Following Initial Response .............................. 
3.4.2.3 Corticosteroid Treatment ................................................................ 
3.4.2.4 Imaging Restrictions ....................................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage and Dispensing..................................................................................... 
4.3.1 Ulocuplumab (BMS-936564) ................................................................... 
4.3.2 Nivolumab (BMS-936558) ....................................................................... 
4.3.3 Ulocuplumab and Nivolumab Combination ............................................ 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Dose Delays and Interruptions ................................................................ 
4.5.1.1 Ulocuplumab Dose Delay ............................................................... 
4.5.1.2 Nivolumab Dose Delay ................................................................... 
4.5.1.3 Criteria to Resume Nivolumab Treatment ...................................... 
4.5.1.4 Ulocuplumab or Nivolumab Dose Interruptions ............................ 
4.5.2 Dose Modifications .................................................................................. 
4.5.2.1 Ulocuplumab Dose Modification Criteria ...................................... 
4.5.2.2 Nivolumab Dose Modification Criteria .......................................... 
4.5.3 Discontinuation Criteria .......................................................................... 
4.5.3.1 Ulocuplumab Discontinuation Criteria .......................................... 
4.5.3.2 Nivolumab Discontinuation Criteria .............................................. 
4.5.4 Treatment of Ulocuplumab- or Nivolumab-Related Infusion Reactions . 
4.5.5 Treatment Beyond Disease Progression .................................................. 
4.5.6 Antiemetic Premedications ...................................................................... 
4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction of Study Drug ................................................................................ 
4.9 Return of Study Drug ........................................................................................ 
4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Imaging Assessment for the Study............................................................ 
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CA212115
ulocuplumab/nivolumab
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5.3.1.1 CT/MRI ........................................................................................... 
5.3.1.2 MRI Brain ....................................................................................... 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Primary Efficacy Assessment ................................................................... 
5.5 Pharmacokinetic and Immunogenicity Assessments ........................................ 
5.6 Biomarker Assessments .................................................................................... 
5.6.1 Soluble Biomarkers .................................................................................. 
5.6.2 Immunophenotyping ................................................................................. 
5.6.3 Peripheral Blood Gene Expression ......................................................... 
5.6.4 Receptor Occupancy Analysis .................................................................. 
5.6.5 Tumor Biomarkers ................................................................................... 
5.6.5.1 Characterization of Tumor Infiltrating Lymphocytes (TILs) and 
Tumor Antigens ..................................................................................... 
5.6.5.2 T Cell Repertoire Analysis .............................................................. 
5.6.5.3 Gene Expression Profiling .............................................................. 
5.6.5.4 Characterization of SDF-1, CXCR4 and FAP expression .............. 
5.6.5.5 Tumor Sample Collection Details ................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.7.1 EQ-5D ...................................................................................................... 
5.7.2 LCSS- SCLC subjects only ....................................................................... 
5.7.3 EORTC-QLQ-C30 - PAC subjects only ................................................... 
5.8 Other Assessments ............................................................................................ 
5.9 Results of Central Assessments ........................................................................ 
5.9.1 Evaluation of Scans .................................................................................. 
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 ............................................................................... 
8.1.1 SCLC Sample Size .................................................................................... 
8.1.2 PAC Sample Size ...................................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.3.3 Exploratory Endpoint(s) .......................................................................... 
8.4 Analyses ............................................................................................................ 
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ulocuplumab/nivolumab
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8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Primary Endpoint Methods ............................................................. 
8.4.2.2 Secondary Endpoint Methods ......................................................... 
8.4.2.3 Exploratory Endpoint Methods ....................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Immunogenicity Analyses ......................................................................... 
8.4.6 Biomarker Analyses ................................................................................. 
8.4.7 Outcomes Research Analyses .................................................................. 
8.4.7.1 EQ-5D ............................................................................................. 
8.4.7.2 LCSS- SCLC subjects only .............................................................. 
8.4.7.3 EORTC-QLQ-C30 - PAC subjects only .......................................... 
8.4.8 Other 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 ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
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 PERFORMANCE STATUS SCALES ................................................. 
APPENDIX 2 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 3 EFFICACY ASSESSMENTS OF OVERALL TUMOR BURDEN .... 
APPENDIX 4 EQ-5D QUESTIONNAIRE .................................................................. 
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CA212115
ulocuplumab/nivolumab
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Clinical Protocol
CA212115
BMS-936564/BMS-936558
ulocuplumab/nivolumab
 
 
 
 
1.2
Research Hypothesis 
Treatment with ulocuplumab in combination with nivolumab will be safe, tolerable and 
demonstrate clinically meaningful efficacy in subjects with advanced or metastatic solid tumors.
1.3
Objectives(s)
1.3.1
Primary Objectives

Stage 1: To identify the recommended dose and schedule of ulocuplumab, based on safety 
and efficacy, in combination with nivolumab in subjects with advanced or metastatic tumors

Stage 2: To evaluate the efficacy, separately by tumor type, based on objective response rate 
(ORR) or overall survival (OS; randomized Phase 2 study in PAC only), of ulocuplumab 
combined with nivolumab in subjects with advanced or metastatic tumors
1.3.2
Secondary Objectives

To assess the safety and tolerability of ulocuplumab combined with nivolumab, in subjects 
with advanced or metastatic tumors

To assess progression-free survival (PFS) with ulocuplumab combined with nivolumab, 
separately by tumor type, in subjects with advanced or metastatic tumors
1.3.3
Exploratory Objectives

 
 
 
 
 
 
 
 
 
 
Revised Protocol No.: 03
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Clinical Protocol
CA212115
BMS-936564/BMS-936558
ulocuplumab/nivolumab
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information to be provided to subjects and any updates.
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the subject volunteers to participate.
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
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Investigators must:
1) Provide a copy of the consent form and written information about the study in the language 
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood
2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
or her informed consent during the study, consent must additionally be obtained from the 
subject
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open-label, multi-center phase 1/2 study of ulocuplumab in combination with 
nivolumab designed to independently evaluate the safety and efficacy in subjects with SCLC and 
PAC. The study design consists of a Dose Evaluation Phase (Stage 1) that will include a DLT 
evaluation period to identify the MTD. If the maximum dose level (DL3) is identified as the 
MTD, a parallel evaluation of three cohorts will assess two dose levels (800 mg, 1600 mg) and 
an additional schedule for 1600 mg (every 2 weeks). If 2 or more DLT are seen with any dose
during the DLT evaluation period, a lower dose will be evaluated as a single arm. A 
recommended dose will be selected based on the safety and efficacy data from Stage 1 and will 
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proceed to Dose Expansion in the form of a Simon optimal 2-stage like design or a randomized 
Phase 2 study with comparative arm if high efficacy is observed.40
The study will consist of Screening, Treatment, and Follow-up. All subjects will undergo a 
screening period to determine eligibility within 28 days prior to initial dosing. During the 
treatment phase, ulocuplumab will be administered weekly or every two weeks (1600 mg dose 
only) and nivolumab will be administered every two weeks. The treatment period will continue 
until disease progression or occurrence of unacceptable toxicity. During follow-up, subjects will 
be monitored for disease activity and safety. The duration of the study is anticipated to be 
approximately 2 years.
The study design schematic is presented in Figure 1.
Figure 1:
Study Design Schematic
Dose Evaluation Phase (Stage 1)
Dose Expansion Phase (Stage 2)
U=ulocuplumab
N=nivolumab
DLT evaluation 
(n=3-6 pts @ 6 wks)
=
Stage 1 safety and efficacy evaluation per 
tumor type @ 3 mos
=
unacceptable 
toxicity/DLTs 
DL 2 
U 800 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
unacceptable 
toxicity/DLTs 
DL 2
U 800 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3A
U 1600 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3B
U 1600 mg q2wk + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 1
U 400 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 2
U 800 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3A
U 1600 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
acceptable 
toxicity
acceptable 
toxicity
randomization
DL 1 
U 400 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC or PAC
DL -1
U 200 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL -1
U 200 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
unacceptable 
toxicity/DLTs 
acceptable 
toxicity
acceptable 
toxicity
Simon 2-stage (per tumor type):
Randomized Phase 2 (per tumor type):. 
DLX (recommended dose from Stage 1)
Nivo Mono (for SCLC) or Inv Choice (for PAC)
DLX  (recommended dose from Stage 1)
n=25 SCLC and 20 PAC
OR
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3.1.1
Dose Evaluation Phase (Stage 1)
The Dose Evaluation Phase will consist of a DLT evaluation period followed by an evaluation of 
up to three cohorts with various doses and schedules of ulocuplumab combined with nivolumab. 
The DLT evaluation period will be conducted in the first 3-6 subjects with either PAC or SCLC 
at dose level 1 (DL1; 400 mg weekly ulocuplumab combined with nivolumab), followed by 3-6 
subjects each with PAC and SCLC at DL2 (800 mg weekly ulocuplumab combined with 
nivolumab), followed by 3-6 subjects each with PAC and SCLC at DL3A (1600 mg weekly 
ulocuplumab combined with nivolumab) for 6 weeks. For DL1, both tumor types will be 
combined for the safety evaluation. If 2 or more DLT are observed at DL1, de-escalation to DL-1 
will occur (200 mg weekly ulocuplumab combined with nivolumab). For all other dose levels, 
each tumor type will be evaluated for safety independently in the event that tumor specific AE 
may emerge.
Enrollment during the DLT evaluation phase will allow for concurrent accrual of up to 6 subjects 
in each dose/tumor cohort (ie, Rolling Six design).  This design allows for 3-6 evaluable subjects 
to contribute to the DLT evaluation depending upon how many are enrolled and still being 
evaluated during the DLT period. Decisions as to whether to enroll a new participant onto the 
current dose level or next highest dose level will be based on available data at the time of new 
participant enrollment. Study stopping rules for the DLT evaluation period and the decision to 
proceed with the Dose Evaluation Phase include the following:

Enrollment in the active cohort will proceed if there are:
o
< 3 subjects enrolled, up to a maximum of 6 subjects
o
1 DLT in 2 or up to 5 subjects evaluable for toxicity

Enrollment in the active cohort will be paused if there are:
o
a maximum of 6 subjects enrolled (including evaluable and non-evaluable)

Active cohort is deemed intolerable and enrollment will be stopped for evaluation if there 
are:
o
2 DLT in up to 6 subjects evaluable for toxicity

Active cohort is deemed tolerable and enrollment will proceed to next step if there are :
o
0 DLT in 3 or up to 6 subjects evaluable for toxicity
o
1 DLT in 6 subjects evaluable for toxicity

Subjects who are not evaluable for DLT (ie, discontinuation due to disease progression) will 
be replaced with a concurrently enrolled subject
Table 3.1.1-1:
Dose Levels for Ulocuplumab and Nivolumab 
Dose Level
Ulocuplumab
Nivolumab
DL-1
200 mg weekly
3 mg/kg every 2 weeks
DL1
400 mg weekly
3 mg/kg every 2 weeks
DL2
800 mg weekly
3 mg/kg every 2 weeks
DL3A
1600 mg weekly
3 mg/kg every 2 weeks
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DL3B
1600 mg every 2 weeks
3 mg/kg every 2 weeks
Depending on the number of DLT observed during the DLT evaluation period, escalation or 
de-escalation of ulocuplumab may be warranted. Dose escalation/de-escalation at the 800 mg 
weekly and 1600 mg weekly ulocuplumab dose levels will occur independently for each tumor 
type. No dose modification of nivolumab will be allowed in this study.

If the toxicity at DL1 and DL2 and DL3A are acceptable, enrollment will proceed with three 
randomized cohorts (DL2, DL3A, and DL3B) to complete Stage 1

If the toxicity at DL3A is unacceptable, enrollment will proceed at DL2 to complete Stage 1

If the toxicity at DL2 is unacceptable, enrollment will proceed at DL1 to complete Stage 1

If the toxicity at DL1 is unacceptable, a new DLT evaluation period will proceed at DL-1

If the toxicity of DL-1 is unacceptable, enrollment will stop for that tumor type

If the toxicity at DL-1 is acceptable, enrollment will proceed at DL-1 to complete Stage 1 at a 
single dose level
3.1.2
Decision Rules to Proceed with Dose Expansion Phase
An interim analysis (IA) will be carried out when all subjects in the Dose Evaluation Phase in an 
individual tumor type have at least three months of treatment, or discontinued prematurely. This 
IA will be conducted independently for each tumor type. Investigator-assessed ORR will be used 
to guide the decision making for the Stage 2 portion of the study. However, all available efficacy 
and safety data will be used to select the recommended dose that will be further evaluated in the 
Dose Expansion Phase. Furthermore, if the level of efficacy observed at the recommended dose 
in the Dose Evaluation Phase does not warrant stopping evaluation of that tumor type, it will be 
used to select the appropriate Expansion Phase study design, either proceeding with a Simon 
2-stage-like design or conducting a randomized Phase 2 study with comparative arm. The 
efficacy thresholds used for the IA analysis are based on the preliminary efficacy data from the 
ongoing Phase 1/2 study evaluating nivolumab monotherapy in SCLC and PAC and the level of 
activity reported for 2L options.12,41 The determination of low, moderate or high efficacy will be 
based primarily on the response rates observed with ulocuplumab and nivolumab, but the totality 
of available safety and efficacy data will be considered. For further information on the interim 
analysis and the efficacy thresholds used for decision rules, please refer to section 8.5.

If the number of responders per tumor type at the recommended dose level is consistent with
low efficacy, the evaluation of that tumor type will be placed on hold pending final review of 
the data.

If the number of responders per tumor type at the recommended dose level is consistent with 
moderate efficacy, the Dose Expansion Phase will continue with a single-arm evaluation.

If the number of responders per tumor type at the recommended dose level is consistent with 
high efficacy, the Dose Expansion Phase will be continue with a randomized Phase 2 study
with comparative arm.
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Table 3.1.2-1:
Stage 1 Efficacy Threshold For Each Tumor Type 
Efficacy Threshold
SCLC
PAC
Low
3 responders / 19 subjects
1 responders / 21 subjects
Moderate
4-8 responders / 19 subjects
2-5 responders / 21 subjects
High
9 responders / 19 subjects
6 responders / 21 subjects
3.1.3
Dose Expansion Phase (Stage 2)
Based on the results of the IA, the Dose Expansion Phase will consist of a second stage of a 
Simon 2-stage like single arm study (moderate efficacy) or a randomized Phase 2 study with 
comparative arm (high efficacy).
The second stage of a Simon 2-stage like design will expand enrollment at the recommended 
dose level in a single arm study. An additional 25 SCLC subjects and 20 PAC subjects will be 
enrolled to complete this evaluation. The primary endpoint will be investigator-assessed ORR for 
both tumor types and PFS will be considered a secondary endpoint.
The randomized Phase 2 study will compare the combination therapy at the recommended dose 
level versus a comparative arm appropriate for that tumor type. The primary endpoint of this 
study will be dictated by the tumor type, where ORR is the endpoint for a randomized Phase 2 
study in SCLC and OS for a randomized Phase 2 study in PAC. For ORR, independent radiology 
review committee (IRRC) will perform blinded independent review of the imaging per RECIST 
1.1 criteria. More details regarding the randomized Phase 2 for each tumor type are described 
below.
SCLC
A randomized Phase 2 study with comparative arm in SCLC will compare the recommended 
dose of ulocuplumab combined with nivolumab versus nivolumab monotherapy. The main goal 
of this comparison will be to determine whether the combination therapy is superior to 
nivolumab monotherapy. The primary endpoint of this study will be evaluation of IRRC assessed
ORR. Safety, tolerability and PFS will be considered as secondary endpoints. A randomized 
Phase 2 study would require an additional 50 subjects per arm (ie. 100 for the two arms). The 
SCLC subjects included in the Dose Evaluation Phase will not be part of the efficacy analysis of
the randomized Phase 2 study. A stratification factor will be used for this portion of the study to 
balance recruitment and will include performance status (ECOG 0 vs 1). For additional statistical 
considerations for the randomized Phase 2 study with comparative arm in SCLC subjects, please 
see Section 8.
PAC
A randomized Phase 2 study with comparative arm in PAC will compare the recommended dose 
of ulocuplumab combined with nivolumab versus Investigator’s Choice 2L chemotherapy. The 
main goal of this comparison will be to determine if ulocuplumab plus nivolumab combination 
therapy is superior to 2L chemotherapy. The primary endpoint of this study will be OS. Safety, 
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tolerability and PFS will be considered as secondary endpoints. For PAC, a randomized Phase 2 
study would require an additional 125 subjects per arm (ie. 250 for the two arms). 
. The PAC subjects included in 
the Dose Evaluation Phase will not be considered in the analysis of the randomized Phase 2
study. Investigator’s choice chemotherapy options in this study are based on NCCN guidelines 
for PAC and include the following.27

Subjects that have failed FOLFIRINOX or other fluoropyrimidine based regimens can 
consider gemcitabine-based therapies for this study

Subjects that have failed gemcitabine based regimens can consider fluoropyrimidine-based 
regimens for this study
Stratification factors will be used for this portion of the study and will include performance 
status (ECOG 0 vs
1) and type of chemotherapy used in the first line
setting
(fluoropyrimidine-containing vs gemcitabine-containing regimens). For additional statistical 
considerations for the randomized Phase 2 study with comparative arm in PAC subjects, please 
see Section 8.
3.1.4
Dose Limiting Toxicity
The incidence of DLT(s) assessed in the first 3-6 evaluable subjects per tumor type (if 
applicable) during the first 6 weeks will be used to initially determine whether a dose level is 
tolerable. A subject will be considered evaluable for DLT if they have received at least 5 out of 6 
ulocuplumab doses and at least 2 out of 3 nivolumab doses in a 6 week dosing period or 
experienced a DLT. DLT should not be AE considered by the investigator to be disease related.
The following drug-related AE (whether related to one or both agents) will be considered a DLT:

Any Grade 3 drug-related non-hematological AE, including the following laboratory 
abnormalities

If a subject has baseline Grade 1 AST, ALT, or total bilirubin, a drug-related Grade 3 
toxicity will be considered a DLT

If a subject has baseline Grade 2 AST or ALT, drug-related elevations in AST and/or 
ALT > 2x baseline or a maximum of > 8x ULN will be considered a DLT

Any Grade 4 drug-related hematological AE or hematological or non-hematological 
laboratory abnormality with the following exceptions:

Grade 4 amylase or lipase not associated with symptoms or clinical manifestations

Grade 4 lymphocytopenia not associated with symptoms or clinical manifestations

Any drug-related AE that results in dose reduction of ulocuplumab during the DLT period

Any drug related AE that results in dose delay of ulocuplumab > 14 days during DLT period

Any toxicity managed by discontinuation of ulocuplumab (see section 4.5.3.1)

Any toxicity managed by discontinuation of nivolumab (see section 4.5.3.2)
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3.2
Post Study Access to Therapy 
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee 
or through another mechanism at the discretion of BMS. BMS reserves the right to terminate 
access to BMS supplied study drug if any of the following occur: a) the marketing application is 
rejected by responsible health authority; b) the study is terminated due to safety concerns; c) the 
subject can obtain medication from a government sponsored or private health program; or 
d) therapeutic alternatives become available in the local market.
3.3
Study Population
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, potential tumor biopsies, and other requirements of the study.
2. Target Population
a) Subjects with pathologically confirmed metastatic disease of the following tumor types:
i)
Subjects with histologically confirmed pancreatic ductal adenocarcinoma (PDAC)
who must meet the following:
(1) Subjects must have had progression, refractory disease or best response of stable 
disease during or after at least 1 chemotherapy regimen for the treatment of 
metastatic (Stage IV) disease.
Note: For DLT evaluation phase only, subjects may have had progression, refractory disease or 
best response of stable disease during or after at least 1 chemotherapy regimen for the treatment 
of locally advanced or metastatic (Stage IV) disease.
AND
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(2) Subjects must not have clinically relevant ascites at baseline, such as ascites in 
need of paracentesis.
ii) Subjects with histologically or cytologically confirmed SCLC. Subjects must have 
progression or refractory disease to most recent therapy. Subjects must have had at 
least 1 platinum based chemotherapy regimen for the treatment of limited or 
extensive stage disease.
b) Subjects must have measurable disease by CT or MRI per RECIST 1.1 criteria 
(radiographic tumor assessment must be performed within 28 days prior to first dose).
c) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
d) All baseline laboratory requirements will be assessed and should be obtained within 
14 days of first dose. Screening laboratory values must meet the following criteria:
-
WBCs 2000/L
-
Neutrophils 1500/L
-
Platelets 120 x 10³/L
-
Hemoglobin 9.0 g/dL
-
Creatinine serum creatinine 1.5 x ULN or creatinine clearance (CrCl) 
40 mL/minute (using Cockcroft/Gault formula)
-
AST and ALT levels 3 x ULN or 5 x ULN if liver metastases are present
-
Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome who can 
have total bilirubin < 3.0 mg/dL)
-
Albumin 3 g/dL
-
Lipase 1.5 ULN. Subjects with Lipase > 1.5 ULN may enroll if there are 
neither clinical nor radiographic signs of a pancreatitis.
-
Amylase 1.5 ULN. Subjects with Amylase > 1.5 ULN may enroll if there 
are neither clinical nor radiographic signs of a pancreatitis.
e) Prior focal radiotherapy to an isolated bony or soft tissue metastasis must be completed at 
least 2 weeks before study drug administration.
3. Age and Reproductive Status
a) Men and women 18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception from the time 
of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of 
nivolumab plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post 
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treatment completion. (note: nivolumab half-life is approximately 25 days and is greater 
than ulocuplumab half-life) 
e) Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-
lives of study drug (s) plus 90 days (duration of sperm turnover) for a total of 31 weeks 
post-treatment completion
f)
Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However they must still undergo pregnancy 
testing as described in this section
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method 
being highly effective and the other method being either highly effective or less effective as 
listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

Male condoms with spermicide

Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirenaby WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects participating in 
the study may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug

Nonhormonal IUDs, such as ParaGard

Tubal ligation

Vasectomy

Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION

Diaphragm with spermicide

Cervical cap with spermicide
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
Vaginal sponge

Male Condom without spermicide 

Progestin only pills by WOCBP subject or male subject’s WOCBP partner 

Female Condom*
* A male and female condom must not be used together
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI) 
evidence of progression for at least 4 weeks after treatment is complete and within 
28 days prior to first dose of study drug administration. There must also be no 
requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration. 
2. Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
b) Other prior malignancy active within the previous 3 years except for local or organ 
confined early stage cancer that has been definitively treated with curative intent, does 
not require ongoing treatment, has no evidence of residual disease, and has a negligible 
risk of recurrence and is therefore unlikely to interfere with the primary and secondary 
endpoints of the study, including response rate and safety.
c) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll.
d) Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of first dose. Inhaled or topical steroids, and adrenal replacement steroid doses 
are permitted in the absence of active autoimmune disease.
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e) Prior therapy with any T cell co-stimulation or checkpoint pathways, such as anti-PD-1, 
anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, including ipilimumab
and nivolumab; or other medicines specifically targeting T cells.
f)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after platinum 
based therapy, are permitted to enroll.
g) Treatment with any chemotherapy, radiation therapy, biologics for cancer, or 
investigational therapy within 21 days of first administration of study treatment (subjects 
with prior cytotoxic or investigational products < 3 weeks prior to treatment might be 
eligible after discussion between investigator and sponsor, if toxicities from the prior 
treatment have been resolved to CTC grade 1 level).
3. Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or 
positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV 
antibody test indicating acute or chronic infection.
b) Positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS).
c) Subjects must not be dependent on continuous supplemental oxygen use.
4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in 
a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause.
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*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal:

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:

Immunosuppressive agents (except to treat a drug-related adverse event, see also Section 
3.4.2.3)

Systemic corticosteroids > 10 mg daily prednisone equivalent (except to treat a drug-related 
adverse event, see also Section 3.4.2.3)

Any concurrent antineoplastic therapy (ie, surgery [exception described in Section 3.4.2.2], 
chemotherapy, hormonal therapy, immunotherapy, radiation therapy except for palliative 
radiation therapy described in Section 3.4.2.1)

Medications that Durably Inhibit Platelet Function:

With the exception of low-dose aspirin, warfarin (coumadin) and heparin (including 
unfractionated and low molecular weight), subjects enrolled in this study should not take 
concomitant medications that durably inhibit platelet function. For such medications, a 
wash-out period of 7 days is required prior to starting treatment. Agents that inhibit 
platelet function transiently or inhibit coagulation by other mechanisms should be used 
with caution.

Medications that directly and durably inhibit platelet function include aspirin containing 
combinations, 
clopidogrel, 
dipyridamole, 
tirofiban, 
dipyridamole, 
epoprostenol, 
eptifibatide, cilostazol, abciximab, ticlopidine, cilostazol

Supportive care for disease-related symptoms may be offered to all subjects on the trial.
3.4.2
Other Restrictions and Precautions
3.4.2.1
Palliative Radiation Therapy
Palliative (limited-field) radiation therapy is permitted, but only for pain control to sites of bone 
disease present at baseline and only if all of the following criteria are met:
1) Repeat imaging (mandatory) demonstrates no new sites of bone metastases
2) The lesion being considered for palliative radiation is not a target lesion
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3) The case is discussed with the BMS Medical Monitor, and the medical monitor agrees that 
the conditions required to receive palliative radiation are met
3.4.2.2
Surgical Resection Following Initial Response
Investigators may choose to resect solitary lesions in subjects with residual disease and render 
the subject free of macroscopic disease. Subjects enrolled in this study may have lesions 
surgically resected only following consultation with the Medical Monitor and following the 
Week 24 tumor assessments. If additional tumor shrinkage is noted compared to the tumor 
assessments at Week 18, it is highly encouraged that surgical resection be delayed until 
subsequent scans fail to demonstrate further shrinkage. Subjects with a confirmed PR who go on 
to have surgical resection of remaining disease will be considered a PR. Subjects with SD who 
go on to have surgical resection of remaining disease will be considered a SD. Patients may 
continue treatment after surgery. Tumor tissue of any resected solitary lesion should be 
submitted to BMS (see Section 5.6.1). Detailed instructions of the obtaining, processing, 
labeling, handling, storage and shipment of these specimens will be provided in a separate 
Procedure Manual at the time of study initiation.
3.4.2.3
Corticosteroid Treatment
The use of corticosteroids for the management of related AE in accordance with the algorithms 
in the IB and this protocol is permitted. Subjects are permitted to use topical, ocular, 
intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). 
Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day 
prednisone equivalents are needed. A brief course of corticosteroids for prophylaxis (eg, contrast 
dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by contact allergen) is permitted. However, the use of systemic corticosteroids at 
baseline, before starting ulocuplumab or nivolumab, should be avoided because of their potential 
interference with the PD activity and efficacy of checkpoint inhibitors. Subjects with a condition 
requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or 
other immunosuppressive medications within 14 days of first dose are not eligible.
Concomitant medications are recorded at baseline and throughout the treatment phase of the 
study in the appropriate section of the CRF. All medications (prescriptions or over the counter 
medications) continued at the start of the study or started during the study and different from the 
study drug must be documented in the concomitant therapy section of the CRF.
3.4.2.4
Imaging Restrictions
It is the local imaging facility’s responsibility to determine, based on subject attributes (eg,
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each subject. Imaging contraindications and contrast risks should be considered in 
this assessment. Subjects with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
subjects 
with 
severe 
renal 
insufficiency 
(ie, 
estimated 
glomerular 
filtration 
rate 
(eGFR) < 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
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contrast should not be given to this subject population. In addition, subjects are excluded from 
MRI if they have tattoos, metallic implants, pacemakers, etc.
The ultimate decision to perform MRI in an individual subject in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness

Pregnancy

Additional protocol specific reasons for discontinuation (see Sections 4.5.3.1 and 4.5.3.2)
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
3.6
Post Study Drug Study Follow up
In this study, ORR and OS are key endpoints of the study. Post study follow-up is of critical 
importance and is essential to preserving subject safety and the integrity of the study. Subjects 
who discontinue study drug must continue to be followed for collection of outcome and/or 
survival follow-up data as required and in line with Section 5 until death or the conclusion of the 
study.
BMS may request that survival data be collected on all treated/randomized subjects outside of 
the protocol defined window (See Section 5.1). At the time of this request, each subject will be 
contacted to determine their survival status unless the subject has withdrawn consent for all 
contact.
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3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. 
All attempts should be documented in the subject’s medical records. If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information. If after all 
attempts, the subject remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
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Table 4-1:
Study Drugs for CA212115
Product Description / 
and Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging/ Appearance
Storage Conditions
(per label)
BMS-936564 
(ulocuplumab) Solution 
for Injection
100 mg 
(10 mg/mL)
IP
Open-label
Primary packaging: 10 mL per vial/Open-label
Secondary packaging: carton containing 10 mg/mL 
kitted vials/ Open-label
Colorless, clear to slightly opalescent solution, 
essentially free of particles. 
Store at 2°C to 8°C. 
Protect from light
BMS-936558 (nivolumab) 
Solution for Injection
100 mg 
(10 mg/mL)
IP
Open-label
Primary packaging: 10 mL per vial/Open-label
Secondary packaging: carton containing 10 mg/mL 
kitted vials/Open-label
Clear to opalescent colorless to pale yellow liquid. 
May contain particles
Store at 2°C to 8°C. 
Protect from light
and freezing
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this protocol, investigational products are: BMS-936564 (ulocuplumab) and BMS-936558 
(nivolumab).
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products.
In this protocol, non-investigational product(s) is/are the following: 

Dose Evaluation Phase (Stage 1): Not applicable

Dose Expansion (Stage 2): For PAC subjects, if Stage 1 results in a decision to move to a 
randomized Phase 2 study with comparative arm in Dose Expansion Phase, Investigator’s 
Choice for advanced or metastatic PAC subjects will be the comparator arm. The treatment 
options for 2L PAC include the following:
o
Gemcitabine with or without albumin-bound paclitaxel
o
Capecitabine and other fluoropyrimidine based regimens
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained 
that includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Please refer to the current version of the Investigator Brochures and/or pharmacy manual or 
reference sheets for complete storage, handling, dispensing and infusion information for 
BMS-936564 (ulocuplumab) and BMS-936558 (nivolumab).
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4.3.1
Ulocuplumab (BMS-936564)
Ulocuplumab (BMS-936564) vials must be stored refrigerated 2°C to 8°C in a tightly closed 
container and must be protected from light. If stored in a glass front refrigerator, vials should be 
stored in the carton. Once the ulocuplumab injection is transferred to the IV bag, it can be stored 
for a maximum of 12 hours at room temperature/under ambient light at 15°C - 25°C. If the 
solution in the IV bag cannot be used for infusion within the 12 hours at room temperature, it 
must be refrigerated at 2°C - 8°C, not to exceed 12 hours maximum in the refrigerator. The 
solution is stable for a total storage combination time of 24 hours. 
Following transfer to the IV bag, preparation time of dilution to the end time of infusion should 
not exceed 24 hours as the diluted solution of BMS-936564 once prepared, must be infused 
within a 24 hour timeframe. 
Any temperature deviations from the recommended storage conditions would require the site to 
contact the Sponsor for further instruction and disposition.
4.3.2
Nivolumab (BMS-936558)
Nivolumab (BMS-936558) vials must be stored at a temperature of 2°C to 8°C and should be 
protected from light, freezing and shaking. If stored in a glass front refrigerator, vials should be 
stored in the carton. Recommended safety measures for preparation and handling of nivolumab 
include laboratory coats and gloves.
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Bag
The dosing calculations should be based on the body weight. Nivolumab injection is to be 
administered as an IV infusion over 60 minutes at 3 mg/kg.
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C) for up to 24 hours and a maximum of 4 hours of the total 24 hours can be at room 
temperature and room light. The maximum 4-hour period under room temperature and room 
light conditions includes the product administration period.
For details on prepared drug storage and use time of nivolumab under room temperature/light 
and refrigeration, please refer to the nivolumab Investigator Brochure sections 3.2.2 and 3.2.3 
and/or pharmacy reference sheets.13
4.3.3
Ulocuplumab and Nivolumab Combination
When both ulocuplumab and nivolumab are to be administered on the same day, separate 
infusion bags and filters must be used for each infusion. Ulocuplumab is to be administered first. 
The ulocuplumab infusion must be promptly followed by a saline flush to clear the line of 
ulocuplumab before starting the nivolumab infusion.
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4.4
Method of Assigning Subject Identification
A subject number will be assigned through an interactive voice response system (IVRS) once the 
subject has signed the informed consent form and is registered. Specific instructions for using 
IVRS will be provided in a separate document.
Enrolled subjects that have met all eligibility criteria will continue with treatment assignment 
and drug vial assignment through the IVRS.
There will be two requirements for IVRS randomization in this study. The first one will occur in 
the Dose Evaluation Phase (Stage 1) after the DLT evaluation period. In this instance, the IVRS 
will be used to assign subjects to one of three cohorts for the dose evaluation (DL2, DL3A, 
DL3B). Additionally, if a randomized Phase 2 study with comparative arm is initiated in the 
Dose Expansion Phase (Stage 2), IVRS will be used to assign subjects to one of the two 
treatment arms.
4.5
Selection and Timing of Dose for Each Subject
Ulocuplumab will be administered every week or every two weeks depending on the cohort 
being evaluated. Nivolumab will be administered every two weeks for all cohorts. On the day of 
study drug administration, ulocuplumab is to be administered first. The second infusion will 
always be nivolumab, and will start no sooner than 30 minutes after completion of the 
ulocuplumab infusion.
For weekly ulocuplumab dosing, subjects may be dosed +/-1 day from their scheduled dosing 
date, but no less than 6 days between doses. For every 2 week dosing (ulocuplumab or 
nivolumab), subjects may be dosed ±2 days from their scheduled dosing date, but no less than 12 
days between doses. If dosing cannot be administered within the window of the scheduled dosing 
date, the dose will be considered a missed dose and the subject should come in for their next 
regular visit relative to Day 1. If the next regular visit is less than 6 days from the last 
ulocuplumab dose for weekly dosing, nivolumab may be administered alone for that visit.
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.5.1
Dose Delays and Interruptions
4.5.1.1
Ulocuplumab Dose Delay
Investigators should, whenever possible, determine which medication is causing the toxicity and 
delay or dose reduce ulocuplumab and/or delay nivolumab, as applicable. If ulocuplumab is 
delayed due to an AE, nivolumab dosing may continue at the discretion of the Investigator. 
Ulocuplumab should be delayed for the following:

Any Grade 3 drug-related AE, including laboratory abnormalities except for Grade 3 AEs 
that do not require nivolumab dose delay (see section 4.5.1.2)
If the decision is to resume ulocuplumab dosing, the subject should restart treatment on the next
regularly scheduled ulocuplumab dosing visit. Skipped doses are not to be replaced. If treatment 
is delayed > 6 weeks, the subject must be permanently discontinued from ulocuplumab therapy.
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4.5.1.2
Nivolumab Dose Delay
Investigators should, whenever possible, determine which medication is causing the toxicity and 
delay or dose reduce ulocuplumab and/or delay nivolumab, as applicable. If nivolumab is 
delayed due to an AE, ulocuplumab dosing should also be delayed. Nivolumab should be 
delayed for the following:

Any Grade 2 non-skin, drug-related AE, with the following exceptions:

Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay

Any Grade 3 skin drug-related AE

Any Grade ≥ 3 drug-related laboratory abnormality, with the following exceptions for 
thrombocytopenia, lymphocytopenia, AST, ALT, total bilirubin or asymptomatic amylase or 
lipase:

Grade 3 thrombocytopenia < 7 days (not associated with Grade ≥hemorrhage) does not 
require dose delay

Grade 3 lymphocytopenia not associated with symptoms or clinical manifestations does 
not require dose delay. It is recommended to consult with the BMS Medical Monitor for 
Grade lymphocytopenia.

Grade 3 drug-related amylase or lipase abnormality that is not associated with symptoms 
or clinical manifestations of pancreatitis does not require dose delay. It is recommended 
to consult with the BMS Medical Monitor for Grade 3 amylase or lipase abnormalities

If a subject has baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity

If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade 3 toxicity

If a subject has baseline AST or ALT within the Grade 2 toxicity range, delay dosing for 
drug-related elevations in AST and/or ALT > 2x baseline or a maximum of > 8x ULN

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication
If the decision is to resume nivolumab dosing, the subject should restart treatment on the next 
regularly scheduled nivolumab dosing visit. Skipped doses are not to be replaced. If treatment is 
delayed > 6 weeks, the subject must be permanently discontinued from all study therapy, except 
as specified in Section 4.5.3.2.
Because of the potential for nivolumab-related AE requiring early recognition and prompt 
intervention, management algorithms have been developed and are included for suspected 
pulmonary toxicity, GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity, neurological 
toxicity and nephrotoxicity. In order to standardize the management of AEs for all subjects, 
recommended treatment management algorithms are included in Appendix 2. Adverse event 
treatment management algorithms included in the nivolumab IB might be considered for 
individual cases.
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4.5.1.3
Criteria to Resume Nivolumab Treatment
Subjects may resume treatment with nivolumab when the drug-related AE resolves to 
Grade 1 or baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue

Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of a Grade 2 toxicity

Subjects with baseline AST/ALT or total bilirubin in the Grade 1 or 2 toxicity range who 
require dose delays for reasons other than a 1 or 2-grade shift in AST/ALT or total bilirubin 
may resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin

Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.5.3.2) should have treatment permanently 
discontinued

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment
4.5.1.4
Ulocuplumab or Nivolumab Dose Interruptions
If an ulocuplumab infusion is interrupted or an ulocuplumab-related infusion reaction prevents 
subsequent infusion of nivolumab on the same day, the dose of nivolumab should be replaced as 
soon as possible. In such instances, at least 12 days must elapse between the replacement dose of 
nivolumab and the administration of the next dose of ulocuplumab combined with nivolumab to 
maintain a 2 week period (+/-2 days) in between nivolumab dosing. 
4.5.2
Dose Modifications
4.5.2.1
Ulocuplumab Dose Modification Criteria
Investigators should, whenever possible, determine which medication is causing the toxicity and 
delay or dose reduce ulocuplumab and/or delay nivolumab, as applicable. Depending on the 
nature of the AE, intrapatient ulocuplumab dose modifications may occur according to Table 
4.5.2.1-1. The following rules apply when modifying the dose of ulocuplumab:

Assessment of causality must be determined and documented by the Investigator and also 
discussed by the BMS Medical Monitor

Following implementation of a dose reduction for ulocuplumab, the dose should not be re-
escalated

If the same AE recurs despite a dose reduction, a second dose reduction versus 
discontinuation of the subject from ulocuplumab will be discussed and agreed upon by the 
Investigator and BMS Medical Monitor
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Table 4.5.2.1-1:
Ulocuplumab Dose Modification Criteria
Adverse Event
Dose Delay
(refer to
section 
4.5.1.1)
Criteria to Resume Ulocuplumab Treatment
For DL-1
For DL1
For DL2
For DL3A/3B
Any Gr 3 drug-related 
AE, including laboratory 
abnormalities, except for 
Grade 3 hematologic 
AEs 
listed below or other 
exceptions listed in 
section 4.5.1
Hold 
ulocuplumab 
until return to 
baseline or 
Grade 1, 
whichever is 
lower
1st event: 
Resume at 200 
mg weekly
1st event: 
Resume at 
400 mg
weekly
1st event: 
Resume at 
800 mg weekly
1st event: 
Discontinue 
ulocuplumab
2nd event: 
Discontinue 
ulocuplumab
2nd event: 
Resume at 
200 mg
weekly
2nd event: 
Resume at 
400 mg weekly
3rd event: 
Discontinue 
ulocuplumab
3rd event: 
Discontinue 
ulocuplumab
Any Gr3 drug-related 
neutropenia, Gr3 
thrombocytopenia > 7 
days
Hold 
ulocuplumab 
until return to 
baseline or 
Grade 1, 
whichever is 
lower
1st event: 
Resume at 
200 mg 
weekly
1st event: 
Resume at 
400 mg weekly
1st event: 
Resume at 
800 mg 
weekly
1st event: 
Resume at 
1600 mg 
weekly
2nd event: 
Discontinue 
ulocuplumab
2nd event: 
Resume at 
200 mg weekly
2nd event: 
Resume at 
400 mg 
weekly
2nd event: 
Resume at 
800 mg weekly
3rd event: 
Discontinue 
ulocuplumab
3rd event: 
Discontinue 
ulocuplumab
3rd event: 
Discontinue 
ulocuplumab
Gr4 asymptomatic lipase 
or amylase elevations
Hold 
ulocuplumab 
until return to 
baseline or 
Grade 1, 
whichever is 
lower
All events: Resume at same dose.
Consult with BMS Medical Monitor if recurrent or sustained.
4.5.2.2
Nivolumab Dose Modification Criteria
Intrapatient dose modifications of nivolumab for the management of toxicities are not permitted. 
Dose delay criteria for nivolumab can be found in section 4.5.1.2.
4.5.3
Discontinuation Criteria
4.5.3.1
Ulocuplumab Discontinuation Criteria
Discontinuation criteria apply for all drug-related AE attributed to ulocuplumab and consist of 
the following:

Grade 3 thrombocytopenia associated with bleeding (occurring concomitant with Grade 2 
hemorrhage)
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
Grade 3 drug-related infusion reaction of any duration

Any Grade 4 drug-related AE or laboratory abnormality except for Grade 4 AE listed as
exceptions to the nivolumab discontinuation criteria (see section 4.5.3.2)

Any recurring drug-related Grade 3 AE or laboratory abnormality that requires multiple 
dose reductions of ulocuplumab (see specific criteria in section 4.5.2.1)

Any drug-related AE resulting in dose delay of ulocuplumab > 6 weeks

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued ulocuplumab 
dosing
4.5.3.2
Nivolumab Discontinuation Criteria
Discontinuation criteria apply for all drug-related AE attributed to nivolumab and consist of the 
following:

Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment

Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurological toxicity, hypersensitivity reactions, and infusion reactions:

Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation

Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:
o
If a subject has a baseline AST or ALT within normal limits:
o
AST or ALT > 5-8x ULN for > 2 weeks
o
AST or ALT > 8x ULN, irrespective of duration
o
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
o
If a subject has a baseline AST or ALT within Grade 1 or 2 toxicity range:
o
AST or ALT > 10x ULN for > 2 weeks
o
AST or ALT > 15x ULN, irrespective of duration
o
Total bilirubin > 5x ULN
o
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
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
Any Grade 4 non-skin drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation:

Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset

Grade 4 thrombocytopenia or neutropenia < 5 days

Grade 4 lymphocytopenia or leukopenia not associated with symptoms or clinical 
manifestations. It is recommended to consult with the BMS Medical Monitor for Grade 4 
lymphocytopenia.

Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical/radiographic manifestations of pancreatitis. It is recommended to consult with the 
BMS Medical Monitor for Grade 4 amylase or lipase abnormalities.

Grade 4 drug-related endocrinopathy adverse events, such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose-controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the Medical Monitor. 

Any dosing delay lasting > 6 weeks with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting 
> 6 weeks, the BMS Medical Monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is delayed. 

Dosing delays > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS Medical Monitor. Prior to re-initiating treatment in a subject with a 
dosing delay lasting > 6 weeks, the BMS Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed.

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued ulocuplumab 
or nivolumab dosing
4.5.4
Treatment of Ulocuplumab- or Nivolumab-Related Infusion Reactions
Infusion reactions have been reported in subjects treated with ulocuplumab and nivolumab. If an 
infusion reaction was to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the BMS Medical Monitor and reported 
as an SAE if criteria are met. Infusion reactions should be graded according to NCI CTCAE 
(version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
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For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention not 
indicated):
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg IV
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab or ulocuplumab administrations.
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours):
Stop the nivolumab or ulocuplumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, restart the infusion at 50% of the original infusion rate when symptoms resolve; if 
no further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab or 
ulocuplumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and 
remain at bedside and monitor the subject until resolution of symptoms. The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered at 
least 30 minutes before additional nivolumab or ulocuplumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be 
used.
For Grade 3 or Grade 4 symptoms (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]; Grade 4: (life threatening; pressor or ventilatory 
support indicated):
Immediately discontinue infusion of ulocuplumab or nivolumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms will not recur. Ulocuplumab or nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
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generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids).
4.5.5
Treatment Beyond Disease Progression
As described in Section 1.1.10 accumulating evidence indicates that subjects treated with 
immunotherapy may derive clinical benefit despite evidence of progressive disease (PD).
Subjects will be permitted to continue with treatment beyond initial RECIST 1.1 defined PD as 
long as they meet the following criteria:

Investigator-assessed clinical benefit

Subject is tolerating study drugs

Subject has provided written informed consent prior to receiving additional study treatment
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.
All decisions to continue treatment beyond progression must be discussed with the BMS Medical 
Monitor and documented in the study records.
Subjects should discontinue study therapy upon evidence of further progression, defined as an 
additional 10% or greater increase in tumor burden from time of initial progression (including all 
target lesions and new measurable lesions).
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden measurement if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes, which must have an 
increase in short axis to at least 15 mm).
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event. Subjects who have tumor shrinkage following RECIST 1.1-defined progression will also 
be descriptively summarized separately since these immune responses may be used in decision 
rules for selecting Dose Expansion Phase (Stage 2) study design.
4.5.6
Antiemetic Premedications
Antiemetic medications should not be routinely administered prior to dosing of drugs. See 
Section 4.5.4 for subsequent premedication recommendations following ulocuplumab- or 
nivolumab-related infusion reaction.
4.6
Blinding/Unblinding
Not applicable.
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4.7
Treatment Compliance
The investigator or designated study personnel will maintain a drug accountability log of all 
study drug(s); received, dispensed, destroyed and the amount returned to the Sponsor or supply 
depot. The investigator and study personnel will ensure that each subject receives the calculated 
dose of the study drug, dependent on either fixed dosing (ulocuplumab) or body weight 
(nivolumab).
Drug supplies will be inventoried and accounted for throughout the study. The drug 
accountability log will be reviewed by the study monitor during site visits and at the completion 
of the study.
4.8
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as 
partially used study drug containers, vials and syringes may be destroyed on site.
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics).
On-site destruction is allowed provided the following minimal standards are met:

On-site disposal practices must not expose humans to risks from the drug.

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor.
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It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
Arrangements for the return of study drug will be made by the responsible Study Monitor.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Table 5.1-1:
Screening Procedural Outline (CA212115)
Procedure
Screening
Visita
Notes
Call IVRS
X
To obtain subject number
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first dose.
Medical History
X
Screening/Baseline Tumor 
Assessment
X
MRI brain, CT chest, CT/MRI abdomen, pelvis and all other known sites of disease within 28 days prior 
to first dose. Baseline MRI is required to rule out active brain metastasis (SCLC only).
Safety Assessments
Physical Examination
X
Within 14 days prior to first dose
Vital Signs and oxygen saturation
X
Including BP, HR, respiratory rate, temperature and oxygen saturation by pulse oximetry (at rest). Obtain 
vital signs at the screening visit and within 72 hours prior to first dose. 
Physical Measurements (including 
performance status)
X
Height, Weight and ECOG status. Within 14 days prior to first dose
ECG (12-lead)
X
Within 14 days prior to first dose
Chest X-ray
X
Within 14 days prior to first dose
Assessment of Signs and 
Symptoms
X
Within 14 days prior to first dose
Concomitant Medication 
Collection
X
Within 14 days prior to first dose
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Table 5.1-1:
Screening Procedural Outline (CA212115)
Procedure
Screening
Visita
Notes
Laboratory Tests
X
CBC w/differential, Chemistry panel including: total protein, LDH, AST, ALT, ALP, total bilirubin, BUN 
or serum urea level, uric acid, creatinine, albumin, Ca, Mg, Na, P, K, Cl, glucose, amylase, lipase, TSH, 
Free T4, Free T3, hepatitis B surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) or Hepatitis 
C RNA (HCV RNA), within 14 days prior to first dose. Screening labs done within 72 hours prior to first 
dose can also be used for on treatment lab purposes at Day 1 dosing.
Pregnancy Test (WOCBP only)
X
Serum or urine within 24 hours of first dose
FSH
X
If needed to document post-menopausal status as defined in Section 3.3.3.
Tumor Tissue Samples
X
Sufficient tumor tissue obtained in the metastatic setting or from an unresectable site (block or minimum 
of 15 slides, obtained from fresh core biopsy, punch biopsy, excisional biopsy or surgical specimen). 
Archival sample within 6 months of screening is permitted.
a Within 28 days of treatment
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Table 5.1-2:
On-Study Assessments for Dose Evaluation Phase (Stage 1): Ulocuplumab Weekly Dosing (CA212115)
Procedure
Ulocuplumab administered every week
Nivolumab administered every 2 weeks
Notes
Week 1, 3, 5, 7, 9, etc
Ulocuplumab + 
Nivolumab dosing visits
Week 2, 4, 6, 8, 10, etc
Ulocuplumab dosing visits
Safety Assessments
Targeted Physical Examination
X
X
Within 72 hours prior to dosing.
Vital Signs and Oxygen 
Saturation
X
X
Including BP, HR, respiratory rate, temperature and oxygen 
saturation by pulse oximetry. Pulse oximetry at rest within 
72 hours prior to dosing.
Weight
X
Nivolumab dosing calculations should be based on body 
weight. If the subject’s weight on the day of dosing differs 
by > 10% from the weight used to calculate the dose, the 
dose must be recalculated. All doses should be rounded to 
the nearest milligram.
ECOG Status
X
ECG (12-lead)
See Notes
Every 6 weeks from first dose for the first 12 weeks, then 
every 12 weeks (1 wk)
Adverse Events Assessment
Continuous
Review of Concomitant
Medications
X
X
Chest X-Ray
X
Week 2 only (monitor for pulmonary toxicity)
Laboratory Tests
X
X
On-study local laboratory assessments should be done 
within 72 hours prior to each dose: total protein, CBC 
w/differential, ALT, AST, total bilirubin, direct bilirubin 
(reflex testing when total bilirubin is elevated), alkaline 
phosphatase, BUN or serum urea level, uric acid, creatinine, 
albumin, Ca, Mg, Na, K, P, Cl, LDH, glucose, amylase, 
lipase, TSH (Free T4 and Free T3 reflex testing if TSH 
result abnormal).
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ulocuplumab/nivolumab
Table 5.1-2:
On-Study Assessments for Dose Evaluation Phase (Stage 1): Ulocuplumab Weekly Dosing (CA212115)
Procedure
Ulocuplumab administered every week
Nivolumab administered every 2 weeks
Notes
Week 1, 3, 5, 7, 9, etc
Ulocuplumab + 
Nivolumab dosing visits
Week 2, 4, 6, 8, 10, etc
Ulocuplumab dosing visits
CRP
See Notes
Day 1, then every 6 weeks from first dose for the first 
12 weeks, then every 12 weeks (1 wk)
CA19.9 tumor marker
See Notes
PAC subjects only. Day 1, then every 6 weeks from first 
dose for the first 12 weeks, then every 12 weeks (1 wk)
Immunogenicity blood sample
See Notes
Samples will be collected at time points per Section 5.5
Pregnancy Test (WOCBP only)
See Notes
Serum or urine within 24 hours prior to first dose and then 
every 4 weeks.
Pharmacokinetic Assessments
PK Samples
See Notes
Samples will be collected at time points per Section 5.5
Biomarker Testing
 
 
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ulocuplumab/nivolumab
Table 5.1-2:
On-Study Assessments for Dose Evaluation Phase (Stage 1): Ulocuplumab Weekly Dosing (CA212115)
Procedure
Ulocuplumab administered every week
Nivolumab administered every 2 weeks
Notes
Week 1, 3, 5, 7, 9, etc
Ulocuplumab + 
Nivolumab dosing visits
Week 2, 4, 6, 8, 10, etc
Ulocuplumab dosing visits
Efficacy Assessment
Tumor Assessment
Every 6 weeks (1 wk) from first dose for the first 
24 weeks, then every 12 wks (1 wk) until disease 
progression or treatment is discontinued (whichever 
occurs later).
CT chest, CT/MRI abdomen, pelvis and all known sites of 
disease. Use same imaging method as was used at 
screening/baseline.
Subjects with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or 
sooner if clinically indicated
Outcomes Research 
Assessment
EQ-5D
See notes
Assessments should be collected on day 1 and at the same 
time as tumor assessments. Questionnaires should be 
completed prior to study drug administration and before any 
clinical activities.
Clinical Drug Supplies
IVRS call for vial assignment 
and randomization
X
X
Randomization call will be implemented after the DLT 
period, if applicable
Administer Ulocuplumab
treatment
X
X
Ulocuplumab will be administered first on days where both 
therapies are given. See section 4.5.
Administer Nivolumab treatment
X
See section 4.5
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Table 5.1-3:
On-Study Assessments for Dose Evaluation Phase (Stage 1): Ulocuplumab Dosing Every 2 Weeks 
(CA212115)
Procedure
Ulocuplumab administered every 2 weeks
Nivolumab administered every 2 weeks
Notes
Week 1, 3, 5, 7, 9, etc
Ulocuplumab + Nivolumab dosing visits
Safety Assessments
Targeted Physical Examination
X
Within 72 hours prior to dosing.
Vital Signs and Oxygen 
Saturation
X
Including BP, HR, respiratory rate, temperature and oxygen 
saturation by pulse oximetry. Pulse oximetry at rest within 
72 hours prior to dosing.
Weight
X
Nivolumab dosing calculations should be based on body 
weight. If the subject’s weight on the day of dosing differs 
by > 10% from the weight used to calculate the dose, the 
dose must be recalculated. All doses should be rounded to 
the nearest milligram.
ECOG Status
X
ECG
See Notes
Every 6 weeks from first dose for the first 12 weeks, then 
every 12 weeks (1 wk)
Adverse Events Assessment
X
Review of Concomitant
Medications
X
Laboratory Tests
X
On-study local laboratory assessments should be done 
within 72 hours prior to each dose: total protein, CBC 
w/differential, ALT, AST, total bilirubin, direct bilirubin 
(reflex testing when total bilirubin is elevated), alkaline 
phosphatase, BUN or serum urea level, uric acid, creatinine, 
albumin, Ca, Mg, Na, K, P, Cl, LDH, glucose, amylase, 
lipase, TSH (Free T4 and Free T3 reflex testing if TSH 
result abnormal).
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Table 5.1-3:
On-Study Assessments for Dose Evaluation Phase (Stage 1): Ulocuplumab Dosing Every 2 Weeks 
(CA212115)
Procedure
Ulocuplumab administered every 2 weeks
Nivolumab administered every 2 weeks
Notes
Week 1, 3, 5, 7, 9, etc
Ulocuplumab + Nivolumab dosing visits
CRP
See Notes
Day 1, then every 6 weeks from first dose for the first 
12 weeks, then every 12 weeks (1 wk)
CA19.9 tumor marker
See Notes
PAC subjects only. Day 1, then every 6 weeks from first 
dose for the first 12 weeks, then every 12 weeks (1 wk)
Immunogenicity blood sample
See Notes
Samples will be collected at time points per Section 5.5
Pregnancy Test (WOCBP only)
See Notes
Serum or urine within 24 hours prior to first dose and then 
every 4 weeks.
Pharmacokinetic Assessments
PK Samples
See Notes
Samples will be collected at time points per Section 5.5
Biomarker Testing
 
 
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Table 5.1-3:
On-Study Assessments for Dose Evaluation Phase (Stage 1): Ulocuplumab Dosing Every 2 Weeks 
(CA212115)
Procedure
Ulocuplumab administered every 2 weeks
Nivolumab administered every 2 weeks
Notes
Week 1, 3, 5, 7, 9, etc
Ulocuplumab + Nivolumab dosing visits
Efficacy Assessment
Tumor Assessment
Every 6 weeks (1 wk) from first dose for the first 
24 weeks, then every 12 wks (1 wk) until disease 
progression or treatment is discontinued (whichever 
occurs later).
CT chest, CT/MRI abdomen, pelvis and all known sites of 
disease. Use same imaging method as was used at 
screening/baseline.
Subjects with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or 
sooner if clinically indicated
Outcomes Research 
Assessments
EQ-5D
See notes
Assessments should be collected on day 1 and at the same 
time as tumor assessments. Questionnaires should be 
completed prior to study drug administration and before 
any clinical activities.
Clinical Drug Supplies
IVRS call for vial assignment 
and randomization
X
Randomization call will be implemented after the DLT 
period, if applicable
Administer Ulocuplumab 
treatment
X
Ulocuplumab will be administered first on days where both 
therapies are given. See section 4.5
Administer Nivolumab treatment
X
See section 4.5
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Table 5.1-4:
On-Study Assessments for Dose Expansion Phase (Stage 2) (CA212115)
Procedure
Ulocuplumab administered weekly or every 2 weeks
Nivolumab administered every 2 weeksa
Notes
Week 1, 3, 5, 7, 9, etc
ulocuplumab + nivolumab 
dosing visits
Week 2, 4, 6, 8, 10, etc
ulocuplumab dosing 
visitsb
Safety Assessments
Targeted Physical Examination
X
X
Within 72 hours prior to dosing
Vital Signs and Oxygen 
Saturation
X
X
Including BP, HR, respiratory rate, temperature and oxygen 
saturation by pulse oximetry. Pulse oximetry at rest within 
72 hours prior to dosing.
Weight
X
The nivolumab dosing calculations should be based on the 
body weight. If the subject’s weight on the day of dosing 
differs by > 10% from the weight used to calculate the dose, 
the dose must be recalculated.
ECOG Status
X
ECG (12-lead)
See notes
Every 6 weeks from first dose for the first 12 weeks, then 
every 12 weeks (1 wk)
Adverse Events Assessment
Continuous
Review of Concomitant 
Medications
X
X
Laboratory Tests
X
X
Local laboratory assessments should be done within 
72 hours prior to each dose through Week 24 and every 
alternate dose thereafter and include total protein, CBC 
w/differential, ALT, AST, total bilirubin, direct bilirubin 
(reflex testing when total bilirubin is elevated), alkaline 
phosphatase, BUN or serum urea level, uric acid, creatinine, 
albumin, Ca, Mg, Na, K, P, Cl, LDH, glucose, amylase, 
lipase, TSH (Free T4 and Free T3 reflex test if TSH result 
abnormal).
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Table 5.1-4:
On-Study Assessments for Dose Expansion Phase (Stage 2) (CA212115)
Procedure
Ulocuplumab administered weekly or every 2 weeks
Nivolumab administered every 2 weeksa
Notes
Week 1, 3, 5, 7, 9, etc
ulocuplumab + nivolumab 
dosing visits
Week 2, 4, 6, 8, 10, etc
ulocuplumab dosing 
visitsb
CRP
X
Day 1, then every 6 weeks from first dose for the first 
12 weeks, then every 12 weeks (1 wk)
CA19.9 tumor marker
X
PAC subjects only. Day 1, then every 6 weeks from first 
dose for the first 12 weeks, then every 12 weeks (1 wk)
Immunogenicity blood sample
Samples will be collected at time points per Section 5.5
Pregnancy Test (WOCBP only)
See Notes
Serum or urine within 24 hours prior to first dose and then 
every 4 weeks.
Outcomes Research Assessments
EQ-5D
See Notes
Assessments should be collected on day 1 and every 6 
weeks from first dose for 24 weeks, then every 12 weeks
(1 wk). Subjects will be asked to complete questionnaires 
prior to study drug administration and before any clinical 
activities.
Cancer-specific questionnaire:
LCSS (SCLC)
EORTC-QLQ-C30 (PAC)
Cancer-specific questionnaires only to be included in 
randomized Phase 2 study with comparative arm, if 
initiated
Pharmacokinetic Assessments
PK Samples
Samples will be collected at time points per Section 5.5
Exploratory Biomarker 
Testing
 
 
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Table 5.1-4:
On-Study Assessments for Dose Expansion Phase (Stage 2) (CA212115)
Procedure
Ulocuplumab administered weekly or every 2 weeks
Nivolumab administered every 2 weeksa
Notes
Week 1, 3, 5, 7, 9, etc
ulocuplumab + nivolumab 
dosing visits
Week 2, 4, 6, 8, 10, etc
ulocuplumab dosing 
visitsb
Efficacy Assessment
Tumor Assessment
See Notes
Every 6 weeks (1 wk) from first dose for the first 
24 weeks, then every 12 wks (1 wk) until disease 
progression or treatment is discontinued (whichever occurs 
later).
CT chest, CT/MRI abdomen, pelvis and all known sites of 
disease. Use same imaging method as was used at 
screening/baseline.
Subjects with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or sooner 
if clinically indicated
Clinical Drug Supplies
IVRS call for vial assignment 
and randomization
X
X
Randomization call will be implemented if a phase 2 
randomized study design is initiated
Administer Ulocuplumab 
treatment (See section 4.5)
X
X
Ulocuplumab will be administered first on days where both 
therapies are given. For 1600mg every 2 week dosing, 
ulocuplumab doses will be given Week 1, 3, 5, etc.b
Administer Nivolumab treatment
(See section 4.5)
X
If a randomized phase 2 design is initiated for SCLC, the 
comparator will be nivolumab monotherapy every 2 weeks
Investigator choice 
chemotherapy treatment
X
X
If a randomized phase 2 design is initiated for PAC, the 
comparator will be investigator choice chemotherapy
a If a randomized phase 2 design is initiated for SCLC, the comparator will be nivolumab monotherapy following the every 2 week visit schedule (eg, week 1, 3, 
5, 7, etc.). If a randomized phase 2 design is initiated for PAC, the comparator will be investigator choice chemotherapy following the weekly visit 
assessments, as applicable.
b For ulocuplumab every 2 week dosing, ulocuplumab doses will be given Week 1, 3, 5, etc. Visits at Week 2, 4, 6, etc. will not be required.
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Table 5.1-5:
Follow-up Assessments (CA212115) - All Subjects
Procedure
Follow Up,a
Visits 1 and 2
Survival,b
Follow up Visits
Notes
Safety Assessments
Targeted Physical Examination
X
Adverse Event Assessments
X
X
AEs during the survival follow up visits considered study drug-related 
should be followed until resolution, stabilization, or returned to baseline.
Laboratory Tests
X
CBC w/differential, total protein, ALT, AST, total bilirubin, direct 
bilirubin (reflex testing when total bilirubin is elevated), alkaline 
phosphatase, BUN or serum urea level, uric acid, creatinine, albumin, 
Ca, Mg, Na, K, P, Cl, LDH, glucose, amylase, lipase, TSH (Free T4 and 
Free T3 reflex testing if TSH result abnormal).
Pregnancy Test (WOCBP Only)
X
Serum or urine
Review of Concomitant Medications
X
PK Samples
X
See section 5.5
Immunogenicity blood sample
X
See section 5.5
Survival Status
Subject Status
X
X
Every 3 months, may be accomplished by visit, phone contact or email, 
to assess subsequent anti-cancer therapy
Efficacy Assessments
Tumor Assessment
See Notes
Only for subjects without progression on study therapy and even if they 
receive subsequent treatment.
Every 6 weeks (1 wk) from first dose for the first 24 weeks, then every 
12 wks (1 wk) until disease progression or treatment is discontinued 
(whichever occurs later).
CT chest, CT/MRI abdomen, pelvis and all known sites of disease. Use 
same imaging method as was used at screening/baseline.
Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks, or sooner if clinically indicated
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Table 5.1-5:
Follow-up Assessments (CA212115) - All Subjects
Procedure
Follow Up,a
Visits 1 and 2
Survival,b
Follow up Visits
Notes
Outcomes Research Assessments
EQ-5D
X
X
The EQ-5D can be done via a phone contact when a clinic visit is not 
feasible (ie, follow up scans are being done at another facility or 
department) in order to not miss the assessment.
Cancer-specific questionnaire*
LCSS (SCLC)
EORTC-QLQ-C30 (PAC)
X
X
*Only for Stage 2 Randomized study subjects
a Follow-up visit 1 (FU1) = 35 days (7 days) from the last dose or coincide with the date of discontinuation (7 days) if date of discontinuation is greater than 
42 days after last dose, Follow-up visit 2 (FU2) = 80 days (7 days) from follow-up visit 1
b Survival visits = every 3 months from FU2. Regardless of any subsequent treatment, all subjects will remain on study follow-up for disease progression and 
survival assessment.
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5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory 
value). Any new result will override the previous result (ie, the most current result prior to start 
of therapy) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
5.2
Study Materials

NCI CTCAE Grading Criteria

BMS-936564 (ulocuplumab) Investigator Brochure

BMS-936558 (nivolumab) Investigator Brochure

Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens

Manual for operation of interactive voice response system

Manual for entry of local laboratory data

Pregnancy surveillance forms

RECIST 1.1 pocket guide

Questionnaires: EQ-5D, LCSS (for SCLC) and EORTC-QLQ-C30 (for PAC)
5.3
Safety Assessments
Safety assessments should be performed per tables in Section 5.1.
Physical examinations are to be performed per tables in Section 5.1 and as clinically indicated. If 
there are any new or worsening clinically significant changes since the last exam, report changes 
on the appropriate non-serious or serious adverse event page.
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of 
study drug and at time points specified in Section 5.1. Chest X-ray is to be performed for 
monitoring of pulmonary toxicity per tables in Section 5.1.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
inducted liver enzyme elevations) will be monitored during the follow-up phase via on site/local 
labs until all study drug-related toxicities resolve, return to baseline or are deemed irreversible.
Vital signs should be assessed at each on-study visit prior to dosing. Vital signs should also be 
taken as per institutional standard of care prior to, during and after dosing. Oxygen saturation by 
pulse oximetry should be obtained prior to dosing and at any time a subject has any new or 
worsening respiratory symptoms. A reading at rest should be obtained at each time point. If a 
subject shows changes on pulse oximetry or other pulmonary related signs (eg, hypoxia, fever) or 
symptoms (eg, dyspnea, cough) consistent with possible pulmonary adverse events, the patient 
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subject should be immediately evaluated to rule out pulmonary toxicity. An algorithm for the 
management of suspected pulmonary toxicity can be found in Appendix 2.
Some of the previously referred to assessments may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.1
Imaging Assessment for the Study
For details on the imaging assessments for response evaluation, refer to Appendix 3. 
5.3.1.1
CT/MRI 
Contrast-enhanced Computed Tomography (CT) scans acquired on dedicated CT equipment is 
preferred for this study. CT with contrast of the chest, abdomen and pelvis are to be performed 
for tumor assessments every 6 weeks for the first 24 weeks, then every 12 wks until disease 
progression or treatment is discontinued. CT scans should be acquired with 5mm slices with no 
intervening gap (contiguous). 
Should a subject have a contraindication for CT IV contrast, a non-contrast CT of the chest and a 
contrast enhanced MRI of the abdomen and pelvis may be obtained. MRI’s should be acquired 
with slice thickness of 5 mm with no gap (contiguous). 
Every attempt should be made to image each subject using an identical acquisition protocol on 
the same scanner for all imaging time points.

Note: Use of CT component of a PET/CT scanner:
Combined modality scanning such as with FDG-PET/CT is increasingly used in clinical care, 
and is a modality/technology that is in rapid evolution; therefore, the recommendations outlined 
here may change rather quickly with time. At present, low dose or attenuation correction CT 
portions of a combined FDG-PET/CT are of limited use in anatomically based efficacy 
assessments and it is therefore suggested that they should not be substituted for dedicated 
diagnostic contrast enhanced CT scans for anatomically based RECIST 1.1 measurements. 
However, if a site can document that the CT performed as part of a FDG-PET/CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast) then the CT portion of the FDG-
PET/CT can be used for RECIST 1.1 measurements. Note, however, that the FDG-PET portion 
of the CT introduces additional data which may bias an investigator if it is not routinely or 
serially performed 
5.3.1.2
MRI Brain 
MRI of brain is required at screening for subjects with SCLC in order to rule out active 
metastatic disease. Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks, or sooner if clinically indicated.
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MRI brain scans during on-study treatment and follow up periods are required only if there is a 
prior history of lesions present at Screening, or as clinically indicated for new signs and 
symptoms that suggest central nervous system (CNS) involvement.
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the investigator as per standard 
medical/clinical judgment.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline 
tumor assessments should be performed within 28 days prior to the first dose utilizing CT or 
MRI. In addition to chest, abdomen, pelvis, and brain, all known sites of disease should be 
assessed at baseline. Subsequent assessments should include chest, abdomen, and pelvis, and all 
known sites of disease and should use the same imaging method as was used at baseline. 
Subjects will be evaluated for tumor response beginning 6 weeks (1 week) from first dose and 
continuing every 6 weeks (1 week) for the first 24 weeks and every 12 weeks (1 week) 
thereafter, until disease progression is documented or treatment is discontinued (whichever 
occurs later). Tumor assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST 1.1 criteria. For details on the efficacy assessments of overall tumor 
burden including baseline documentation of “target” and “non-target” lesions and RECIST 1.1 
criteria, please see Appendix 3.
5.4.1
Primary Efficacy Assessment
The primary efficacy endpoint will be ORR, as determined by the investigators, for the Dose 
Evaluation Phase and if a Simon 2-stage like design is selected for the Expansion Phase. If an 
open label randomized Phase 2 with a comparative arm is selected for the Expansion Phase, the 
primary efficacy endpoint will be ORR for SCLC and OS for PAC. If a randomized Phase 2 
study is initiated for either tumor type, a blinded independent review of all imaging scans will be 
used to determine ORR, best overall response (BOR) and the magnitude of reduction in tumor 
volume. Refer to Section 8.3 for the definition of these endpoints. For OS, every effort should be 
made to collect survival date on all treated subjects including withdrawal from treatment for any 
reason, who are eligible to participate in the study and who have not withdrawn consent for 
survival data collection. If the death of a subject is not reported every date collected in this study 
representing a date of subject contact will be used in determining the subject's last known alive 
date.
 
 
 
 
 
 
 
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5.6.5.5
Tumor Sample Collection Details
Detailed instructions of the obtaining, processing, labeling, handling, storage and shipment of 
specimens will be provided in a separate Procedure Manual at the time of study initiation.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.7.2
LCSS- SCLC subjects only
The LCSS is designed as a lung-cancer specific measure of QoL, specifically for use in clinical 
trials. It consists of 9 visual analogue scales that are administered in a fixed order and completed 
by the subject. The LCSS evaluates 6 major symptoms associated with lung malignancies and 
their effect on overall symptomatic distress, functional activities and global QoL. For subjects 
with SCLC, the LCSS will be administered only if a randomized Phase 2 study with comparative 
arm is initiated.
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5.8
Other Assessments
Not applicable.
5.9
Results of Central Assessments
5.9.1
Evaluation of Scans
In addition to investigator assessed response, the protocol contains a plan to use an independent 
radiology review committee (IRRC) to also assess ORR if a randomized Phase 2 study is 
initiated. For instance, investigator assessed ORR will be the primary endpoint for subjects 
enrolled in the Dose Evaluation Phase or in the Dose Expansion Phase (Simon 2-stage single arm 
study only). For SCLC subjects enrolled in the Randomized Phase 2 with comparative arm, 
IRRC-assessed ORR will be the primary endpoint and an exploratory endpoint for PAC subjects. 
BMS may request the transfer of de-identified scans for internal or external evaluation through a 
third party.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all AE. The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect 

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE.
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must
be handled as
SAEs. 
(See Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section 6.1.1 for reporting details).
NOTE:
The following hospitalizations are not considered SAE in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy)
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
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason).

Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols)
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 
and within 100 days of discontinuation of dosing. Subjects who are randomized and never 
treated with study drug must have SAEs collected for 30 days from the date of randomization. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure 
(eg, a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
An SAE report must be completed for any event where doubt exists regarding its seriousness.
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The 
preferred method for SAE data reporting collection is through the eCRF. The paper 
SAE/pregnancy surveillance forms are only intended as a back-up option when the eCRF system 
is not functioning. In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, 
the original paper forms are to remain on site.
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SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report must be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or delayed

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the BMS 
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Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for subject safety).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough 
discussion of benefits and risk with the subject.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
of awareness of the event and in accordance with SAE reporting procedures described in 
Section 6.1.1.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 6.1.1 for reporting details).
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs.
Potential drug induced liver injury is defined as:
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase)
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
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6.7
Other Safety Considerations
Any 
significant 
worsening
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
Ulocuplumab has demonstrated a manageable safety profile in over 140 subjects enrolled in two 
Phase 1 clinical trials at exposures that are related to the recommended starting dose proposed in 
CA212115. Nivolumab has demonstrated a manageable safety profile in more than 4000 patients 
in numerous early and late stage clinical trials. The AE profile of nivolumab appears to be 
independent of tumor type. Adverse events observed at 3 mg/kg nivolumab were manageable 
and generally reversible with the use of existing treatment algorithms. When comparing the 
toxicity profile of ulocuplumab and nivolumab in solid tumor indications, there is little overlap 
of AE profiles. Therefore, a data monitoring committee (DMC) will not be utilized for the open 
label, Dose Expansion Phase (Stage 1) of this study.
The subjects’ safety will be monitored on an ongoing basis. Safety conference calls with 
investigators and representatives of the sponsor will be held regularly during the DLT evaluation 
period. The BMS Medical Monitor is a physician responsible for reviewing, on a systematic and 
continuous basis, the safety of patients on this study. This includes a review of serious and non 
serious adverse events, which includes all hematological and non-hematological events.
In addition, separate BMS medical safety teams (MST) routinely review safety signals across the 
nivolumab and ulocuplumab programs. The MST is independent from the BMS Medical 
Monitor. The MST has the primary responsibility within BMS for assessing emerging safety 
trends, identifying potential safety signals, notifying appropriate stakeholders of relevant 
findings, and implementing risk management plans.
The MST is responsible for reviewing data from all sources including non-clinical studies and 
clinical trials, monitoring the progress of various nivolumab and ulocuplumab safety support 
activities, and recommending and implementing necessary changes to the safety plan and any 
other specific safety-related activities.
If a randomized Phase 2 study with comparative arm is initiated, a DMC will be established to 
provide oversight of safety and efficacy evaluation and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of subjects 
enrolled in the randomized Phase 2 study with comparative arm. The DMC will be charged with 
assessing such actions in light of an acceptable benefit/risk profile for ulocuplumab plus 
nivolumab and nivolumab monotherapy (for SCLC) or Investigator’s Choice chemotherapy (for 
PAC). The DMC will act in an advisory capacity to BMS and will monitor subject safety and 
evaluate the available efficacy data for the study. The oncology therapeutic area of BMS has 
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primary responsibility for design and conduct of the study. A separate charter will provide 
further guidance and describe the activities of this committee.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
The sample size will start at DL1 with a minimum of 3 treated subjects with either SCLC or PAC 
using a Rolling Six design for evaluation of DLT. Then, the sample size will be increased by the 
number of subjects, separately by tumor type, needed to continue the DLT evaluation at each 
dose level followed by the number of subjects, separately by tumor type, needed for one or three 
randomized cohort(s) to complete the Dose Evaluation Phase. Finally, the sample size will be 
increased by the number of subjects needed for the Dose Expansion Phase for each tumor type.
8.1.1
SCLC Sample Size
For SCLC, up to approximately 175 treated subjects may be needed. This sample size considers 
the following:

3 to 18 subjects for the DLT evaluation

19 subjects per cohort for the Dose Evaluation Phase (57 subjects for three randomized 
cohorts)

A second stage of a Simon 2-stage like design in the Dose Expansion Phase that would 
require an additional 25 subjects 
OR

A randomized Phase 2 study with comparative arm in the Dose Expansion Phase that would 
require an additional 50 subjects per arm (ie. 100 for the two arms) 
These numbers are obtained using the following methods and assumptions:

A Simon optimal 2-stage design will test the null hypothesis that the true response rate is less 
than or equal to 15% versus the alternative hypothesis that it exceeds 15%. The type I error 
rate will be 5% (one-sided) and the design will have 90% power to reject the null hypothesis 
when the true response rate is 35%. The Simon design in this tumor type will require 
19 treated subjects for the first stage and at least 4 responders to initiate Stage 2. An 
additional 25 treated subjects will be needed for the second stage and the drug will be 
considered of potential clinical interest if, at the end of the second stage, there are 11 or more 
responders out of the total of 44 treated subjects. Subjects who were assigned treatment but 
never treated will not count towards the total of 19 treated subjects for the first stage or the 
44 treated subjects in a cohort and will be replaced.

If an open label randomized Phase 2 with comparative arm study is initiated (1:1 ratio), the 
primary measurement for efficacy will be IRRC assessed ORR. Considering one-sided alpha 
level of 0.10 a sample size of 50 subjects per arm would provide approximately 80% power 
to detect a difference of 20% in the response rates between the two arms (based on a Fisher’s 
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exact test) assuming an ORR of 35% for the combination arm of ulocuplumab plus 
nivolumab and an ORR of 15% for the nivolumab monotherapy arm.
8.1.2
PAC Sample Size
For PAC, up to approximately 331 treated subjects may be needed. This sample size considers 
the following:

3 to 18 subjects for the DLT evaluation

21 subjects per cohort for the Dose Evaluation Phase (63 subjects for three randomized 
cohorts)

A second stage of a Simon 2-stage like design in the Dose Expansion Phase that would 
require an additional 20 subjects 
OR

A randomized Phase 2 study with comparative arm in the Dose Expansion Phase that would 
require an additional 125 subjects per arm (ie, 250 for the two arms) 
These numbers are obtained using the following methods and assumptions:

A Simon optimal 2-stage design will test the null hypothesis that the true response rate is less 
than or equal to 5% versus the alternative hypothesis that it exceeds 5%. The type I error rate 
will be 5% (one-sided) and the design will have 90% power to reject the null hypothesis 
when the true response rate is 20%. The Simon design in this tumor type will require 
21 treated subjects for the first stage and at least 2 responders to initiate Stage 2. An 
additional 20 treated subjects will be needed for the second stage and the drug will be 
considered of potential clinical interest if, at the end of the second stage, there are 5 or more 
responders out of the total of 41 treated subjects. Subjects who were assigned treatment but 
never treated will not count towards the total of 21 treated subjects for the first stage or the 
total of 41 subjects in a cohort and will be replaced.

If an open label randomized Phase 2 study with comparative arm is initiated (1:1 ratio), the 
primary measurement for efficacy will be OS. A one-sided alpha level of 0.10 log-rank test 
will be used to compare the OS of subjects randomized to the combination arm of 
ulocuplumab plus nivolumab to that of subjects randomized to the investigator’s choice 
chemotherapy arm. In order for the test to have at least 80% power to reject the null 
hypothesis of no difference in OS among treatment arms when the hazard ratio of the 
experimental arm to the control arm is 0.75, the study will require 218 events (deaths) to 
complete. The analysis of OS will take place when the following two conditions have been 
met: 218 events have been observed and all subjects have been on study for at least 6 months. 
The requirement that subjects be on study for at least 6 months is meant to ensure adequate 
follow-up. A total of 250 subjects are to be randomized. Assuming an accrual rate of 
20 subjects per month, the accrual will last approximately 13 months. Assuming 
exponentially distributed OS and median OS times in the control and experimental arms of 
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4.5 months28,41 and 6.0 months, respectively, it is expected that the requisite number of 
events (deaths) will occur approximately 10 months after all subjects have been randomized.
8.2
Populations for Analyses

All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IVRS

All Treated Subjects: All subjects who received at least one dose of any study medication

All DLT-evaluable Subjects: All subjects who completed the DLT evaluation phase 
(ie. received at least 5 out of 6 doses of ulocuplumab and at least 2 out of 3 doses of 
nivolumab in a 6 week dosing period or experienced a DLT)

All Dose Evaluation Randomized Subjects: All subjects who were randomized to a cohort 
(DL2, DL3A, DL3B) or allocated to an unique DL2, DL1 or DL-1 cohort during the Dose 
Evaluation Phase

All Dose Evaluation Randomized Treated Subjects: All subjects who were randomized to a 
cohort (DL2, DL3A, DL3B) or allocated to an unique DL2, DL1 or DL-1 cohort during the 
Dose Evaluation Phase and were treated

All Dose Expansion Phase Randomized Subjects: All subjects who were randomized to a 
treatment arm during the Dose Expansion Phase
Where applies, the above populations will be defined for each phase individually or pooled 
across phases (eg. for the analysis of the 2-stage design).
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The incidence of DLTs is the primary safety endpoint during the DLT evaluation phase.
In terms of efficacy, the primary endpoint for SCLC is investigator assessed ORR for the Dose 
Evaluation Phase and the single arm Dose Expansion Phase. If the randomized Phase 2 study in 
SCLC subjects is triggered, an IRRC will perform blinded independent review of the imaging 
per RECIST 1.1 criteria for the assessment of ORR. The ORR is defined as the number of 
subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) 
divided by the number of treated subjects (the number of randomized subjects for the 
randomized Phase 2 study with comparative arm). The BOR is defined as the best response 
designation, as determined by the investigator, recorded between the first dosing date 
(randomization date for the randomized Phase 2 study with comparative arm) and the date of 
objectively documented progression per RECIST 1.1 or the date of subsequent anti-cancer 
therapy, whichever occurs first. CR or PR determinations included in the BOR assessment must 
be confirmed by a second scan no less than 4 weeks after the criteria for response are first met. 
For subjects without documented progression or subsequent therapy, all available response 
designations will contribute to the BOR assessment. For subjects who continue treatment beyond 
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progression, the BOR should be determined based on response designations recorded up to the 
time of the initial RECIST 1.1-defined progression. 
For PAC, the primary endpoint is investigator assessed ORR for the Dose Evaluation Phase and 
the single arm Dose Expansion Phase. Overall survival (OS) is the primary endpoint for the 
randomized two-arm Phase 2 study. The ORR is defined as above and OS is defined as the time 
between the randomization date and the date of death due to any cause. A subject who has not 
died will be censored at the last known alive date.
8.3.2
Secondary Endpoint(s)
Safety and tolerability will be analyzed through the incidence of DLTs, adverse events, serious 
adverse events, and specific laboratory abnormalities (worst grade). Toxicities will be graded 
using the NCI CTCAE version 4.0.
PFS is defined as the time from first dosing date (randomization date for the randomized Phase 2 
study with comparative arm) to the date of the first documented tumor progression, as 
determined by the investigator (per RECIST 1.1), or death due to any cause, whichever occurs 
first. Subjects who die without a reported prior progression will be considered to have progressed 
on the date of their death. Subjects who did not progress or die will be censored on the date of 
their last evaluable tumor assessment. Subjects who did not have any on-study tumor 
assessments and did not die will be censored on the date of their first dosing date (randomization 
date for the randomized Phase 2 study with comparative arm). Subjects who started anti-cancer 
therapy without a prior reported progression will be censored on the date of their last evaluable 
tumor assessment prior to the initiation of subsequent anti-cancer therapy.
8.3.3
Exploratory Endpoint(s) 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4
Analyses
All analyses will be presented separately by tumor type. 
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized using descriptive statistics.
8.4.2
Efficacy Analyses
For the Dose Evaluation Phase, efficacy analyses will be summarized using the All Dose
Evaluation Randomized Treated Subjects by randomized cohort (primary population). 
Additionally, analyses including all efficacy data collected during that Phase using the All 
Treated Subjects population will be provided by regimen. Analyses will be presented as-treated.
If the form of the Expansion Phase is a Simon 2-stage like design, efficacy analyses will be 
summarized for the regimen recommended for the Dose Expansion Phase, pooling data from the 
related randomized cohort from the All Dose Evaluation Randomized Treated Subjects during 
Stage 1 with the Stage 2 data (primary population). Additionally, analyses using the All Treated
Subjects and including all efficacy data collected for that regimen during the Dose Evaluation 
and the Dose Expansion Phases will be provided. Analyses will be presented as-treated.
If a randomized Phase 2 study with comparative arm is initiated, efficacy analyses will be 
presented separately by treatment arm using the All Expansion Phase Randomized Subjects.
Analyses will be presented as-randomized.
8.4.2.1
Primary Endpoint Methods
ORR will be summarized by a binomial response rate and corresponding two-sided 90% exact CI 
using the Clopper and Pearson method. If a randomized Phase 2 study with comparative arm is 
initiated, ORR will be compared between the treatment arms using a one-sided alpha level of 
0.10 with Cochran-Mantel-Haenszel (CMH) test stratified by the stratification factors defined for 
each tumor type. A two-sided, 80% CI for the difference in response rates will also be computed, 
adjusting for the stratification factors.
The primary analysis of OS as primary endpoint for PAC will be a comparison of the OS of 
subjects randomized to ulocuplumab plus nivolumab to that of subjects randomized to the 
investigator’s choice chemotherapy using a one-sided alpha level of 0.10 log-rank test stratified 
by the stratification factors defined for each tumor type. The hazard ratio and associated 
two-sided 80% confidence interval will be computed using an univariate Cox proportional 
hazards model with treatment as the sole covariate. Further analyses of OS will be summarized 
descriptively using Kaplan-Meier methodology. Median values of OS, along with two-sided 95% 
CIs using the Brookmeyer and Crowley method considering a log-log transformation, will be 
calculated. OS rates at 3, 6, 9, 12, 18 and 24 months will be estimated as well as associated 
two-sided 95% CIs considering a log-log transformation. 
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8.4.2.2
Secondary Endpoint Methods
PFS as a secondary endpoint will be descriptively summarized as for OS above. PFS rates at 3, 6, 
9, 12, and 18 months will be estimated as well as associated two-sided 95% CIs considering a 
log-log transformation. 
8.4.2.3
Exploratory Endpoint Methods
 
 
 
 
 
 
 
 
 
8.4.3
Safety Analyses
Except where indicated, safety analyses will be using the All Treated Subjects population and 
will be presented as-treated.
During the DLT evaluation Phase, the primary analysis will consist of the incidence of DLTs
among DLT-evaluable Subjects but all available safety and tolerability data will be used to 
assess the safety of the regimens.
For the Dose Evaluation Phase, safety analyses will be summarized by randomized cohort. 
Additionally, analyses including all safety data collected during that Phase will be provided by 
regimen.
If the form of the Expansion Phase, is a Simon 2-stage like design, safety analyses will be 
summarized for the regimen recommended for the Dose Expansion, pooling data from both 
stages of the study. Additionally, analyses including all safety data collected for that regimen 
during the Dose Evaluation and the Dose Expansion Phases will be provided. 
If a randomized Phase 2 study with comparative arm is initiated, safety analyses will be 
presented separately by treatment arm.
Events (AEs or laboratory) will be counted as on-study if the event occurred within 100 days of 
the last dose of ulocuplumab or within 100 days of the last dose of nivolumab, whichever is later. 
All on-study AEs, treatment-related AEs, SAEs, treatment-related SAEs, AEs leading to 
discontinuation and treatment-related AEs leading to discontinuation will be tabulated 
(All Grades and Grade 3-4) using worst grade per NCI CTCAE v 4.0 criteria by system organ 
class and preferred term. On-study laboratory abnormalities including hematology, chemistry, 
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liver function, and renal function will be summarized (All Grades and Grade 3-4) using worst 
grade NCI CTCAE v 4.0 criteria.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Baseline and change from baseline in EORTC-QLQ-C30 global health status/QoL composite 
scale data and the remaining EORTC QLQ-C30 scale data will be summarized by time point 
using descriptive statistics for each cohort (N, mean, standard deviation, median, first and third 
quartiles, minimum, maximum). In addition, the percentage of subjects demonstrating a 
clinically meaningful change (defined as a 10 point change from baseline) will be presented for 
each scale at each subsequent time point. Percentages will be based on number of subjects 
assessed at assessment time point.
8.4.8
Other Analyses 
Not applicable.
8.5
Interim Analyses
Within each tumor type, an interim analysis (IA) will be conducted when all subjects in the Dose 
Evaluation Phase have a minimum of 3 months of treatment or discontinued prematurely. The 
objectives of this IA will be: 1) to determine if further study of ulocuplumab combined with 
nivolumab is warranted in the tumor type; 2) if further study is warranted, to select a 
recommended dose for the Dose Expansion Phase; and 3) if the Dose Expansion Phase is to be 
completed, to determine whether to conduct a single arm second stage of a Simon optimal 2 
stage like design or an open label randomized Phase 2 design with a comparative arm.
The decision to further study ulocuplumab combined with nivolumab in each tumor type will 
primarily be based on the pre-defined Simon 2-stage design thresholds for the Dose Evaluation 
Phase (at least 4 responders for SCLC and at least 2 responders for PAC). In addition, the 
selection of the recommended dose will be based on all available safety and efficacy data for that 
IA from both tumor types. The decision to proceed from the Dose Evaluation Phase to the Dose 
Expansion Phase will be conducted for each tumor type independently. Consideration may be 
given to evaluating final data before decision is reached to stop further study the combination to 
ensure the full characterization of the response pattern is evaluated.
The decision to proceed with an open label randomized two-arm Phase 2 design rather than 
completing the second stage of a Simon optimal 2-stage like design for the Expansion Phase will 
be taken if, among the treated subjects in the recommended dose selected during the Dose 
Evaluation Phase, a “high” frequency of responders is observed. For SCLC, this “high” number 
will be at least 9 responders and, for PAC, at least 6 responders.
This number of responders has been defined considering clinical input but, ensuring that the 
related proportion of responders also presents with a 90% exact CI lower limit above 25% for 
SCLC or above 12% for PAC. These percentages correspond to the minimum proportion of 
responders that would be needed at the end of a Simon 2-stage design in order to further evaluate 
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the drug (for SCLC, 11 responders among the 44 subjects is 25% and, for PAC, 5 responders 
among the 41 subjects is 12%).
During the Expansion phase, an IA will be conducted when all subjects of the second stage of the 
Simon 2-stage like design have a minimum of 3 months of treatment or discontinued 
prematurely. If a randomized Phase 2 study with comparative arm is initiated, IA will be 
conducted for the DMC as specified in the DMC charter on a regular basis.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects.
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable.
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In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS.
9.1.2.1
Source Documentation
The investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original.
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and 
procedure, electronic CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) is maintained at the study site to include investigational product and 
the following non-investigational product(s): For PAC subjects, if Stage 1 results in a decision to 
move to a randomized Phase 2 study with comparative arm in Dose Expansion Phase, 
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Investigator’s Choice for advanced or metastatic PAC subjects will be the comparator arm. The 
treatment options for 2L PAC include the following:

Gemcitabine with or without albumin-bound paclitaxel

Capecitabine and other fluoropyrimidine containing regimens
Records or logs must comply with applicable regulations and guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number 

amount dispensed to and returned by each subject, including unique subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (eg, lost, wasted) 

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable

dates and initials of person responsible for Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to SAEs and pregnancy, which will be reported on 
the paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be 
left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS.
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs.
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The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a sub-investigator
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the BMS electronic data capture tool.
The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS electronic data capture tool using the unique user account 
provided by BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report.
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:
External Principal Investigator designated at protocol development
Subject recruitment (eg, among the top quartile of enrollers)
Regional representation (eg, among top quartile of enrollers from a specified region or 
country)
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing [Study site or Investigator] participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to BMS at 
the earliest practicable time prior to submission or presentation and otherwise within the time 
period set forth in the CTA.
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GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete Abstinence is defined as 
complete avoidance of heterosexual intercourse and is an acceptable form of 
contraception for all study drugs. Female subjects must continue to have pregnancy 
tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete abstinence is defined as 
complete avoidance of heterosexual intercourse and is an acceptable form of 
contraception for all study drugs. Subjects who choose complete abstinence are not 
required to use a second method of contraception, but female subjects must 
continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego 
complete abstinence.
Expanded definition Complete abstinence as defined as complete avoidance of 
heterosexual intercourse is an acceptable form of contraception for all study drugs. 
This also means that abstinence is the preferred and usual lifestyle of the patient. 
This does not mean periodic abstinence (eg, calendar, ovulation, symptothermal, 
profession of abstinence for entry into a clinical trial, post-ovulation methods) and 
withdrawal, which are not acceptable methods of contraception. Subjects who 
choose complete abstinence are not required to use a second method of 
contraception, but female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the subject chooses to forego complete abstinence
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LIST OF ABBREVIATIONS
Term
Definition
ACTH
Adrenocorticotropic hormone
AE
Adverse Event
AIDS
Acquired Immune Deficiency Syndrome
ALP
Alkaline Phosphatase
ALT
alanine aminotransferase
AML
Acute Myeloid Leukemia
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
Area Under the Curve
BMS
Bristol-Myers Squibb
BOR
Best Overall Response
BP
blood pressure
BUN
Blood Urea Nitrogen
Ca++
Calcium
CAF
Cancer Associated Fibroblast
CA19.9
Cancer Antigen 19.9
CBC
complete blood count
CI
confidence interval
CLL
Chronic Lymphocytic Leukemia
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CR
Complete response
CrCl
Creatinine Clearance
CRF
Case Report Form, paper or electronic
CRP
C Reactive Protein
CT
Computed tomography
CTA
Clinical Trial Agreement
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Term
Definition
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CV
coefficient of variation
CXCR4
CXC Chemokine Receptor 4
DCR
Disease control rate
DILI
Drug Induced Liver Injury
DL
Dose Level
DLBCL
Diffuse Large B Cell Leukemia
DLT 
Dose limiting toxicity
DMC
Data Monitoring Committee
DOR
Duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ED-SCLC
Extensive Disease Small Cell Lung Cancer
EQ-VAS
EQ visual analog scale
EMR
Electronic Medical Records
EHR
Electronic Health Records
EOI
End of Infusion
EQ-5D
EuroQol 5 Dimensions Questionnaire
FAP
Fibroblast Activating Protein
FDA
Food and Drug Administration
FDG/PET
18-Fluoro-deoxyglucose positron emission tomography
FFPE
Formalin-fixed, paraffin-embedded
FL
Follicular Lymphoma
FOLFIRINOX
combination of 5-FU, leucovorin, irinotecan, oxaliplatin
FSH
follicle stimulating hormone
FU1
Follow-up 1
FU2
Follow-up 2
GCP
Good Clinical Practice
GEM
Gemcitabine
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Term
Definition
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
Hormonal Replacement Therapy
IRB
Institutional Review Board
IA
Interim Analysis
IB
Investigator Brochure
IC
Informed Consent
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRRC
Independent Radiology Review Committee
IV
Intravenous
IVRS
interactive voice response system
KM
Kaplan-Meier
LD-SCLC
Limited Disease - Small Cell Lung Cancer
LDH
Lactate Dehydrogenase
LFT
Liver Function Tests
MEC
mitoxantrone, etoposide, and cytarabine
MM
Multiple Myeloma
MST
medical safety team
MRI
Magnetic resonance imaging
MTD
maximum tolerated dose
N
Nivolumab
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI 
National Cancer Institute 
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Term
Definition
NIMP
non-investigational medicinal products 
NK
Natural Killer
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PAC
Pancreatic adenocarcinoma
PD
Pharmacodynamics
PDAC
Pancreatic ductal adenocarcinoma
PD-1
Programmed death 1
PD-L1
Programmed cell death 1 ligand 1
PE
Physical Exam
PE
Platinum plus etopiside
PFS
Progression-Free Survival
PK
Pharmacokinetics
PR
Partial response
Q2W
Every two weeks
QC
quality control
RCC
Renal Cell Carcinoma
RNA
Ribonucleic Acid
RBC
red blood cell
RO
Receptor Occupancy
RECIST
Response Evaluation Criteria in Solid Tumors
RT-PCR
Reverse transcription-polymerase chain reaction
SAE
serious adverse event
SCLC
Small cell lung cancer
SD
stable disease
SDF-1
stromal cell-derived factor 1
SOC
Standard of care
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Term
Definition
T3, T4
triiodothyronine (T3), thyroxine (T4)
TSH
Thyroid Stimulating Hormone
U
Ulocuplumab
ULN
Upper Limit of Normal
US
United States
VGPR
Very Good Partial Response
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
2L
Second Line
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12
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Ghobrial I, Perez R, Baz R, Richardson P, Anderson K, Sabbatini P, DiLea C, Cardarelli P, 
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10 Galsky MD, NJ Vogelzang, Conkling P, Raddad E, Polzer J, Roberson S, Stille JR, Saleh M 
and D Thomton. A Phase 1 trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients 
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11 Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, 
Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake 
CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, 
Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, 
Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New 
England Journal of Medicine (2012) 366: 2443-54.
12 CA209032 clinical protocol
13 Nivolumab Investigator’s Brochure Version 13. July 21, 2014.
14 Siegel R, Miller KM, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 65:5-29, 2015
15 NCCN Guidelines Version 2.2013 Small Cell Lung Cancer; Sorensen M.Annals of Oncology 
(Supplement 5) v120-v125, 2010
16 Jänne PA, Freidlin B, Saxman S,et al. Twenty-five years of clinical research for patients with 
limited-stage small cell lung carcinoma in North America. Cancer 95:1528-38, 2002
17 Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for 
patients with extensive-stage small-cell lung cancer: perceptible progress. JCO 17:1794-
1801, 1999
18 Califano R, Abidin AZ, Peck R, Faivre-Finn C and P Lorigan. Management of Small Cell 
Lung Cancer: Recent Developments for Optimal Care. Drugs (2012) 72: 471-490
19 Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Lu H, 
Cuillerot JM and TJ Lynch, Ipilimumab in combination with paclitaxel and carboplatin as 
first-line therapy in extensive-disease-small-cell-lung-cancer: results from a randomized, 
double-blind, multicenter phase 2 trial. Annals of Oncology (2013) 24: 75-83.
20 Burger JA, DJ Stewart, O Wald and A Peled. Potential of CXCR4 Antagonists for the 
treatment of metastatic lung cancer. Experimental Reviews in Anticancer Therapy (2011); 
11(4): 621-630.
21 Burger M, Glodeck A, Hartmann T, Schmitt-Graff A, Silberstein LE, Fujii N, Kipps TJ and 
JA Burger. Functional expression of CXCR4 9CD184) on small-cell lung cancer cells 
mediates migration, integrin activation and adhesion to stromal cells. Oncogene (2003); 22: 
8093-8101.
22 Gangadhar T, S Nandi and R Salgia. The role of chemokine receptor CXCR4 in lung cancer. 
Cancer Biol Ther (2010); 15:9(6):409-16.
23 Hartmann TN, Burger JA, Glodeck A, Fujii N and M Burger. CXCR4 chemokine receptor 
and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell 
lung cancer (SCLC) cells. Oncogene (2005); 24: 4462-4471. 
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24 Otani Y, Kijima T, Kohmo S, Oishi S, Minami T, Nagatomo I, Takahashi R, Hirato H, 
Suzuki M, Inoue K, Takeda Y, Kida H, Tachibana I, Fujii N and A Kumanogoh. Suppression 
of metastates of small cell lung cancer cells in mice by a peptidic CXCR4 inhibitor TF14016. 
FEBS Letters (2012); 586: 3639-3644.
25 Pina Cardarelli, Research Report: Ulocuplumab treatment in solid tumor models. In Progress.
26 Spigal DR, Weaver R, McCleod M, Harrid O, Stille JR, Polzer J, Roberson S and R Salgia. 
Phase 2 Study of Carboplatin/Etoposide plus LY2510924, a CXCR4 peptide antagonist, 
versus Carboplatin/Etoposide in Patients with Extensive Stage Small Cell Lung Cancer. 
ESMO 2014. Abstract 1472
27 NCCN Guidelines Version 2.2013: Pancreatic Adenocarcinoma; Tempero MA. J. Natl 
Compr Canc Netw (2012) 10:703-713.
28 Conroy T, Desseigne F, Ychou M, et al FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. NEJM 364(19):1817-25, 2011
29 Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay, T, Tjulandin SA, 
Ma WW, Saleh M, Harris M, Reni M, et al. Increased Survival in Pancreatic Cancer with 
nab-Paclitaxel plus Gemcitabine. NEJM (2013); 369: 1691-1702.
30 Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, 
Yagita H, Azuma M and Y Nakajima. Clinical Significance and Therapeutic Potential of the 
Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer. 
Clinical Cancer Research (2007); 13(7): 2151-2157.
31 Wang Z. et al. Aberrant Expression of CXCR4 and Beta-catenin in Pancreatic Cancer. 
Anticancer Research (2013); 33(9): 4103-4110.
32 Gao Z, Wang X, Wu K, Zhao Y, Hu G. Pancreatic stellate cells increase the invasion of 
human pancreatic cancer cells through the stromal cell-derived factor-1/cxcr4 axis. 
Pancreatology. 10(2–3):186–193. [PubMed: 20484957]
33 Feig C, Jones JO, Kraman M, Wells RJB, Deonarine A, Chan DS, Connell CM, Roberts EW, 
Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA and DT Fearon. 
Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with 
anti-PD-L1 immunotherapy in pancreatic cancer. PNAS (2013); 110 (50): 20212-20217.
34 Ulocuplumab Investigator’s Brochure. Version 6. 12May2014. 
35 Fearon DT. The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein 
and Escape from Immune Surveillance. Cancer Immunology Research (2014). 2 (3): 187-93.
36 Chen Y, Ramjiawan RR, Reiberger T, Ng MR, Hato T, Huang Y, Ochiai H, Kitahara S, 
Unan EC, Reddy TP, Fan C, Huang P, Bardeesy N, Zhu AX, Jain RK and DG Duda. CXCR4 
inhibition in tumor microenvironment facilitates anti-PD-1 immunotherapy in sorafenib-
treated HCC in mice. Hepatology (2015). In press.
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37 Skolnik JM, Barrett JS, Jayaraman B, Patel D and PC Adams. Shortening the Timeline of 
Pediatric Phase 1 Trials: The Rolling Six Design. Journal of Clinical Oncology (2007); 26 
(2): 190-195
38 Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang M, Allison DE, 
Lu D, Zhang Y, Joshi A, Dresser MJ. A guide to rational dosing of monoclonal 
antibodies.Clin Pharmacokinet. 2012 Feb 1;51(2):119-35.
39 Spigal DR, Weaver R, McCleod M, Harrid O, Stille JR, Polzer J, Roberson S and R Salgia. 
Phase 2 Study of Carboplatin/Etoposide plus LY2510924, a CXCR4 peptide antagonist, 
versus Carboplatin/Etoposide in Patients with Extensive Stage Small Cell Lung Cancer. 
ESMO 2014. Abstract 1472
40 Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 
(1989); 10:1-10.
41 Hurwitz H, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade S, Nemunaitis JJ, Stella PJ, 
Pipas JM, Wainberg ZA, Manges R, Gerrett WM, Hunter DS, Clark J, Leopold L, Levy RS 
and V Sandor. A randomized double-blind plase 2 study of ruxolitinib (RUX) or placebo 
(PBO) with capecitabine (CAPE) as second-line therapy in patients with metastatic 
pancreatic cancer. ASCO oral presentation. (2015)
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APPENDIX 1
PERFORMANCE STATUS SCALES
STATUS
SCALES
STATUS
KARNOFSKY
ZUBROD-
ECOG-WHO
Normal, no complaints
100
0
Normal activity
Able to carry on normal activities Minor 
signs or symptoms of disease
90
0
Symptoms, but fully 
ambulatory
Normal activity with effort
80
1
Cares for self. Unable to carry on 
normal activity or to do active work
70
1
Symptomatic, but in bed 
< 50% of the day.
Requires occasional assistance, but able 
to care for most of his needs
60
2
Requires considerable assistance and 
frequent medical care
50
2
Needs to be in bed > 50% of 
the day, but not bedridden
Disabled. Requires special care and 
assistance
40
3
Severely disabled. Hospitalization 
indicated though death non imminent
30
3
Very sick. Hospitalization necessary. 
Active supportive treatment necessary
20
4
Unable to get out of bed
Moribund
10
4
Dead
0
5
Dead
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APPENDIX 2
MANAGEMENT ALGORITHMS 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology (I-O) agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 3
EFFICACY ASSESSMENTS OF OVERALL TUMOR BURDEN
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To serially evaluate tumor response to therapy, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable tumor lesion. When CT or MRI 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. At baseline, tumor lesions/lymph nodes will be categorized as 
measurable or non-measurable as follows
1.1
Measurable Lesions
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of:

10 mm by CT/MRI scan - (CT/MRI scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)

20 mm by chest x-ray

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow up, 
only the short axis will be measured and followed
1.2
Non-Measurable Lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with 10 to < 15 mm short axis), as well as truly non-measurable 
lesions

Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques
1.3
Special Consideration Regarding Lesion Measurability
1.3.1
Bone Lesions
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions.
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Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. Blastic bone lesions are non-measurable.
1.3.2
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are by definition, 
simple cysts. Cystic lesions’ thought to represent cystic metastases can be considered as
measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions.
1.3.3
Lesions with Prior Local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression 
in the lesion.
1.4
Specifications by Method of Measurement
1.4.1
Measurement of Lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should 
be performed as close as possible to the treatment start and never more than 28 days before the 
beginning of treatment.
1.4.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI Scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
Imaging-based evaluation is preferred to clinical examination. Helical (spiral) CT scans of the 
chest and abdomen are preferred. If not available, conventional (non helical, non spiral CT) 
should be used. If IV contrast is contraindicated, CT without contrast may be used, or MRI 
should be used at the Screening exam and at all TA time points. Subjects who develop contrast 
allergy after study enrollment must be followed by CT without contrast or MRI for subsequent 
tumor measurements.
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Response and progression of disease must be documented by CT or MRI similar to the methods 
used at Screening.
1.4.2.2
Chest X-Ray
Chest CT is preferred over chest x-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than x-ray, particularly in identifying new lesions. However, lesions 
on chest x-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung.
1.4.2.3
Clinical Lesions
Clinical lesions will only be considered measurable when they are superficial and 10 mm
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated both by clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound
Ultrasound is not useful in the assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.
1.4.2.5
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
2
BASELINE DOCUMENTATION OF “TARGET” AND “NON-TARGET 
LESIONS”
2.1
Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted below, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
Previously treated CNS metastases are not considered measurable lesions for purposes of 
RECIST 1.1 determined response.
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2.1.1
Lymph Nodes
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum.
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed.
2.2
Non-Target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION
3.1
Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression)

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study
3.1.1
Target Lesions that Become “Too Small to Measure”
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (eg, 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
3.1.2
Target Lesions that Split or Coalesce on Treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. As lesions coalesce, a plane between them 
maybe maintained that would aid in obtaining maximal diameter measurements of each 
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individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
3.2
Evaluation of Non-Target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol.

Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10 mm short axis)

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) above the normal limits

Progressive Disease (PD): Unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered progression)
Special Notes on Assessment of Non-target Lesions
3.2.1
When the Subject Also Has Measurable Disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy

A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status
3.2.2
When the Subject Has Only Non-measurable Disease

To achieve ‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy

A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status

Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: ie, an increase in tumor burden representing 
an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’

If ‘unequivocal progression’ is seen, the subject should be considered to have had overall PD 
at that point
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3.3
New Lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of preexisting lesions. This is 
particularly important when the subject’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan reported as a ‘new’ cystic 
lesion, which it is not.)
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.
4
RESPONSE CRITERIA (RECIST 1.1)
Table 4-1 provides a summary of the Time Point Response overall response status in subjects 
with Target and non-Target Disease
Table 4-1:
Time Point Response - Subjects With Target ( Non-target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, 
NE = Not Evaluable
4.1
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular time point, the subject is not
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an
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assessment, the case is also considered NE at that time point, unless a convincing argument can
be made that the contribution of the individual missing lesion(s) would not have changed the
assigned time point response.
4.2
Confirmation Scans
Verification of Response: Confirmation of response (CR or PR) is required. Confirmed CR or 
PR will be claimed only if the criteria for each are met at a subsequent time point (minimum 
4 weeks after criteria for an objective response are first met. After an initial PR or CR is noted,
the subsequent protocol-specified tumor assessment may serve as the confirmation.
Verification of Progression: Progression of disease should be verified only in cases where
progression is equivocal. If repeat scans confirm PD, then progression should be declared using
the date of the initial scan. If repeat scans do not confirm PD, then the subject is considered not
to have progressive disease per RECIST 1.1.
.
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SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 1/2 STUDY OF THE SAFETY AND EFFICACY OF
ULOCUPLUMAB COMBINED WITH NIVOLUMAB
IN SUBJECTS WITH ADVANCED OR METASTATIC SOLID TUMORS
(CXCESSOR4: CLINICAL TRIAL OF THE ANTI-CXCR4 ANTIBODY ULOCUPLUMAB 
IN MALIGNANT TUMORS)
PROTOCOL CA212115
VERSION # 1.0
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Page 2
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................6
1
BACKGROUND AND RATIONALE......................................................................7
2
STUDY DESCRIPTION ..........................................................................................8
2.1
Study Design ............................................................................................................9
2.1.1
Dose Evaluation Phase (Stage 1)............................................................................10
2.1.2
Decision Rules to Proceed with Dose Expansion Phase ..........................................11
2.1.3
Dose Expansion Phase (Stage 2).............................................................................12
2.2
Treatment Assignment............................................................................................12
2.3
Blinding and Unblinding.........................................................................................13
2.4
Protocol Amendments.............................................................................................13
3
OBJECTIVES ........................................................................................................13
3.1
Primary...................................................................................................................13
3.2
Secondary...............................................................................................................13
3.3
Exploratory.............................................................................................................14
4
ENDPOINTS..........................................................................................................14
4.1
Efficacy Endpoints .................................................................................................15
4.1.1
Primary Endpoint...................................................................................................15
4.1.2
Secondary Endpoints ..............................................................................................15
4.1.3
Exploratory Endpoints............................................................................................15
4.2
Safety Endpoints.....................................................................................................16
4.2.1
Select Adverse Events .............................................................................................16
4.2.2
Immune-mediated Adverse Events...........................................................................17
4.2.3
Other Events of Special Interest..............................................................................17
4.6
Biomarkers .............................................................................................................19
4.8
Other Endpoints......................................................................................................20
5
SAMPLE SIZE AND POWER...............................................................................21
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5.1
SCLC Sample Size .................................................................................................21
5.2
PAC Sample Size ...................................................................................................21
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................22
6.1
Study Periods..........................................................................................................22
6.1.1
Baseline Period ......................................................................................................22
6.1.2
Post Baseline Period...............................................................................................23
6.2
Treatment Regimens...............................................................................................23
6.3
Populations for Analyses ........................................................................................24
7
STATISTICAL ANALYSES..................................................................................25
7.1
General Methods ....................................................................................................25
7.2
Study Conduct........................................................................................................25
7.2.1
Accrual...................................................................................................................25
7.2.2
Relevant Protocol Deviations..................................................................................26
7.3
Study Population ....................................................................................................27
7.3.1
Subject Disposition.................................................................................................27
7.3.2
Demographics and Other Baseline Characteristics.................................................27
7.3.2.1
Demographics and Baseline Disease Characteristics..............................................27
7.3.2.2
Prior Cancer Therapy.............................................................................................28
7.3.2.3
Other Baseline Medical Evaluations.......................................................................29
7.3.3
Baseline Laboratory Examinations .........................................................................29
7.4
Extent of Exposure .................................................................................................29
7.4.1
Study Therapy.........................................................................................................29
7.4.2
Modifications of Study Therapy ..............................................................................30
7.4.2.1
Infusion Interruption and Infusion with IV Rate Reduction......................................30
7.4.2.2
Dose Delay.............................................................................................................30
7.4.2.3
Dose Discontinuation .............................................................................................31
7.4.3
Concomitant Medications.......................................................................................31
7.4.4
Immune Modulating Medications............................................................................31
7.5
Efficacy..................................................................................................................31
7.5.1
Objective Response Rate.........................................................................................31
7.5.2
Overall Survival .....................................................................................................32
7.5.3
Progression-free Survival .......................................................................................32
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7.5.4
Duration of Objective Response..............................................................................33
7.5.5
Disease Control Rate..............................................................................................33
7.5.6
Magnitude of Reduction in Tumor Volume..............................................................33
7.5.7
Subsequent Therapy................................................................................................33
7.6
Safety.....................................................................................................................33
7.6.1
DLT Evaluation Period / Maximum Tolerated Dose................................................34
7.6.2
Deaths ....................................................................................................................34
7.6.3
Serious Adverse Events...........................................................................................34
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy.................................34
7.6.5
Adverse Events Leading to Dose Modification........................................................35
7.6.6
All Adverse Events..................................................................................................35
7.6.7
Infusion-related Events...........................................................................................35
7.6.8
Select Adverse Events .............................................................................................36
7.6.8.1
Incidence of Select Adverse Events .........................................................................36
7.6.8.2
IMM Received for Management of Select Adverse Events .......................................36
7.6.9
Immune-mediated Adverse Events...........................................................................37
7.6.10
Other Events of Special Interest..............................................................................37
7.6.11
Multiple Adverse Events .........................................................................................37
7.6.12
Clinical Laboratory Evaluations.............................................................................37
7.6.12.1
Hematology, Serum Chemistry, and Electrolytes.....................................................37
7.6.12.2
Abnormal Hepatic Function Tests...........................................................................38
7.6.12.3
Abnormal Thyroid Function Tests...........................................................................38
7.6.13
Electrocardiograms................................................................................................39
7.6.14
Vital Signs and Physical Findings...........................................................................39
7.6.15
Clinical Safety Program (CSP)...............................................................................39
8
CONVENTIONS....................................................................................................42
9
CONTENT OF REPORTS .....................................................................................42
10
REFERENCES.......................................................................................................43
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LIST OF TABLES
Table 2.1.2-1:
Stage 1 Efficacy Threshold For Each Tumor Type..................................12
Table 4.2.1-1:
Select Adverse Events ............................................................................16
Table 7.4.1-1:
Administration of Study Therapy: Definition of Parameters....................29
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LIST OF FIGURES
Figure 2.1-1:
Dose Evaluation Phase (Stage 1) ............................................................10
Figure 2.1-2:
Dose Expansion Phase (Stage 2).............................................................10
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1
BACKGROUND AND RATIONALE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will clinically evaluate the combination of nivolumab with ulocuplumab to determine 
whether this combined novel mechanism will benefit metastatic cancers poorly treated by standard 
therapies.
Research Hypothesis:  
Treatment with ulocuplumab in combination with nivolumab will be safe, tolerable and 
demonstrate clinically meaningful efficacy in subjects with advanced or metastatic solid tumors.
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2
STUDY DESCRIPTION
Within each tumor type (Small Cell Lung Cancer, SCLC and Pancreatic Adenocarcinoma, PAC), 
the study is divided into different phases and the design of each phase generally depends on the 
results from earlier phases: 

The “Dose Evaluation Phase” (Stage 1) which is further divided into a dose limiting toxicity 
(DLT) “DLT evaluation period” and the “Dose Evaluation Phase” itself that, depending on the 
outcome of the DLT evaluation period, will consist either of a randomized design considering 
three cohorts or a single arm design considering one cohort. During that phase a unique
“recommended dose and schedule” of ulocuplumab will be determined for use during the Dose 
Expansion Phase.
Using the recommended dose and schedule and, depending on the magnitude of the efficacy of 
that regimen during the Dose Evaluation Phase, the “Dose Expansion Phase” (Stage 2) will have
the following form: in case of moderate efficacy (see Table 2.1.2-1), the form of this phase will be 
a single arm consisting of the second stage of a Simon 2-stage design; in case of high efficacy (see 
Table 2.1.2-1), it will have the form of a two-arm open label randomized Phase 2 design with a 
comparative arm.
The selected design and recommended dose and schedule may be different for each tumor type.
Schedule of Analyses:
The analyses presented in this Statistical Analysis Plan (SAP) are intended to take place 
independently for each tumor type (SCLC and PAC) and at the following time points for each 
phase of the study:

Dose Evaluation Phase (note that data from the DLT evaluation period will be included in 
some of the below analyses):

An interim analysis (IA) will be conducted when all subjects in the Dose Evaluation Phase 
have a minimum of 3 months of treatment or discontinued prematurely. The objectives of 
this IA will be: 1) to determine if further study of ulocuplumab combined with nivolumab 
is warranted; 2) if further study is warranted, to select a recommended dose and schedule 
for the Dose Expansion Phase; and 3) if the Dose Expansion Phase is to be completed, to 
determine the design to be used.

The final analysis will take place when all subjects will have discontinued the study. In 
relation to this:
If the Dose Expansion Phase is of the form of a Simon 2-stage design, this analysis 
may be integrated into the Simon 2-stage analyses (IA or final). 
If the Dose Expansion Phase is of the form of a Randomized Phase 2 design, a summary 
of the Dose Expansion Phase will take place, separately from the Randomized data.
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
Dose Expansion Phase:

2-stage design
An IA will be conducted when all subjects have a minimum of 3 months of treatment 
or discontinued prematurely. The objectives of this IA will be similar to item 1) and 2) 
of the Dose Evaluation Phase IA objectives.
The final analysis will take place when all subjects will have discontinued the study.

Randomized Phase 2 
IAs will be conducted on a regular basis for the interim monitoring as specified in the 
Data Monitoring Committee (DMC) charter.
The final analysis will take place when all subjects will have discontinued the study.
At the time of finalizing this SAP, it is known that subjects reported more than 2 DLTs in the 
“ulocuplumab 400mg weekly combined with nivolumab” cohort (DL1, in PAC subjects). 
Therefore, and according to protocol, the DL-1 cohort (ulocuplumab 200mg weekly combined 
with nivolumab) has been initiated. Following this and, considering the current study design, there 
will be no randomization during the Dose Evaluation phase and no use of the DL3B regimen: 
“ulocuplumab at 1600mg every 2 weeks combined with nivolumab”. The current version of this 
SAP is using this information and does not consider that randomization nor the DL3B regimen
while describing the planned analyses. Also, as no ulocuplumab dose reduction were reported for 
the DL1 cohort and as the DL-1 cohort does not allow dose reduction no analysis related to 
ulocuplumab dose reduction will be planned.
Also, to streamline the document, any reference to the analysis of the potential “Randomized 
Phase 2” part of the study are not included at this time and may be added at a later time if warranted.
2.1
Study Design
This is an open-label, multicenter phase 1/2 study of ulocuplumab in combination with nivolumab 
designed to independently evaluate the safety and efficacy in subjects with SCLC and PAC. The 
study design consists of a Dose Evaluation Phase (Stage 1) that will include a DLT evaluation 
period to identify the maximum tolerated dose (MTD). If the maximum dose level (DL3) is 
identified as the MTD, a parallel evaluation of three cohorts will assess two dose levels (800 mg, 
1600 mg) and an additional schedule for 1600 mg (every 2 weeks). If 2 or more DLT are seen with 
any dose during the DLT evaluation period, a lower dose will be evaluated as a single arm. 
Nivolumab will be administered every two weeks.
A recommended dose will be selected based on the safety and efficacy data from Stage 1 and will 
proceed to Dose Expansion in the form of a Simon optimal 2-stage like design or a randomized 
Phase 2 study with comparative arm if high efficacy is observed.
The treatment period will continue until disease progression or occurrence of unacceptable 
toxicity. The duration of the study is anticipated to be approximately 2 years.
The study design schematic is presented the Figure below.
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Figure 2.1-1:
Dose Evaluation Phase (Stage 1)
Figure 2.1-2:
Dose Expansion Phase (Stage 2)
2.1.1
Dose Evaluation Phase (Stage 1)
The Dose Evaluation Phase will consist of a DLT evaluation period followed by an evaluation of 
up to three cohorts with various doses and schedules of ulocuplumab combined with nivolumab. 
The DLT evaluation period will be conducted in the first 3-6 subjects with either PAC or SCLC at 
dose level 1 (DL1; 400 mg weekly ulocuplumab combined with nivolumab), followed by 3-6 
subjects each with PAC and SCLC at DL2 (800 mg weekly ulocuplumab combined with 
nivolumab), followed by 3-6 subjects each with PAC and SCLC at DL3A (1600 mg weekly 
ulocuplumab combined with nivolumab) for 6 weeks. For DL1, both tumor types will be combined 
for the safety evaluation. If 2 or more DLT are observed at DL1, de-escalation to DL-1 will occur 
(200 mg weekly ulocuplumab combined with nivolumab). For all other dose levels, each tumor 
U=ulocuplumab
N=nivolumab
DLT evaluation 
(n=3-6 pts @ 6 wks)
=
Stage 1 safety and efficacy evaluation per 
tumor type @ 3 mos
=
unacceptable 
toxicity/DLTs 
DL 2 
U 800 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
unacceptable 
toxicity/DLTs 
DL 2
U 800 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3A
U 1600 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3B
U 1600 mg q2wk + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 1
U 400 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 2
U 800 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL 3A
U 1600 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
acceptable 
toxicity
acceptable 
toxicity
randomization
DL 1 
U 400 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC or PAC
DL -1
U 200 mg wkly + N 3 mg/kg q2wk
n=19 SCLC and 21 PAC
DL -1
U 200 mg wkly + 
N 3 mg/kg q2wk
n=3-6 SCLC and 
n=3-6 PAC
unacceptable 
toxicity/DLTs 
acceptable 
toxicity
acceptable 
toxicity
Simon 2-stage (per tumor type):
Randomized Phase 2 (per tumor type):. 
DLX (recommended dose from Stage 1)
Nivo Mono (for SCLC) or Inv Choice (for PAC)
DLX  (recommended dose from Stage 1)
n=25 SCLC and 20 PAC
OR
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type will be evaluated for safety independently in the event that tumor specific AE may emerge.
Enrollment during the DLT evaluation phase will allow for concurrent accrual of up to 6 subjects 
in each dose/tumor cohort (i.e., Rolling Six design1).
The incidence of DLT(s) assessed during the first 6 weeks of treatment will be used to initially 
determine whether a dose level is tolerable. DLT should not be adverse event (AE) considered by 
the investigator to be disease related. The following drug-related AE (whether related to one or 
both agents) will be considered a DLT:

Any drug-related non-hematological AE of Grade 3, including the following laboratory 
abnormalities:

If a subject has baseline Grade 1 AST, ALT, or total bilirubin, a drug-related Grade 3 
toxicity will be considered a DLT

If a subject has baseline Grade 2 AST or ALT, drug-related elevations in AST and/or ALT 
> 2x baseline or a maximum of > 8x ULN will be considered a DLT

Any Grade 4 drug-related hematological AE or hematological or non-hematological laboratory 
abnormality with the following exceptions:

Grade 4 amylase or lipase not associated with symptoms or clinical manifestations

Grade 4 lymphocytopenia not associated with symptoms or clinical manifestations

Any drug-related AE that results in dose reduction of ulocuplumab during the DLT period

Any drug related AE that results in dose delay of ulocuplumab > 14 days during DLT period

Any toxicity managed by discontinuation of ulocuplumab or nivolumab.
Depending on the number of DLT observed during the DLT evaluation period, escalation or de-
escalation of ulocuplumab may be warranted. Dose escalation/de-escalation at the 800mg weekly 
and 1600mg weekly ulocuplumab dose levels will occur independently for each tumor type. No 
dose modification of nivolumab will be allowed in this study.
2.1.2
Decision Rules to Proceed with Dose Expansion Phase
An interim analysis (IA) will be carried out when all subjects in the Dose Evaluation Phase in an 
individual tumor type have at least three months of treatment, or discontinued prematurely. This 
IA will be conducted independently for each tumor type. Investigator-assessed ORR will be used 
to guide the decision making for the Stage 2 portion of the study. However, all available efficacy 
and safety data will be used to select the recommended dose that will be further evaluated in the 
Dose Expansion Phase. Furthermore, if the level of efficacy observed at the recommended dose in 
the Dose Evaluation Phase does not warrant stopping evaluation of that tumor type, it will be used 
to select the appropriate Expansion Phase study design, either continuing with the second stage of 
a Simon 2-stage-like design or conducting a randomized Phase 2 study with comparative arm. The 
determination of low, moderate or high efficacy will be based primarily on the response rates 
observed with ulocuplumab and nivolumab (see Table 2.1.2-1), but the totality of available safety 
and efficacy data will be considered. For further information on the interim analysis and the 
efficacy thresholds used for decision rules, refer to Section 7.5.1.
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
If the number of responders per tumor type at the recommended dose level is consistent with
low efficacy, the evaluation of that tumor type will be placed on hold pending final review of
the data.

If the number of responders per tumor type at the recommended dose level is consistent with
moderate efficacy, the Dose Expansion Phase will continue with a single-arm evaluation.

If the number of responders per tumor type at the recommended dose level is consistent with
high efficacy, the Dose Expansion Phase will be continue with a randomized Phase 2 study
with comparative arm.
Table 2.1.2-1:
Stage 1 Efficacy Threshold For Each Tumor Type
Efficacy Threshold
SCLC
PAC
Low
3 responders / 19 subjects
1 responders / 21 subjects
Moderate
4-8 responders / 19 subjects
2-5 responders / 21 subjects
High
9 responders / 19 subjects
6 responders / 21 subjects
2.1.3
Dose Expansion Phase (Stage 2)
Based on the results of the IA, the Dose Expansion Phase will consist of a second stage of a Simon 
2-stage single arm study (moderate efficacy) or a randomized Phase 2 study with comparative arm 
(high efficacy).
The second stage of a Simon 2-stage design will expand enrollment at the recommended dose level 
in a single arm study. The primary endpoint will be investigator-assessed ORR for both tumor 
types.
The randomized Phase 2 study will compare the combination therapy at the recommended dose
level versus a comparative arm appropriate for that tumor type. The primary endpoint of this study 
will be dictated by the tumor type, where ORR is the endpoint for a randomized Phase 2 study in 
SCLC and OS for a randomized Phase 2 study in PAC. For ORR, independent radiology review 
committee (IRRC) will perform blinded independent review of the imaging per RECIST 1.1 
criteria. Stratification factors will be used for this portion of the study and will include performance 
status (ECOG 0 vs. 1) and type of chemotherapy used in the first line setting (fluoropyrimidine-
containing vs. gemcitabine-containing regimens). More details regarding the randomized Phase 2 
for each tumor type are described in the protocol.
2.2
Treatment Assignment
A subject number will be assigned through an interactive voice response system (IVRS) once the 
subject has signed the informed consent form and is registered. Enrolled subjects that have met all 
eligibility criteria will continue with treatment assignment and drug vial assignment through the 
IVRS. 
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2.3
Blinding and Unblinding
Not applicable (open label study whatever the study phase).
2.4
Protocol Amendments
There are currently 5 approved amendments. The history of protocol amendments including the 
dates and changes to the protocol are summarized below.

Amendment 1 (25-Mar-2015, all sites in the USA): The objective of this amendment was to 
initiate a biopsy sub-study that will allow to explore the changes in cellular architecture and 
localization of immune cell populations before and during treatment with ulocuplumab and 
nivolumab for use in future exploratory research (e.g., to validate the hypothesis that the 
refractory nature of SCLC and PAC results from an immunosuppressive environment 
surrounding the tumor that prevents activated lymphocytes from accessing the tumor site).

Amendment 2 (20-May-2015, all sites): The objective of this amendment was to add a sentinel 
400mg weekly ulocuplumab dose level in the dose evaluation phase at the request of regulatory 
authorities. It also incorporated administrative edits and minor clarifications to the study 
procedures.

Amendment 3 (30-Sep-2015, all sites): This amendment changed dose delay, dose 
modification, discontinuation and DLT criteria to account for the known toxicity profiles of 
ulocuplumab and nivolumab and corrected internal inconsistencies in the management of 
toxicity. The major change was to remove the requirement to discontinue study therapy for 
> 7 days of grade 3 thrombocytopenia and replace it with a recommendation to delay therapy 
for > 7 days of grade 3 thrombocytopenia that occurs in the absence of bleeding. 
Discontinuation is still required for grade 4 thrombocytopenia lasting longer than 5 days. 

Amendment 4 (13-Jan-2016, all sites): This amendment changed DLT, dose delay, dose 
modification and dose discontinuation criteria to align with nivolumab program standard 
language. Additional changes have been made to platelet inclusion criteria and prohibited 
medications. Also, chest x-rays were added to monitor for potential early pulmonary toxicity.

Amendment 5 (13-Jan-2016, all sites in the USA): The objective of this amendment was to 
add optional peripheral blood DNA sample to the biopsy sub study.
3
OBJECTIVES
3.1
Primary

Stage 1: To identify the recommended dose and schedule, based on safety and efficacy, of 
ulocuplumab in combination with nivolumab in subjects with advanced or metastatic tumors.

Stage 2: To evaluate the efficacy, separately by tumor type, based on objective response rate 
(ORR) or overall survival (OS; randomized Phase 2 study in PAC only), of ulocuplumab 
combined with nivolumab in subjects with advanced or metastatic tumors.
3.2
Secondary

To assess the safety and tolerability of ulocuplumab combined with nivolumab, in subjects 
with advanced or metastatic tumors.
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
To assess progression-free survival (PFS) with ulocuplumab combined with nivolumab, 
separately by tumor type, in subjects with advanced or metastatic tumors.
3.3
Exploratory
 
 
 
 
 
 
 
 
 
4
ENDPOINTS
Dose Evaluation Phase: 

DLT evaluation period: the primary endpoint (safety) is the incidence of DLTs.

Dose Evaluation Phase: the primary endpoint is the investigator assessed ORR. Secondary 
endpoint is PFS.
Dose Expansion Phase: 

2-stage design: the primary endpoint is the investigator assessed ORR. Secondary endpoint is
PFS.
Common exploratory endpoints are duration of response, disease control rate, and the magnitude 
of reduction in tumor volume. For all tumor types and phases secondary endpoints will include the 
safety parameters as described in Section 4.2.
Disease progression will primarily be determined using RECIST 1.1 criteria but “clinical 
progression” will be considered when RECIST 1.1 criteria cannot be evaluated and only clinical 
progression data is available (e.g., for some PAC subjects).
Timing of evaluation of the efficacy and safety endpoints is detailed in protocol Table 5.1-1
(Screening), 5.1-2 (On-Study Assessments for Dose Evaluation Phase, Stage 1: Ulocuplumab 
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Weekly Dosing), 5.1-4 (On-Study Assessments for Dose Expansion Phase, Stage 2) and 5.1-5
(Follow-up Assessments).
4.1
Efficacy Endpoints
4.1.1
Primary Endpoint
Investigator assessed ORR is defined as the number of subjects with a best overall response (BOR) 
of complete response (CR) or partial response (PR) divided by the number of treated subjects. The 
BOR is defined as the best response designation, as determined by the investigator, recorded 
between the first dosing date and the date of objectively documented progression or the date of 
subsequent anti-cancer therapy (systemic medication, surgery or radiotherapy for cancer), 
whichever occurs first. CR or PR determinations included in the BOR assessment must be 
confirmed by a second scan no less than 4 weeks after the criteria for response are first met. For 
subjects without documented progression or subsequent anti-cancer therapy, all available response 
designations will contribute to the BOR assessment. For subjects who continue treatment beyond 
progression, the BOR should be determined based on response designations recorded up to the 
time of the initial progression.
4.1.2
Secondary Endpoints
Progression-free survival is defined as the time from first dosing date to the date of the first 
documented tumor progression, as determined by the investigator, or death due to any cause, 
whichever occurs first. Subjects who die without a reported prior progression will be considered 
to have progressed on the date of their death. Subjects who did not progress or die will be censored 
on the date of their last evaluable (i.e., with non-missing tumor data) tumor assessment. Subjects 
who did not have any baseline or on-study tumor assessments and did not die will be censored on 
the date of their first dose. Subjects who started anti-cancer therapy without a prior reported 
progression will be censored on the date of their last evaluable tumor assessment prior to the 
initiation of subsequent anti-cancer therapy.
4.1.3
Exploratory Endpoints
 
 
 
 
 
 
 
 
 
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4.2
Safety Endpoints
Beside the evaluations used to address the primary endpoint of the DLT evaluation period (the 
incidence of DLTs), safety endpoints include deaths, SAEs and AEs, select AEs, immune-
mediated AEs (IMAEs), and other events of special interest, laboratory evaluations, 
electrocardiograms (ECG), and reasons off treatment.
4.2.1
Select Adverse Events
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category that are of relevance for understanding the risks of immune therapies such as nivolumab.
To date, 7 categories of select AEs have been identified see Table 4.2.1-1. 
Table 4.2.1-1:
Select Adverse Events
Category
Subcategory
Endocrine Adverse Events
Adrenal Disorder 
Diabetes
Pituitary Disorder
Thyroid Disorder 
Hypersensitivity/Infusion Reactions
Gastrointestinal Adverse Events
Hepatic Adverse Events
Pulmonary Adverse Events
Renal Adverse Events
Skin Adverse Events
AEs that may differ from or be more severe than AEs caused by non-immunotherapies and AEs 
whose early recognition and management may mitigate severe toxicity are included as select AEs. 
The select AEs and the categories are defined by the Sponsor and the list that is the most current 
at the time of analysis will be used. Changes may be made to this list with each new version of the 
Medical Dictionary for Regulatory Activities (MedDRA), prior to database lock. Categories of 
select AEs may include subcategories (e.g. adrenal disorders, diabetes, pituitary disorders, and 
thyroid disorders are subcategories of the endocrine event category). Other categories could be 
created during the conduct of the study. If so, similar table/listing will be produced for these 
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additional categories. Similarly, some category can be removed or regrouped and corresponding 
table/listing will be updated accordingly.
The analysis of select adverse events will be conducted using the 30-day safety window.
4.2.2
Immune-mediated Adverse Events
In order to further characterize the safety profile of immune therapies such as nivolumab, an 
analysis of immune-mediated AEs (IMAE) will be conducted. IMAEs are specific events (or 
groups of PTs describing specific events) that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal 
dysfunction, 
rash, 
and 
endocrine 
events 
(hypothyroidism/thyroiditis,
hyperthyroidism, hypophysitis, diabetes mellitus, adrenal insufficiency).
In addition, 
hypersensitivity/infusion-related reactions will be analyzed along with the IMAE categories 
because multiple event terms may be used to describe such events and pooling of terms is therefore 
necessary for full characterization. Hypersensitivity/infusion-related reactions do not otherwise 
meet criteria to be considered IMAEs.
IMAE analyses include events, regardless of causality, occurring within 100 days of the last dose. 
Related analyses are limited to subjects who received immunosuppressive medication for
treatment of the event, with the exception of endocrine events which will be included regardless 
of treatment since these events are often managed without immunosuppression. IMAE categories 
will be populated using the list that is the most current at the time of analysis.
4.2.3
Other Events of Special Interest
The other events of special interest (OESI) consist of a list of preferred terms grouped by specific 
category (i.e.: myasthenic syndrome, demyelination, Guillain-Barre syndrome, pancreatitis, 
uveitis and encephalitis). The OESI categories and terms are defined by the Sponsor and the list 
that is the most current at the time of analysis will be used. 
 
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
Within each tumor type, the sample size will start with a minimum of 3 treated subjects using a
Rolling Six design for evaluation of DLT. Then, the sample size will be increased by the number
of subjects needed to continue the DLT evaluation then, by the number of subjects needed for one 
or three randomized cohort(s) to complete the Dose Evaluation Phase. Finally, the sample size will 
be increased by the number of subjects needed for the Dose Expansion Phase.
5.1
SCLC Sample Size
For SCLC, up to approximately 175 treated subjects may be needed. This sample size considers
the following:

Up to 18 subjects for the DLT evaluation

19 subjects per cohort for the Dose Evaluation Phase (57 subjects for three randomized
cohorts)

A second stage of a Simon 2-stage like design in the Dose Expansion Phase that would require 
an additional 25 subjects
OR

A randomized Phase 2 study with comparative arm in the Dose Expansion Phase that would 
require an additional 50 subjects per arm (i.e. 100 for the two arms)
These numbers are obtained using the following methods and assumptions:

A Simon optimal 2-stage design will test the null hypothesis that the true response rate is less 
than or equal to 15% versus the alternative hypothesis that it exceeds 15%. The type I error 
rate will be 5% (one-sided) and the design will have 90% power to reject the null hypothesis 
when the true response rate is 35%. The Simon design in this tumor type will require 19 treated 
subjects for the first stage and at least 4 responders to initiate Stage 2. An additional 25 treated 
subjects will be needed for the second stage and the drug will be considered of potential clinical 
interest if, at the end of the second stage, there are 11 or more responders out of the total of 44 
treated subjects. Subjects who were assigned treatment but never treated will not count towards 
the total of 19 treated subjects for the first stage or the 44 treated subjects in a cohort and will 
be replaced.

If an open label randomized Phase 2 with comparative arm study is initiated (1:1 ratio), the 
primary measurement for efficacy will be IRRC assessed ORR. Considering one-sided alpha 
level of 0.10 a sample size of 50 subjects per arm would provide approximately 80% power to 
detect a difference of 20% in the response rates between the two arms (based on a Fisher’s 
exact test) assuming an ORR of 35% for the combination arm of ulocuplumab plus nivolumab 
and an ORR of 15% for the nivolumab monotherapy arm.
5.2
PAC Sample Size
For PAC, up to approximately 331 treated subjects may be needed. This sample size considers the 
following:
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
Up to 18 subjects for the DLT evaluation

21 subjects per cohort for the Dose Evaluation Phase (63 subjects for three randomized 
cohorts)

A second stage of a Simon 2-stage like design in the Dose Expansion Phase that would require 
an additional 20 subjects
OR

A randomized Phase 2 study with comparative arm in the Dose Expansion Phase that would 
require an additional 125 subjects per arm (i.e. 250 for the two arms)
These numbers are obtained using the following methods and assumptions:

A Simon optimal 2-stage design will test the null hypothesis that the true response rate is less 
than or equal to 5% versus the alternative hypothesis that it exceeds 5%. The type I error rate 
will be 5% (one-sided) and the design will have 90% power to reject the null hypothesis when 
the true response rate is 20%. The Simon design in this tumor type will require 21 treated 
subjects for the first stage and at least 2 responders to initiate Stage 2. An additional 20 treated 
subjects will be needed for the second stage and the drug will be considered of potential clinical 
interest if, at the end of the second stage, there are 5 or more responders out of the total of 41 
treated subjects. Subjects who were assigned treatment but never treated will not count towards 
the total of 21 treated subjects for the first stage or the total of 41 subjects in a cohort and will 
be replaced.

If an open label randomized Phase 2 study with comparative arm is initiated (1:1 ratio), the 
primary measurement for efficacy will be OS. A one-sided alpha level of 0.10log-rank test will 
be used to compare the OS of subjects randomized to the combination arm of ulocuplumab 
plus nivolumab to that of subjects randomized to the investigator’s choice chemotherapy arm. 
In order for the test to have at least 80% power to reject the null hypothesis of no difference in 
OS among treatment groups when the hazard ratio of the experimental arm to the control arm 
is 0.75, the study will require 218 events (deaths) to complete. The analysis of OS will take 
place when the following two conditions have been met: 218 events have been observed and 
all subjects have been on study for at least 6 months. The requirement that subjects be on study 
for at least 6 months is meant to ensure adequate follow-up. A total of 250 subjects are to be 
randomized. Assuming an accrual rate of 20 subjects per month, the accrual will last 
approximately 13 months. Assuming exponentially distributed OS and median OS times in the 
control and experimental arms of 4.5 months and 6.0 months, respectively, it is expected that 
the requisite number of events (deaths) will occur approximately 10 months after all subjects 
have been randomized.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
6.1.1
Baseline Period

Baseline AEs will be defined as AEs with an onset date prior to but not including the first day 
of treatment.
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
For infusion related events, baseline will be defined as AEs with an onset date and time prior 
to but not including the first day and time of treatment.

For all other evaluations (ECOG, laboratory data, ECGs, vital signs, etc.) baseline will be 
defined as evaluations with an onset date on or prior to the first day of treatment.
If there are multiple valid assessments, the assessment that is closest to day (and time if collected) 
of the first dose of study treatment will be used as the baseline in the analyses. If multiple 
assessments are collected on the same date (and time, if collected), the assessment with the latest 
database entry date (and time, if collected) will be considered as baseline. 
6.1.2
Post Baseline Period

On-treatment AEs will be defined as AEs with an onset date on or after the first day of 
treatment. 

For infusion related events, on-treatment will be defined as AEs with an onset date and time 
on or after the first day and time of treatment. 

For all other evaluations (ECOG, laboratory data, ECGs, vital signs, etc.) on-treatment will be 
defined as evaluations taken after the first day of treatment. 

If a subject is still on study treatment, any AE/evaluation post baseline is considered as on-
treatment. For subjects off study treatment, AEs/evaluations will be counted as on-treatment if 
the event occurred within 30 days or 100 days (depending on the analysis) after the last dose 
of ulocuplumab or nivolumab, whichever is later.

Late-emergent drug-related AEs will be defined as drug-related AEs with an onset date greater 
than 100 days after the last dose of study treatment in subjects who are off study treatment.
6.2
Treatment Regimens
As indicated at the end of Section 3, the current version of this SAP does not consider any
randomization nor the DL3B regimen while describing the planned analyses.
The cohorts are defined by the ulocuplumab regimen only. The nivolumab regimen will always be 
3mg/kg every 2 weeks (no nivolumab dose modification is allowed).
The cohort “as allocated” will be retrieved from the IVRS.
The cohort “as treated” will be the same as the cohort “as allocated” by IVRS. However, if a 
subject received an incorrect drug for the entire period of treatment, the subject’s cohort will be 
defined by the incorrect drug the subject actually received. 
For the Dose Evaluation Phase and the 2-stage design, all analysis will be presented “as-treated”.
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6.3
Populations for Analyses
All populations will be defined separately by tumor type. 

Dose Evaluation Phase:

All DLT-evaluable Subjects: All subjects who completed the DLT evaluation period
(i.e., received at least 5 out of 6 doses of ulocuplumab and at least 2 out of 3 doses of 
nivolumab in a 6 week dosing period or experienced a DLT).

All Dose Evaluation Enrolled Subjects: All subjects who signed an informed consent form 
and were registered into the IVRS during the Dose Evaluation Phase (this population 
includes subjects from the DLT evaluation period).

All Dose Evaluation Treated Subjects: All subjects who received at least one dose of any 
study medication during the Dose Evaluation Phase (this population includes subjects from 
the DLT evaluation period).

All Dose Evaluation Excluding DLT Treated Subjects: All subjects who were allocated to 
a unique cohort during the Dose Evaluation Phase and were treated (this population 
excludes subjects from the DLT evaluation period).

Dose Expansion Phase:

All Dose Expansion Enrolled Subjects: All subjects who signed an informed consent form 
and were registered into the IVRS during the Dose Expansion Phase.

All Dose Expansion Treated Subjects: All subjects who were allocated to a unique cohort 
during the Dose Expansion Phase and were treated (this population correspond to the 
second stage of a 2-stage design and it will not be used as such for reporting, see “Both 
Phases combined” below).

Both Phases combined:

All 2-stage Enrolled Subjects: This population consists of the pooling of the “All Dose 
Evaluation Enrolled Subjects” with the “All Dose Expansion Enrolled Subjects”.

All 2-stage Treated Subjects: This population consists of the pooling of the “All Dose 
Evaluation Excluding DLT Treated Subjects” with the “All Dose Expansion Treated 
Subjects”.

All 2-stage Including DLT Treated Subjects: This population consists of the pooling of the 
“All Dose Evaluation Treated Subjects” with the “All Dose Expansion Treated Subjects”.

Other populations (note that the PK and the immunogenicity are study drug specific as these 
populations are defined for ulocuplumab or for nivolumab, separately):

All Dose Evaluation PK Evaluable Subjects: All subjects who received at least one dose 
of study medication and have available serum concentration data during the Dose 
Evaluation Phase.
All Dose Expansion PK Evaluable Subjects: All subjects who received at least one dose of 
study medication and have available serum concentration data during the Dose Expansion 
Phase.

All Dose Evaluation Biomarker Evaluable Subjects: All subjects who received at least one 
dose of study medication and have baseline and at least one post-baseline biomarker 
assessment during the Dose Evaluation Phase.
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
All Dose Expansion Biomarker Evaluable Subjects: All subjects who received at least one 
dose of study medication and have baseline and at least one post-baseline biomarker 
assessment during the Dose Expansion Phase.

All Dose Evaluation Immunogenicity Evaluable Subjects: All subjects who received at 
least one dose of study medication and have baseline and at least one post-baseline 
immunogenicity assessment during the Dose Evaluation Phase.

All Dose Expansion Immunogenicity Evaluable Subjects: All subjects who received at 
least one dose of study medication and have baseline and at least one post-baseline 
immunogenicity assessment during the Dose Expansion Phase.
7
STATISTICAL ANALYSES
7.1
General Methods
All analyses will be presented separately by tumor type. 
Descriptive summaries of continuous and other numeric variables will at least consist of the 
following summary statistics: median, minimum and maximum values. Categorical variables will 
be summarized by the frequency and proportion of subjects falling into each category. Unless 
otherwise indicated, percentages in tables will be column percentages, using the total number of 
observations in the population, grouped by cohort, as the denominator. Percentages will be 
rounded to one decimal place, and thus may not always add up to exactly 100%.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and the 
most recent version of the dictionary at the time of the database lock will be used. AEs and 
laboratory tests will be graded using the National Cancer Institute - Common Toxicity Criteria for 
Adverse Event (NCI-CTCAE) Version 4.03. Clinical laboratory values will be first reported in 
using International System of Units (SI). Analyses will be repeated using US conventional units.
Medications will be coded using the most recent version of the BMS WHO Drug Dictionary.
Time-to event variables (e.g., PFS, OS, DOR, etc.) will be analyzed using the Kaplan-Meier 
product limit method (KM). When specified, the median will be reported along with 95% 
confidence interval (CI) using Brookmeyer and Crowley methodology4 (using the log-log 
transformation for construction of CI). Rates at fixed timepoints (e.g., PFS at 6 months) will be 
derived from the Kaplan-Meier estimate along with their corresponding log-log transformed CIs. 
Exact confidence intervals for binomial proportions will be derived using the Clopper-Pearson 
method5.
7.2
Study Conduct
7.2.1
Accrual
For the Dose Evaluation Phase the analyses on accrual will be using the All Dose Evaluation 
Enrolled Subjects population. For the Dose Expansion Phase the analyses will be using the All 2-
stage Enrolled Subjects population.
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For each phase, the number of subjects enrolled and treated will be provided for the following:

Enrollment summary by country and site.

Enrollment summary by month.
A subject listing of accrual (informed consent date, first dose date, country, investigational site,
and as treated dose level) will also be produced.
For the Dose Evaluation Phase, a distribution of the number of subjects by cohort will be provided 
for the DLT Period (number enrolled, treated and DLT-evaluable) and for the Dose Evaluation 
Phase itself (number enrolled and treated).
7.2.2
Relevant Protocol Deviations
For the Dose Evaluation Phase, the relevant protocol deviations will be summarized by cohort 
using the All Dose Evaluation Excluding DLT Treated Subjects population. 
For the Dose Expansion Phase, the relevant protocol deviations will be summarized by cohort 
using the All 2-stage Treated Subjects population.
The following programmable deviations from inclusion and exclusion criteria will be considered 
as relevant protocol deviations. Non-programmable relevant eligibility and on-treatment protocol 
deviations, as well as significant (both programmable and non-programmable) eligibility and on-
treatment protocol deviations will be reported through ClinSIGHT listings.
At Entrance:

Subjects without histologically or cytologically-documented SCLC or without histologically-
documented PAC.

For PAC, subjects without current disease stage of IV.

Subjects without measurable disease at baseline.

Subject with baseline ECOG performance status > 1.

For PAC, subjects without at least one prior line of chemotherapy for metastatic disease.

For SCLC, subjects without at least one prior platinum therapy. 

Subject with prior therapy including any T cell co-stimulation or checkpoint pathways such as 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, including 
ipilimumab and nivolumab; or other medicines specifically targeting T cells.
On-study:

Subjects receiving concurrent anti-cancer therapy (chemotherapy, hormonal therapy, 
immunotherapy, non-palliative radiation therapy, standard or investigational agents for 
treatment of SCLC or PAC).
For each summary, a subject listing will also be produced.
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7.3
Study Population
7.3.1
Subject Disposition
For the Dose Evaluation Phase, the enrolment will be summarized using the All Dose Evaluation 
Enrolled Subjects population. 
For the Dose Expansion Phase, the enrolment will be summarized using the All 2-stage Enrolled 
Subjects population.
For each phase, the following enrolment summary will be provided (supporting listing will be 
supplied):

Number of subjects enrolled, entering or not the treatment period,

Reason for not entering the treatment period.
For the Dose Evaluation Phase, the discontinuation will be summarized by cohort using the All 
Dose Evaluation Treated Subjects population.
For the Dose Expansion Phase, the discontinuation will be summarized using the All 2-stage 
Treated Subjects population.
The following discontinuation summary will be provided (supporting listing will be supplied):

Number of subjects who discontinued treatment,

Reason for treatment discontinuation,

Number of subjects who discontinued the study,

Reason for study discontinuation.
For the tabulation of discontinuations during the Dose Evaluation Phase, if more than one cohort 
is to be reported pooled data across cohorts will also be presented.
7.3.2
Demographics and Other Baseline Characteristics
For the Dose Evaluation Phase, demographics and other baseline characteristics will be 
summarized by cohort using the All Dose Evaluation Treated Subjects population.
For the Dose Expansion Phase, demographics and other baseline characteristics will be 
summarized by cohort using the All 2-stage Treated Subjects population.
For the Dose Evaluation Phase, if more than one cohort is to be reported pooled data across cohorts 
will also be presented.
7.3.2.1
Demographics and Baseline Disease Characteristics
The following characteristics will be summarized. All baseline presentations will identify subjects 
with missing measurements. Demographic data will be listed.

Age (in years, descriptive statistics),

Age category (< 65, 65 and < 65, 65 - < 75, 75 years),
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
Gender, Race, Ethnicity,

Weight (kg),

ECOG performance status (0, 1),

Time from initial disease diagnosis to start of treatment (in years, descriptive statistics and by 
categories of: < 6 months, 6 months - < 1 year, 1 - < 2 years, 2 - < 3 years, years),

Disease stage at initial diagnosis (stage I, stage II, stage III, stage IIIA, stage IIIB, stage IIIC, 
stage IV),

Cell type at initial diagnosis (adenocarcinoma, small cell carcinoma, other),

For SCLC, disease classification at initial diagnosis (limited disease, extensive disease),

Disease stage at current diagnosis (stage III, stage IV),

Smoking status (current or former, never smoker, unknown), 

Alcohol Use (prior use, current use and, for each of these “none”, “average 2 drinks/day”, 
“average 3 drinks/day”),

For PAC, family history of PAC (parent, grandparent, sibling),

All lesions: presence of lesion, site of lesion, number of sites with at least one lesion (1, 2, 3, 
4, 5),

Target lesions: presence of target lesion, site of target lesion, number of sites with at least one 
target lesion (1, 2, 3, 4, 5), sum of reference diameters of target lesions (in mm, descriptive 
statistics and by categories of: < 20, 20 - 50, > 50 - 100, > 100).
7.3.2.2
Prior Cancer Therapy
Agents and medication will be reported using the generic name. The following prior cancer therapy 
will be summarized:

Line of therapy (first, second, third, other - note: the intent is for a line of therapy for metastatic 
disease.  Adjuvant therapy for PAC subjects should not be considered to define line of therapy),

Best response to most recent prior systemic therapy regimen (CR or PR, SD, PD, unknown or 
not reported),

Primary reason regimen was discontinued (disease progression, maximum clinical benefit, 
toxicity, completed treatment, other),

Time from completion of most recent prior systemic therapy regimen to start of treatment 
(< 1, 1 - <3, 3 - 6, > 6 months),

For SCLC, prior medication response on platinum based therapy (resistant/refractory, 
sensitive, unknown or not reported),

Prior surgery related to cancer (yes or no),

Prior radiotherapy (yes or no),

Prior systemic cancer therapy classified by therapeutic class and generic name.
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7.3.2.3
Other Baseline Medical Evaluations
General medical history and pretreatment events will be tabulated. Prior/current non-study 
medication classified by anatomic class, therapeutic class and generic name will be tabulated and 
listed. 
7.3.3
Baseline Laboratory Examinations
Baseline laboratory data needed for the CSR will be extracted from the on-treatment shift tables 
in toxicity grading from baseline (see Section 7.6.12.1).
7.4
Extent of Exposure
For the Dose Evaluation Phase, extent of exposure will be summarized by cohort using the All 
Dose Evaluation Treated Subjects population. 
For the Dose Expansion Phase, extent of exposure will be summarized by cohort using the All 2-
stage Treated Subjects population.
Extent of exposure will be presented separately for ulocuplumab and for nivolumab. A listing of 
study medication dosing (infusion details and dose modification) and a listing of batch number 
will also be provided.
7.4.1
Study Therapy
Below table summarizes the key parameters that will be used to calculate dosing data.
Table 7.4.1-1:
Administration of Study Therapy: Definition of Parameters
Ulocuplumab
Nivolumab
Assigned Starting 
Dose
DL-1: 200mg weekly
DL1: 400mg weekly
DL2: 800mg weekly
DL3A: 1600mg weekly
3mg/kg every 2 weeks
Dose
Dose (mg) is defined as total dose 
administered at each dosing date
Dose (mg/kg) is defined as total dose 
administered at each dosing date (mg) 
divided by the most recent weight (kg). 
Dose administered and weight are collected 
from the CRF
Cumulative Dose
Cumulative dose (mg) is the sum of the 
doses administered to a subject during the 
treatment period
Cumulative dose (mg/kg) is the sum of the 
doses administered to a subject during the 
treatment period
Relative Dose 
Intensity (%)
Cumulative dose divided by [(Last dose date 
- Start dose date + 7) assigned starting 
dose in mg / 7] 100
Cumulative dose divided by [(Last dose 
date - Start dose date + 14) 3 / 14] 100
Duration of 
Treatment  (days)
Last dose date - Start dose date + 1
Last dose date - Start dose date + 1
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The following parameters will be summarized:

Number of doses received (descriptive statistics),

Cumulative dose (descriptive statistics),

Relative dose intensity (110%, 90 - < 110%, 70 - < 90%, 50 - < 70%, < 50%),

Duration of study therapy (months) using:

A Kaplan-Meier curve whereby the last dose date will be the event date for those subjects 
who are off treatment. Subjects who are still on-treatment will be censored on their last 
dose date. 

Descriptive statistics (minimum, maximum, KM median with 95% CI and by categories
of: > 3 months, > 6 months, > 9 months, > 12 months as well as number off treatment).
7.4.2
Modifications of Study Therapy
7.4.2.1
Infusion Interruption and Infusion with IV Rate Reduction
Each ulocuplumab or nivolumab infusion can be interrupted and/or the IV infusion rate can be 
reduced. The following parameters will be summarized using CRF data:

Number of subjects with at least one infusion interrupted,

Number of infusion interrupted per subject (0, 1, 2, 3, 4),

Total number of infusions interrupted / total number of infusions received,

Reason for infusion interrupted (any).
Similar summaries will be provided for infusion with IV rate reduction.
7.4.2.2
Dose Delay
Derived data will be used for reporting dose delay. Starting from the second dose, a dose will be 
considered as actually delayed if the delay is exceeding 3 days (i.e., greater than or equal to 4 days 
from scheduled dosing date) for nivolumab or 2 days (i.e., greater than or equal to 3 days from 
scheduled dosing date) for ulocuplumab. It is defined as “duration since previous administration 
in days -7” for ulocuplumab or as “duration since previous administration in days -14” for 
nivolumab. The following parameters will be summarized:

Number of subjects with at least one dose delayed,

Number of dose delayed per subject (0, 1, 2, 3, 4),

Total number of doses delayed / total number of doses received,

Reason for dose delayed,

Length of delay (4 - 7 days, 8 - 14 days, 15 - 42 days, > 42 days; for ulocuplumab, the first 
class is 3 - 7 days).
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The reason for dose delayed will be any reasons supplied by the investigator for the period during 
which a dose delay was determined. If the reason corresponding to the dose delay (as defined by 
above algorithm) is missing then ‘Not reported’ will be provided.  
7.4.2.3
Ulocuplumab Partial Dose Discontinuation
Ulocuplumab can be discontinued while the subject is continuing on nivolumab alone. The 
following parameters will be summarized using CRF data:

Number of subjects with ulocuplumab discontinuation,

Reason for ulocuplumab discontinuation.
7.4.3
Concomitant Medications
Concomitant medications are medications other than study medications which are taken at any 
time on-treatment (i.e. on or after the first day of study therapy and within 100 days following the 
last dose of study therapy). Concomitant medication classified by anatomic class, therapeutic class
and generic name will be tabulated and listed. 
7.4.4
Immune Modulating Medications
Concomitant IMM classified by anatomic class, therapeutic class and generic name will be 
tabulated as a whole and separately for the following use:

AE management,

Immunomodulating treatment for AE,

Infusion-related

Premedication,

Other use.
Concomitant IMM will be listed.
7.5
Efficacy
Except where indicated, for the Dose Evaluation Phase, efficacy parameters will be summarized 
by cohort using the All Dose Evaluation Excluding DLT Treated Subjects population.
For the Dose Expansion Phase, efficacy parameters will be summarized by cohort using the All 2-
stage Treated Subjects population. 
Supportive listing will be provided for response, time to response, duration of response, PFS and 
OS.
7.5.1
Objective Response Rate
BOR will be summarized by response category and ORR will be computed along with an exact 
90% CI (primary analysis for ORR as primary endpoint, see Section 4).
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The primary population for estimating the ORR will be the All Dose Evaluation Excluding DLT 
Treated Subjects population. Additionally, the parameters will be summarized using the All Dose 
Evaluation Treated Subjects population (supportive analyses). All analyses will be presented as-
treated.
For the Dose Evaluation Phase, the decision to further study ulocuplumab combined with 
nivolumab in each tumor type will primarily be based on the pre-defined Simon 2-stage design 
thresholds (at least 4 responders for SCLC and at least 2 responders for PAC), using data from the 
IA. In addition, the selection of the recommended dose will be based on all available safety and 
efficacy data from both tumor types. The decision to proceed from the Dose Evaluation Phase to 
the Dose Expansion Phase will be conducted for each tumor type independently. Consideration 
may be given for evaluating final data before decision is reached to stop further study of the 
combination to ensure that the full characterization of the response pattern is evaluated.
The decision to proceed with an open label randomized two-arm Phase 2 design rather than 
completing the second stage of a Simon 2-stage design for the Expansion Phase will be taken if, 
among the treated subjects in the recommended dose selected during the Dose Evaluation Phase, 
a “high” frequency of responders is observed. For SCLC, this “high” number will be at least 9 
responders and, for PAC, at least 6 responders. This number of responders has been defined 
considering clinical input but, ensuring that the related proportion of responders also presents with 
a 90% exact CI lower limit above 25% for SCLC or above 12% for PAC. These percentages 
correspond to the minimum proportion of responders that would be needed at the end of a Simon 
2-stage design in order to further evaluate the drug (for SCLC, 11 responders among the 44 
subjects is 25% and, for PAC, 5 responders among the 41 subjects is 12%).
For the Dose Expansion Phase, the primary population will be the All 2-stage Treated Subjects 
population (as-treated analyses).
7.5.2
Overall Survival
OS will be estimated using KM methodology. Median values along with two-sided 95% CIs will 
be calculated. KM based OS rates at 3, 6, 9, 12, 18, and 24 months will be estimated and associated 
two-sided 95% CIs will be provided.
7.5.3
Progression-free Survival
PFS will be estimated using KM methodology. Median values along with two-sided 95% CIs will 
be calculated. KM based PFS rates at 3, 6, 9, 12, and 18 months will be estimated and associated 
two-sided 95% CIs will be provided.
The following information will also be summarized:

Number and type of events (progression: RECIST 1.1 or clinical, death),

Number of subjects censored on first dosing date (number with no baseline tumor assessment 
and no death, number with no on-study tumor assessment and no death) 
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
Number of subjects censored on date of last tumor assessment on-study (number received 
subsequent anti-cancer therapy, still on-treatment, in follow-up, off study [lost to follow-up, 
withdraw consent, other]).
7.5.4
Duration of Objective Response
Duration of response will be estimated using KM methodology for subjects who achieve PR or 
CR. Median values along with two-sided 95% CIs will be calculated.
For the responders only, the time course of the following events of interest will graphically be 
displayed (swimmers plot): tumor response, progression, last dose received and death.
7.5.5
Disease Control Rate
Analyses on disease control rate will be similar to the ones conducted on the ORR.
7.5.6
Magnitude of Reduction in Tumor Volume
The magnitude of reduction in tumor volume will be summarized descriptively using the following 
subject-level graphics:

A bar plot (waterfall plot) showing the best reduction in target lesion (excluding assessment 
after PD and assessments after start of subsequent anti-cancer therapy).

A plot (spider plot) of individual time course of tumor burden change.
7.5.7
Subsequent Therapy
The number of subjects with any of the following subsequent cancer therapy will be summarized: 

Radiotherapy,

Surgery,

Systemic cancer therapy. 
The number of subjects with any allowed on-treatment radiotherapy or surgery will also be 
reported. Systemic cancer therapy will further be reported by therapeutic class and generic name. 
A supportive listing will be provided.
7.6
Safety
Dose limiting toxicities will specifically be reported for the DLT Evaluation period. Other safety 
parameters will be reported according to the different phases of the trial. These parameters will 
consist of the incidence of deaths, adverse events, serious adverse events, adverse events leading 
to discontinuation, adverse events leading to dose modification, select adverse events, IMAEs, 
other adverse events of special interest, ECGs  and specific laboratory abnormalities (worst grade) 
for each cohort.
For the Dose Evaluation Phase, safety parameters (excluding DLTs) will be summarized by cohort 
using the All Dose Evaluation Treated Subjects population.
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For the Dose Expansion Phase, safety parameters will be summarized by cohort using the All 2-
stage Including DLT Treated Subjects population.
For the Dose Evaluation Phase, if more than one cohort is to be reported pooled data across cohorts 
will also be presented.
7.6.1
DLT Evaluation Period / Maximum Tolerated Dose
During the DLT Evaluation period, data and Study Team considerations that led to the 
determination (or not) that the dose levels of 200mg and/or 400mg and/or 800 mg and/or 1600 mg 
weekly are tolerable and can be used during the Dose Evaluation Phase will be described in-text.
This will be based on the incidence of DLTs during the first 6 weeks of treatment with both agents 
for the DLT-evaluable Subjects but other available safety and efficacy data may also be 
considered.
7.6.2
Deaths
The number of deaths and primary reason for death will be summarized for the following:

All deaths,

Deaths within 30 days of last dose,

Deaths within 100 days of last dose.
Listing of deaths will be provided. In addition, to supply some safety information in subjects that 
were not treated, listing on deaths will be provided considering only the subjects who never started 
treatment.
7.6.3
Serious Adverse Events
For SAEs the following will be summarized:

Overall summary of SAEs by worst CTC grade (grade 1, 2, 3, 4, 5, unknown) presented by 
SOC/PT,

Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT,
The analysis will be conducted using the 100-day safety window.
Listing of SAEs will be provided. In addition, to supply some safety information in subjects that 
were not treated, listing on SAEs will be provided considering only the subjects who never started 
treatment.
7.6.4
Adverse Events Leading to Discontinuation of Study Therapy
For AEs leading to discontinuation the following will be summarized:

Overall summary of AEs leading to discontinuation by worst CTC grade (any grade, grade 3-
4, grade 5) presented by SOC/PT,
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
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT,
The analysis will be conducted using the 100-day safety window. 
Listing of AEs leading to discontinuation will be provided.
7.6.5
Adverse Events Leading to Dose Modification
Dose modification consists of dose delay of either drug and the following will be summarized:

Overall summary of AEs leading to study therapy dose delay by worst CTC grade (grade 1, 2, 
3, 4, 5, unknown) presented by SOC/PT.
The analysis will be conducted using the 100-day safety window.
Listing of AEs leading to study therapy dose delay will be provided.
7.6.6
All Adverse Events
For AEs the following will be summarized:

Overall summary of any AEs by worst CTC grade (grade 1, 2, 3, 4, 5, unknown) presented by 
SOC/PT,

Overall summary of any AEs by worst CTC grade (any grade, grade 3-4, grade 5) presented 
by SOC/PT,

Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT,

Overall summary of any non-serious AEs presented by SOC/PT. For the Dose Evaluation 
Phase, only the population of All Dose Evaluation Treated Subjects will be used.

Overall summary of late-emergent drug-related AEs by worst CTC grade (grade 1, 2, 3, 4, 5, 
unknown) presented by SOC/PT,

Overall summary of any AEs that required IMM by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT.
The analyses will be conducted using the 100 days safety window.
Listing of AEs and listing of AEs requiring concomitant IMM will be provided.
7.6.7
Infusion-related Events
For AEs reported as “Infusion-related Event = Yes” on the AE/SAE CRF page, a by-subject listing 
will be provided:
This analysis will be conducted using the 30-day safety window only.
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7.6.8
Select Adverse Events
7.6.8.1
Incidence of Select Adverse Events
For select AEs (see categories and subcategories definition in Table 4.2.1-1) each of the following 
analysis will be repeated for each category of select AE (excluding the endocrine event category). 
Analyses of the endocrine event category will be presented separately by subcategories.

Overall summary of any select AEs by worst CTC grade presented by Category or Subcategory 
(any grade, grade 3-4, grade 5),

Overall summary of drug-related select AEs by worst CTC grade presented by Category or 
Subcategory (any grade, grade 3-4, grade 5),

Overall summary of any serious select AEs by worst CTC grade presented by Category or 
Subcategory (any grade, grade 3-4, grade 5),

Overall summary of drug-related serious select AEs by worst CTC grade presented by 
Category or Subcategory (any grade, grade 3-4, grade 5),

Overall summary of any select AEs leading to discontinuation by worst CTC grade presented 
by Category or Subcategory (any grade, grade 3-4, grade 5),

Overall summary of drug-related select AEs leading to discontinuation by worst CTC grade 
presented by Category or Subcategory (any grade, grade 3-4, grade 5).
These analyses will be conducted using the 30-day safety window only.
The list of PTs used for analysis will be provided. Listing of select AEs (any, serious and leading 
to discontinuation) will be provided.
7.6.8.2
IMM Received for Management of Select Adverse Events
Analysis of concomitant IMM received for management of any select AE among subjects who 
experienced at least one select AE will be provided separately for each category of select AEs 
(including the endocrine event category, as a whole) for the following specific events:

Any grade select AEs, 

Any grade drug-related select AEs, 
For these analyses, the following will be provided:

Concomitant IMM received classified by anatomic class, therapeutic class and generic name,

Number of subjects who received IMM,

Total duration of IMM (in weeks, descriptive statistics),

Number of subjects who received corticosteroid at a dose 40mg prednisone or equivalent,

Duration of corticosteroid at a dose 40mg or equivalent (in weeks, descriptive statistics),

Initial dose (mg/kg) of corticosteroid at a dose 40mg prednisone or equivalent (descriptive 
statistics),

Number of subjects who underwent corticosteroid taper,

Duration of corticosteroid taper (in weeks, descriptive statistics).
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The analyses will be conducted using the 30-day safety window only.
7.6.9
Immune-mediated Adverse Events
For IMAEs (see categories and PT definition in Section 4.2.2) a listing will be provided. Immune-
modulating medications used for IMAE management will be tabulated. The list of PTs used for 
analysis will be provided.
These analyses will be conducted using the 100-day safety window only.
7.6.10
Other Events of Special Interest
For other events of special interest (see categories definition in Section 4.2.3) a listing will be 
provided. Immune-modulating medications used for other events of special interest will be 
tabulated. The list of PTs used for analysis will be provided. 
7.6.11
Multiple Adverse Events
For multiple adverse events, the following will be summarized:

Total number and exposure adjusted AEs summary,

Frequency of unique adverse events summary (for select AEs only and presented for each 
category, including the endocrine event category, as a whole),
The analyses will be conducted using the 30-day safety window.
Listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (i.e. same PT) have been collapsed will 
be provided. No formal comparisons will be made between cohorts.
7.6.12
Clinical Laboratory Evaluations
7.6.12.1
Hematology, Serum Chemistry, and Electrolytes
Thrombocytopenia will mainly be examined using laboratory data. Analyses on hematology, 
serum chemistry, and electrolytes will consist of the followings:

Worst CTC grade on-treatment per subject,

Shift table of worst on-treatment CTC grade compared to baseline CTC grade per subject.
For each analysis, the following laboratory tests will be summarized:

Hematology: hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils 
count (ANC) and absolute lymphocyte count (LYMPA). 

Serum chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), total bilirubin and creatinine. 
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
Electrolytes: sodium (high and low), potassium (high and low), calcium (high and low), 
magnesium (high and low).

Other: amylase (AMYL) and lipase (LIPA and LIPAC, lipase by colorimetric assay).
The analyses will be conducted using the 100-day safety window.
Listing of these laboratory parameters will be provided.
7.6.12.2
Abnormal Hepatic Function Tests
The number of subjects with the following abnormalities vs. lower limit of normal (LLN) or vs. 
upper limit of normal (ULN) will be summarized:

ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN.

Total bilirubin > 2 x ULN.

Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN.

Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN.
The analyses will be conducted using the 100-day safety window.
Listing of these specific abnormalities will be provided.
7.6.12.3
Abnormal Thyroid Function Tests
The number of subjects with the following laboratory abnormalities will be summarized:

Thyroid specific test  (TSH) > ULN:

Any,

With TSH <= ULN at baseline,

With at least one FT3/FT4 test value < LLN,

With all other FT3/FT4 test values >= LLN,

With FT3/FT4 test missing.

Thyroid specific test  (TSH) < LLN:

Any,

With TSH >= LLN at baseline,

With at least one FT3/FT4 test value > ULN,

With all other FT3/FT4 test values ULN,

With FT3/FT4 test missing.
The analyses will be conducted using the 100-day safety window.
Listing of these specific abnormalities will be provided.
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7.6.13
Electrocardiograms
Frequency distribution of maximal QTc(F) intervals and QTc(F) changes from baseline (> 30msec, 
> 60msec, etc.) will be tabulated. This analysis will be conducted using the 30-day safety window.
A listing of Electrocardiogram parameters will be provided.
7.6.14
Vital Signs and Physical Findings
Vital signs and pulse oximetry (i.e. percentage of oxygen saturation) will be provided in separate 
listing.
7.6.15
Clinical Safety Program (CSP)
A listing with the following data from the infusion-related events CSP CRF pages will be provided.

Prophylactic medications, 

Infusion-related event onset date and symptoms, 

Diagnostic procedure and date, 

Relevant risk factors and suspect medications, 

Therapeutic medications and therapeutic procedures.
 
 
 
 
 
 
 
 
 
 
 
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8
CONVENTIONS
Refer to Section 3.3 of the Data Presentation Plan (DPP) for the details of the conventions to be 
used.
9
CONTENT OF REPORTS
Refer to Section 1.2 of the DPP for the list of outputs that will be produced.
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10
REFERENCES
1
Skolnik JM, Barrett JS, Jayaraman B, Patel D and PC Adams. 
Shortening the Timeline of Pediatric Phase 1 Trials: The Rolling Six 
Design. Journal of Clinical Oncology (2007); 26 (2): 190-195
2
Shankar G, Arkin S, Cocea L, et al. Assessment and Reporting of the 
Clinical Immunogenicity of the Therapeutic Proteins and Peptides -
Harmonized Terminology and Tactical Recommendations. The AAPS 
Journal 2014;DOI:10.1208/s12248-014-9599-2
3
Guidance for Industry, Immunogenicity Assessment Therapeutic 
Protein Products, 2013
4
Brookmeyer R. and Crowley J. A confidence interval for the median 
survival time. Biometrics 38:29-41, 1982
5
Clopper, CJ and Pearson, ES. The use of confidence or fiducial limits 
illustrated in the case of the binomial. Biometrika 26: 404-413, 1934
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