Phase 1/2 Study to Evaluate the Safety and Preliminary Efficacy of Nivolumab Combined With Daratumumab in Participants With Advanced or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA2099GW
BMS-936558
nivolumab
Revised Protocol No.: 03
Date: 27-Jul-2018
2
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, e.g., 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
CA2099GW
BMS-936558
nivolumab 
Revised Protocol No.: 03
Date: 27-Jul-2018
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Document
Date of Issue
Summary of Change
definition of HER2 negativity in triple negative breast cancer as 
requested by the FDA. 
•
Revision of creatinine clearance threshold for eligibility, as recommended 
by the FDA.
Original 
Protocol
16-Feb-2017
Not Applicable
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Clinical Protocol
CA2099GW
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised Protocol No.: 03
Date: 27-Jul-2018
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Clinical Protocol
CA2099GW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
 
 
 
 
•
Section 5.1 Overall 
Design
 
This protocol has been 
revised to allow single 
agent treatment of 
nivolumab for on-
study participants with 
non-small cell lung 
cancer (NSCLC). In 
addition, only TNBC
and PAC participants 
who are deriving 
clinical benefit will 
continue to be treated 
with the nivolumab 
plus daratumumab 
combination therapy.
•
Synopsis: Study 
Population, Number of 
Participants
•
Section 5.2 Number of 
Participants.
•
Section 10.1 Sample 
Determination
Enrollment in all 
tumor cohorts is 
closed, as of 26-May-
2018. Total final study 
enrollment is now 
included in the 
protocol. 
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Date: 27-Jul-2018
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Clinical Protocol
CA2099GW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
•
Synopsis Objectives and 
Endpoints 
•
Synopsis, Treatment 
Arms and Duration
•
Section 2, Schedule of 
Activities  Table 2.-3, 
Follow-up Procedural 
Outline (CA2099GW)
•
Section 4 Objectives and 
Endpoints; Table 4.-1 
Objectives and 
Endpoints 
•
Section 9.4.5 Safety 
Assessments
 
•
Synopsis, Overall 
Design
•
Section 5.1 Overall 
Design
Central collection of 
scans has been 
discontinued. Possible 
blinded independent 
review has been 
deleted from the study 
design.
Pharmacokinetic, 
immunogenicity, 
 
 
will no longer be 
collected in this study. 
Tumor biopsy at 
Week 7 deleted. 
Section 5.1 only.
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CA2099GW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
•
Synopsis Study 
Schematic
•
Section 5.1 Study 
Schematic
Updated to reflect the 
closure of enrollment
in all tumor types, 
nivolumab 
monotherapy for 
NSCLC participants, 
the continuation of 
treatment with 
nivolumab and 
daratumumab for on-
study TNBC and PAC 
participants who are 
deriving clinical 
benefit, and the 
removal of survival 
follow-up. 
•
Section 2, Schedule of 
Activities  Table 2.-2, 
On Study Procedural 
Outline (CA2099GW)
•
Section 2, Schedule of 
Activities  Table 2.-3, 
Follow-up Procedural 
Outline (CA2099GW)
Tumor biopsy at Week 
7 deleted. (On Study 
Procedural 
Outline
only) 
Pharmacokinetic, 
immunogenic,
 
 
collection deleted. 
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Date: 27-Jul-2018
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CA2099GW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
•
Section 2, Schedule of 
Activities  Table 2.-2, 
On Study Procedural 
Outline (CA2099GW), 
Radiographic Tumor 
Assessment
•
Section 5.1 Overall 
Design
•
Section 9.1.1,Imaging 
Assessment for the 
Study Table 9.1.1-2:
Schedule of Spiral 
CT/MRI Tumor 
Assessments for
advanced and Metastatic 
Cohort
Specific week(s) for 
imaging 
assessment
removed.
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CA2099GW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
•
Section 2, Schedule of 
Activities  Table 2.-2, 
On Study Procedural 
Outline (CA2099GW)
•
Section 7.1 Treatments 
Administered; Table 
7.1-1: Study Drug 
Dosing Schedule 
•
Section 7.2 Method of 
Treatment Assignment
Text added to each 
section 
listed 
to
specify change in drug 
treatment for all on-
study participants. 
•
Section 6.1 Inclusion 
Criteria 3) Age and 
Reproductive Status 
Azoospermic 
males
are not exempt from 
contraceptive 
requirements 
presented in Appendix 
4. 
•
Section 7.1.4 Criteria to 
Resume Treatment
Now 
specified 
that
adrenal insufficiency
of 
Grade
≥ 3 regardless 
of
control with hormone 
replacement 
requires
discontinuation 
of
treatment.  
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CA2099GW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of 
Change
•
Section 7.5 
Preparation/Handling/
Storage/Accountability, 
Nivolumab Preparation 
and Administration 
Specifics removed and 
reference to pharmacy 
manual included.
Section 7.7 Prohibited 
Medication
Addition of any 
live/attenuated 
vaccine (eg varicella, 
zoster, yellow fever, 
rotavirus, oral polio 
and measles, mumps, 
rubella (MMR)) 
during treatment and 
until 100 days post 
last dose to list of 
prohibited medication.
•
Section 7.7.2.4 Surgical 
Resection Following 
Initial Response
Information 
on
processes for
tissue
specimen deleted.
•
Section 8.1.1 Nivolumab 
Discontinuation Criteria
Recommendations for 
adverse events that 
should or must result 
in discontinuation 
have been 
incorporated. 
•
Section 8.1.2 
Daratumumab 
Discontinuation Criteria 
BMS medical monitor 
must 
be 
consulted
before re-initiation of 
treatment after a dose 
delay of 6 weeks rather 
than 8 weeks.
•
Section 8.1.3 Post Study 
Treatment Follow-up
Updated per deletion 
of overall survival as 
study endpoint.
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CA2099GW
BMS-936558
nivolumab 
1.
SYNOPSIS
Protocol Title: Phase 1/2 Study to Evaluate the Safety and Preliminary Efficacy of Nivolumab
Combined with Daratumumab in Participants with Advanced or Metastatic Solid Tumors 
Study Phase: 1/2
 
 
 
 
 
Study Population: Men or women, ≥18 years of age, with an Eastern Cooperative Oncology 
Group (ECOG) performance status of ≤1, with histologically or cytologically-confirmed 
diagnosis of advanced or metastatic cancer who also meet the corresponding requirements for the 
respective cohort (see Section 6), and who are treatment-naive to immune checkpoint inhibitors 
and CD38 blockers will be eligible to participate in the study. Enrollment of all tumor types is 
closed, as of 26-May-2018. The enrollment of participants with NSCLC was closed due to the 
lack of an efficacy signal. This decision was not related to any serious adverse events associated 
with the use of nivolumab in combination with daratumumab. The enrollment of participants with 
TNBC and PAC was previously closed as the study had met enrollment goals in these 2 cohorts.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To establish the tolerability of the combination of nivolumab and 
daratumumab in participants with advanced or metastatic solid 
tumors. 
Incidence of adverse events (AE), serious 
adverse events (SAE) and specific 
laboratory abnormalities (worst grade).
Secondary
•
To evaluate the objective response rate (ORR) of nivolumab 
combined with daratumumab in participants with advanced or 
metastatic tumors in each cohort. 
•
To assess progression free survival (PFS) of nivolumab 
combined with daratumumab in participants with advanced or 
metastatic tumors in each cohort.
•
To characterize the pharmacokinetics of nivolumab and 
daratumumab in participants with advanced or metastatic 
tumors.
•
To characterize the immunogenicity of nivolumab and 
daratumumab in participants with advanced or metastatic 
tumors
•
ORR, duration of response (DOR), best 
overall response (BOR) in each cohort, 
based 
on 
RECIST 
1.1 
criteria
(Appendix 7).
•
Median PFS in each cohort 
•
Pharmacokinetic parameters, influence 
of intrinsic and extrinsic covariates and 
potential exposure-response 
relationship will be characterized using 
integrated analyses.
•
Immunogenicity of nivolumab and 
daratumumab will be assessed by ADA 
positivity
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CA2099GW
BMS-936558
nivolumab 
Study treatment: 
Study Drug for CA2099GW
Medication 
Potency 
IP/Non-IP 
Nivolumab (BMS -936558)
100 mg (10 mg/ml) 
and 40 mg (10 
mg/mL)
IP
Daratumumab 
100 mg (20 mg/mL)
and/or 400 mg (20 
mg/mL)
IP
Study Design Schematic
Abbreviations: NSCLC= non-small cell lung cancer; PAC= pancreatic adenocarcinoma; NCB= triple-negative breast 
cancer; CR = complete response; PR = partial response; SD= stable disease; PD= progressive disease; Pre-tx = 
pretreatment; Q1W = every week; Q2W = every 2 weeks; Q4W = every 4 weeks; Q6W = every 6 weeks; Q12W = 
every 12 weeks
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CA2099GW
BMS-936558 
nivolumab 
2.
SCHEDULE OF ACTIVITIES
Table 2.-1:
Screening Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Screening
Visit (Day -28)
Notes
Eligibility Assessments
Informed Consent
X
Prior to any screening procedures. 
Register in Interactive Response 
Technology (IRT) system to obtain 
participant number.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be 
assessed at screening and confirmed prior 
to first dose.
Medical History
X
Document EGFR and ALK mutational status
X
EGFR and ALK for participants with 
NSCLC
Tumor Tissue Sample (biopsy)
CL
X
Fresh tissue biopsy at screening is 
required. Alternatively, tumor tissue 
collected after the completion of the most 
recent prior therapy is accepted.
Performance Status (ECOG)
X
Within 14 days prior to first dose. See 
Appendix 5 for ECOG scale.
Interactive Response Technology (IRT)
X
After informed consent form is signed, 
call IRT to enroll participant.
Safety Assessments
Physical Examination
X
Within 14 days prior to first dose:  full 
physical examination including weight 
measurement.
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BMS-936558 
nivolumab 
Table 2.-1:
Screening Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Screening
Visit (Day -28)
Notes
Vital Signs
X
Includes body temperature, respiratory 
rate, and seated blood pressure and heart 
rate. Blood pressure and heart rate must 
be measured after the participant has been 
resting quietly for at least 5 minutes.
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose.
Adverse Events Assessment
X
Collection from the time of informed 
consent. NSAEs and SAEs must be 
collected up to 100 days after study drug 
discontinuation.
ECG
LL
X
ECGs should be recorded after the 
participant has been supine for at least 5 
minutes.
Laboratory Tests
Pregnancy Test 
LL
X
Serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of 
HCG) to be done at screening visit and 
within 24 hours of first dose of study 
therapy.
Blood type Assessment (ABO, Rh, and indirect anti-globulin 
testing)
LL
X
Prior to first dose of daratumumab.
CBC with Differential and Platelets
LL
X
Within 14 days prior to first dose.
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CA2099GW
BMS-936558 
nivolumab 
Table 2.-1:
Screening Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Screening
Visit (Day -28)
Notes
Serum Chemistry
LL
X
Within 14 days prior to first dose. 
Chemistry panel includes LDH, AST, 
ALT, ALP, albumin, total bilirubin, BUN 
or serum urea level, creatinine, Ca, Mg, 
Na, K, Cl, glucose, phosphate, carbon 
dioxide or bicarbonate.
Amylase and lipase: only for participants 
with pancreatic adenocarcinoma.
Creatinine Clearance Assessment
LL
X
By Cockcroft-Gault formula or from 24 
hour urine
Thyroid Function Tests
LL
X
TSH (reflex to free T3 and free T4 if 
abnormal result) to be performed within 
28 days of first dose.
Urinalysis
LL
X
Total protein, glucose, blood, leukocyte 
esterase, specific gravity, and pH
Serology
LL
X
Hepatitis B surface antigen (HBV sAg, 
Australia antigen), and hepatitis C 
antibody (HCV Ab) or HCV ribonucleic 
acid (RNA)
HIV-1 and -2 antibody. Testing for HIV 
must be performed at sites where 
mandated locally.
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CA2099GW
BMS-936558 
nivolumab 
Table 2.-1:
Screening Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Screening
Visit (Day -28)
Notes
Efficacy Assessments
Body Imaging
LL
X
Tumor imaging assessment will occur at 
screening (within 28 days of first dose).
CT or MRI chest, abdomen, pelvis and all 
known sites of disease. Use same imaging 
method as was used at baseline.
See Section 9.1
Brain Imaging (per clinical indication)
LL
X
Participants with active brain metastases 
or leptomeningeal metastases are not 
eligible for enrollment. 
Participants with brain metastases are 
eligible if brain metastases 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.
See Section 9.1
Bone Scan (per clinical indication)
LL
X
Participants with a history of bone 
metastasis may have a bone scan, if 
clinically indicated.  See Section 9.1
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CA2099GW
BMS-936558 
nivolumab 
Table 2.-2:
On Study Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Weeks 1-8
Weeks 9-24
Q2W
Week 25 
and beyond
Q4W
Notes
Procedure Window ±2 Days 
Unless Specified Otherwise
Weeks 1, 3, 5, 7
Weeks 2,4,6, 8
Performance Status 
(ECOG)
X
Weeks 1 and 5
X
X
Week 1 and then every 4 
weeks thereafter. See 
Appendix 5 for ECOG scale.
Safety Assessments
Physical Examination
X
Weeks 1 and 5
X
X
Week 1 and every 4 weeks 
thereafter: targeted physical 
examination prior to dosing:
include weight. Must include 
the following body systems: 
cardiovascular, 
gastrointestinal, pulmonary
Vital Signs
X
X
X
X
Includes body temperature, 
respiratory rate, and seated 
blood pressure and heart rate. 
Blood pressure and heart rate 
must be measured after the 
participant has been resting 
quietly for at least 5 minutes. 
For participants remaining on 
combination therapy, vital 
signs should be monitored 
extensively on Weeks 1 and 2 
before, during, and after the 
infusion of daratumumab as 
follows: immediately before 
the start of the infusion; at 30 
minutes, 1 hour, 90 minutes, 
2 hours, and 3 hours 30 
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CA2099GW
BMS-936558 
nivolumab 
Table 2.-2:
On Study Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Weeks 1-8
Weeks 9-24
Q2W
Week 25 
and beyond
Q4W
Notes
Procedure Window ±2 Days 
Unless Specified Otherwise
Weeks 1, 3, 5, 7
Weeks 2,4,6, 8
Laboratory Tests
Pregnancy Test 
LL
X
Weeks 1 and 5
X
X
To be done within 24 hours 
of first dose of study therapy, 
and then at least once every 
4 weeks (+/-1 week) 
regardless of dosing 
schedule.
CBC with Differential 
and Platelets
LL
X
X
X
X
Weeks 1-8:every week
Weeks 9-24: every other 
week
Week 25 and beyond: every 4 
weeks
Serum Chemistry
LL
X
X
X
Weeks 1-24: every other 
week 
Week 25 and beyond: every 4 
weeks
Chemistry panel includes 
LDH, AST, ALT, ALP, 
albumin, total bilirubin, BUN 
or serum urea level, 
creatinine, Ca, Mg, Na, K, 
Cl, glucose, phosphate, 
carbon dioxide or 
bicarbonate.
Amylase and lipase: only for 
participants with pancreatic 
adenocarcinoma.
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BMS-936558 
nivolumab 
Table 2.-2:
On Study Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Weeks 1-8
Weeks 9-24
Q2W
Week 25 
and beyond
Q4W
Notes
Procedure Window ±2 Days 
Unless Specified Otherwise
Weeks 1, 3, 5, 7
Weeks 2,4,6, 8
Thyroid Function Tests
LL
X
Week 8
X
X
TSH (reflex to free T3 and 
free T4 if abnormal result) to 
be performed every 8 weeks 
(±7 days) from first dose
(starting at Week 8)
regardless of dosing schedule
Clinical Drug Supplies
IRT Drug Vials 
Assignment
X
X
X
X
Vials can be assigned up to 3
days prior to first dose date.
Dispense Study 
Treatment
As of 13-June-2018, only on-study TNBC and PAC participants who are deriving clinical benefit will continue to be 
treated with the nivolumab plus daratumumab combination therapy; NSCLC participants will be treated with 
nivolumab monotherapy.
Daratumumab
X
X
X
X
Treatment schedule for both 
study therapies is specified in 
Table 7.1-1
Dose delay guidance for 
nivolumab: Section 7.1.1.1
and for daratumumab: 
Section7.1.2.1.
Nivolumab
Weeks 3, 5, 7
X
X
Pre-infusion/Post-
infusion medications 
for daratumumab
X
X
X
X
See Sections 7.5.1 and 7.5.2  
for guidance on pre-infusion 
and post-infusion 
medications for 
daratumumab.
Oral Herpes Zoster 
Virus Prophylaxis
Initiate antiviral prophylaxis within 1 week after starting daratumumab. 
Continue antiviral prophylaxis during the Treatment Phase as per institutional 
guidelines, and for 3 months following treatment discontinuation of 
daratumumab.
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CA2099GW
BMS-936558 
nivolumab 
Table 2.-2:
On Study Procedural Outline (CA2099GW)
Procedure
Local Lab 
(LL) or 
Central Lab 
(CL)
Weeks 1-8
Weeks 9-24
Q2W
Week 25 
and beyond
Q4W
Notes
Procedure Window ±2 Days 
Unless Specified Otherwise
Weeks 1, 3, 5, 7
Weeks 2,4,6, 8
Efficacy Assessments
Radiographic Tumor 
Assessment
LL
.
See Notes
X
X
Tumor imaging assessment 
will occur at screening, and 
then every 6 weeks from the 
date of first dose (+/-1wk) for 
the first 24 weeks, then every 
12 weeks (+/-2wk) thereafter 
until PD (even if treatment is 
discontinued before 
progression).
CT or MRI chest, abdomen, 
pelvis and all known sites of 
disease. Use same imaging 
method as was used at 
baseline.
Participants with a history of 
brain metastasis may have 
surveillance MRI 
approximately every 12 
weeks from the date of
first dose, or sooner if 
clinically indicated.
See Table 9.1.1-1
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nivolumab
Table 2.-3:
Follow-up Procedural Outline (CA2099GW)
-
Local Lab (LL) or 
Central Lab (CL
Day 30, 100 Follow-up (±1 wk)
Notes
To be done at Follow-up 1. To be repeated at 
Follow-up 2 if study related toxicity persists.
Oral Herpes Zoster Virus Prophylaxis
X
Continue antiviral prophylaxis for 3 months 
following discontinuation of treatment with 
daratumumab.
Efficacy Assessments
Body Imaging
LL
See Section 9.1
For participants who discontinue treatment before 
progression, tumor imaging assessment will 
continue to be conducted per the regular schedule 
until PD (ie, every 6 weeks from the date of first 
dose [+/-1wk] for the first 24 weeks, then every 12 
weeks [+/-2 wk] thereafter until PD or initiation of 
new therapy, whichever occurs first.
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nivolumab
5.
STUDY DESIGN
5.1
Overall Design
Study CA2099GW is an open-label, multi-center, Phase 1/2 study investigating the safety and 
efficacy of nivolumab in combination with daratumumab in participants with advanced or 
metastatic tumor types including TNBC, NSCLC, and PAC. As of 13-June-2018, only TNBC and 
PAC participants who are deriving clinical benefit will continue to be treated with the nivolumab 
plus daratumumab combination therapy; NSCLC participants will be treated with nivolumab 
monotherapy, only.
Enrollment of all tumor types is closed, as of 26-May-2018. The enrollment of participants with 
NSCLC is closed due to the lack of an efficacy signal. This decision was not related to any serious 
adverse events associated with the use of nivolumab in combination with daratumumab. The 
enrollment of participants with TNBC and PAC was previously closed as the study had met 
enrollment goals in these 2 cohorts.
Participants will be treated for a maximum of 24 months on study, or until confirmed progression, 
unacceptable toxicity, withdrawal of consent, or the study is discontinued by the sponsor. Study 
treatment can continue beyond initial investigator assessed progression as specified in 
Section 7.1.5
The study will consist of Screening, Treatment, and Follow-up. All safety data will be monitored 
on an ongoing basis throughout the study.
The duration of the study is anticipated to be approximately 3 years.
Please refer to Section 7.8 for study termination criteria.
The study design schematic is presented in Figure 5.1-1.
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Clinical Protocol
CA2099GW
BMS-936558
nivolumab
Figure 5.1-1:
Study Design Schematic
Abbreviations: NSCLC= non-small cell lung cancer; PAC= pancreatic adenocarcinoma; NCB= triple-negative breast 
cancer; CR = complete response; PR = partial response; SD= stable disease; PD= progressive disease; Pre-tx = 
pretreatment; Q1W = every week; Q2W = every 2 weeks; Q4W = every 4 weeks; Q6W = every 6 weeks; Q12W = 
every 12 weeks
Screening Period (up to 28 days):
Participants will sign the informed consent form prior to undergoing any study-related procedures. 
Screening evaluations to determine eligibility will be performed within 28 days prior to the start 
of therapy (as outlined in Table 2.-1).
A baseline tumor imaging assessment will be performed prior to the start of therapy. Tumor tissue 
and peripheral blood must be provided for biomarker analysis. Sufficient, recent tumor tissue 
(fresh tumor biopsy or tumor tissue collected after the completion of the most recent prior therapy) 
obtained from a metastatic tumor lesion or from an unresectable primary tumor lesion which has 
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Clinical Protocol
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nivolumab
not been previously irradiated (formalin-fixed paraffin-embedded block (FFPE) or minimum of 
25 slides, obtained from core biopsy, punch biopsy, excisional biopsy or surgical specimen) will 
be submitted to the central laboratory. If not enough tumor sample is available, the investigator 
has to contact the BMS study team to inform the BMS team if less than 25 charged unstained slides 
are available for the potential impact on biomarker testing.
Treatment Period: 
During the Treatment period, (Table 2.-2) participants will receive (1) nivolumab 240 mg every 2 
weeks from Week 3 to 24, then nivolumab 480 mg every 4 weeks from Week 25 and beyond, and 
(2) daratumumab 16 mg/kg every week for 8 weeks, then every 2 weeks for 16 weeks, and then 
every 4 weeks from week 25 onward, for a total treatment duration of 24 months. Due to the 
daratumumab infusion related reactions profile, the first 2 doses of daratumumab will be 
administered alone and nivolumab administration will start with the third dose of daratumumab.
As of 13-June-2018, only TNBC and PAC participants who are deriving clinical benefit will 
continue to be treated with the nivolumab plus daratumumab combination therapy; NSCLC 
participants will be treated with nivolumab monotherapy. The treatment period will continue for a 
maximum of 24 months or until disease progression, occurrence of unacceptable toxicity, consent 
withdrawal, or the study is stopped by the Sponsor. 
On-treatment tumor imaging assessments will occur every 6 weeks (+/-1 week) for the first 24 
weeks, then every 12 weeks (+/- 1 week) until disease progression including participants who
discontinue treatment due to unacceptable toxicity or until initiation of subsequent therapy, 
whichever occurs first. Treatment beyond initial investigator-assessed progression is permitted if 
the participant has an investigator-assessed clinical benefit and is tolerating study drug (Section
7.1.5). The investigator-assessed tumor response based on RECIST 1.1 criteria will be used for 
efficacy analyses. All participants will continue to be followed for safety after discontinuation of 
study medication during the Follow-up period. Participants who discontinue study drug due to 
toxicity will continue to have tumor assessments until disease progression or withdrawal of consent 
during Follow-up as specified in Table 2.-3. 
Participants will be closely monitored for AEs and SAEs throughout the study. Participants who 
experience AEs that require discontinuation of one of the study drugs may be allowed to continue 
therapy with the other study drug, if deemed as in their best interest by both the PI and the BMS 
medical monitor. Participants must be deriving clinical benefit. 
Participants may withdraw or discontinue at any time based on criteria in Section 8.1.
Follow-up Period:
All study participants who discontinue treatment will enter the Follow-up period, with visits 
scheduled on Days 30 and 100 from the last study drug dose, to monitor for AEs. Participants who 
discontinue study treatment due to toxicity will continue to be evaluated for efficacy until 
progression or initiation of subsequent therapy, whichever occurs first, as specified in Table 2.-3.
5.1.1
Data Monitoring Committee and Other External Committees
Not applicable 
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5.2
Number of Participants
Enrollment of all tumor types is closed, as of 26-May-2018. The enrollment of participants with 
NSCLC was closed due to the lack of an efficacy signal. This decision was not related to any 
serious adverse events associated with the use of nivolumab in combination with daratumumab. 
The enrollment of participants with TNBC and PAC was previously closed as the study had met 
enrollment goals in these 2 cohorts.
188 participants were enrolled in the study to ensure a total of 40 participants treated in each cohort, 
which assumed a screen failure rate of 25%. See Section 10.1 for sample size determination. 
Participants at least 18 years old, who have histologic or cytological confirmation of the following 
solid tumors were enrolled: 
•
Triple negative Breast Cancer, TNBC (Cohort A)
•
Non-small cell lung cancer, NSCLC (Cohort B)
•
Pancreatic adenocarcinoma Cancer, PAC (Cohort C)
5.3
End of Study Definition
The start of the trial is defined as first visit for first participant screened. End of trial is defined as 
the last visit or scheduled procedure shown in the Schedule of Activities for the last participant. 
 
 
 
 
 
 
 
 
 
 
 
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5.6
Duration of Treatment: 24 months
The optimal duration of immunotherapy is currently unknown. However, because immunotherapy 
engages the immune system to control the tumor, continuous treatment as is required with targeted 
agents or cytotoxic therapy may not be necessary. Accumulating evidence from different clinical 
trials in different tumors types with nivolumab indicates that most of the responses are generally 
occurring early, with a median time to response of 2-4 months including in patients with 
NSCLC.117,118 and a recent analysis in a melanoma study suggests the majority of patients who 
discontinue nivolumab for toxicity maintain disease control in the absence of further treatment.119
For these reasons, in study CA2099GW, treatment will be given for up to 24 months in the absence 
of disease progression or unacceptable toxicity. 
6.
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants 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 
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, potential tumor biopsies, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Women with histologically or cytologically confirmed breast carcinoma who must meet 
all of the following:
i.
Tumor must be “triple receptor negative” defined as ER/PR negative and HER-2 
negative defined per 2013 American Society of Clinical Oncologists and College 
of American Pathologists (ASCO-CAP) guidelines.120
AND
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ii.
Participants must have had received 1 to 4 prior regimens for the treatment of 
metastatic (Stage IV) or locally advanced disease. There must have been 
progression on or following the last regimen or unacceptable adverse events 
requiring discontinuation or therapy.
b) Participants with histologically or cytologically confirmed pancreatic adenocarcinoma who 
must meet the following:
i.
Participants must not have clinically relevant ascites at baseline, such as ascites in 
need of paracentesis.
AND
ii.
Participants must have received only 1 prior chemotherapy regimen for the 
treatment of metastatic (Stage IV) or locally advanced disease. There must have 
been progression on or following the last regimen or unacceptable adverse events 
requiring discontinuation or therapy. 
c) Participants must have histologic or cytologic confirmation of NSCLC (per the seventh
International Association for the Study of Lung Cancer [IASLC])121 with squamous or 
nonsquamous histology that is advanced (metastatic and/or unresectable) 
i.
Participants must have no more than 2 prior lines of therapy including one line of 
platinum doublet chemotherapy.  
ii.
Participants who will receive study therapy as second line of treatment must have 
experienced disease recurrence or progression during or after one prior platinum 
doublet-based chemotherapy regimen for advanced or metastatic disease.
a.
First line therapy is defined as therapy used to treat advanced disease. Each 
subsequent line of therapy is preceded by disease progression. A switch of 
an agent within a regimen in order to manage toxicity does not define the 
start of a new line of therapy. 
b. Experimental therapies when given as separate regimen are considered as 
separate line of therapy and must have resulted in disease progression.
c.
Maintenance therapy following platinum doublet-based chemotherapy is 
not considered as a separate regimen of therapy and could comprise 
continuation of one or more of the agents used in the first-line therapy 
regimen or switch to another non cross-resistant agent. The initiation of 
maintenance therapy requires the lack of progressive disease with frontline 
therapy. 
d. Treatment given for locally advanced disease is not considered as a line of 
therapy for advanced disease. Participants with recurrent disease > 6 months 
after 
platinum 
containing 
adjuvant, 
neoadjuvant 
or 
definitive 
chemoradiation therapy given for locally advanced disease, who also 
subsequently progressed during or after a platinum doublet-based regimen 
given to treat the recurrence, are eligible.   Adjuvant or neoadjuvant 
platinum-doublet chemotherapy (after surgery and/or radiation therapy) 
followed by recurrent or metastatic disease within 6 months of completing 
therapy is considered as first line therapy for advanced disease.
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iii.
Participants who will receive study therapy as third line of treatment must have 
experienced disease recurrence or progression during or after a separate EGFR or 
ALK tyrosine kinase inhibitor (TKI) regimen in addition to one prior platinum 
doublet-based chemotherapy regimen (regardless of order of administration).
a.
Participants who received an EGFR TKI (erlotinib, gefitinib or 
experimental) in addition to a platinum-based chemotherapy must have a 
tumor with a known activating EGFR mutation.
b. Participants with a tumor with EGFR wild-type or unknown EGFR 
mutation status who received an EGFR TKI after failure of a prior platinum-
based chemotherapy are excluded.
c.
Participants who received an ALK inhibitor (crizotinib or experimental) in 
addition to a platinum-based chemotherapy must have a tumor with a known 
ALK translocation.
d) Participants 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).
e) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
f)
Life expectancy of at least 3 months
g) Must consent to tumor biopsy. 
h) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections, obtained within 3 months prior to first dose, with an associated pathology report, 
must be submitted to the core laboratory for inclusion. Central lab must provide Interactive 
Response Technology (IRT) with confirmation of receipt of evaluable tumor tissue prior 
to study treatment. Biopsy should be excisional, incisional or core needle. Fine needle 
aspiration is unacceptable for submission. If not enough tumor sample is available, the 
investigator has to contact the BMS study team to inform the BMS team if less than 25 
charged unstained slides are available for the potential impact on biomarker testing.
i)
Prior focal palliative radiotherapy to an isolated bone or soft tissue metastasis must be 
completed at least 2 weeks before study drug administration.
j)
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:
i.
WBCs ≥ 2000/μL (growth factors not permitted within 1 week of study drug 
administration; pegylated growth factors not permitted within 3 weeks of first study 
drug administration)
ii.
Neutrophils ≥ 1500/μL (growth factors not permitted within 1 week of study drug 
administration; pegylated growth factors not permitted within 3 weeks of first study 
drug administration)
iii.
Platelets ≥  100 x 10³/μL (transfusions not permitted within 72 hours prior to 
qualifying laboratory value)
iv.
Hemoglobin ≥ 9.0 g/dL (transfusions not permitted within 72 hours prior to 
qualifying laboratory value; recombinant human erythropoietin not permitted 
within 3 weeks of study drug administration)
v.
Estimated creatinine clearance by Cockcroft-Gault formula ≥ 30 mL/min
vi.
AST and ALT levels ≤3 x ULN or ≤5 x ULN if liver metastases are present
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vii.
Total Bilirubin ≤1.5 x ULN (except participants  with Gilbert Syndrome who can 
have total bilirubin < 3.0 mg/dL)
viii.
Albumin ≥ 3 g/dL
ix.
For participants with pancreatic adenocarcinoma
a.
Lipase ≤ 1.5 x ULN. Participants with lipase > 1.5 x ULN may enroll if there 
are neither clinical nor radiographic signs of a pancreatitis
b.
Amylase ≤ 1.5 x ULN. Participants with amylase > 1.5 x ULN may enroll if 
there are neither clinical nor radiographic signs of a pancreatitis
3) Age and Reproductive Status
a) Males and Females, ≥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 treatment.
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 approximately 5 half-lives 
of study drug(s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post 
treatment completion.
e) Males 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 
approximately 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a 
total of 7 months post-treatment completion.
f)
WOCBP who are continuously not heterosexually active are also exempt from 
contraceptive requirements and still must undergo pregnancy testing as described.
Investigators shall counsel WOCBP and male participants 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 participants 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, participants must agree to the use one highly effective method of contraception as 
listed in Appendix 4.
6.2
Exclusion Criteria
1) Medical Conditions
a) Active brain metastases or leptomeningeal metastases. Participants 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. 
b) 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 
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the ability of the participant to receive protocol therapy, or interfere with the interpretation 
of study results.
c) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured or successfully resected, such as basal or squamous cell skin 
cancer, superficial bladder cancer, or gastric cancer, or carcinoma in situ of the prostate, 
cervix, or breast. Participants with active, known or suspected autoimmune disease. 
Participants with skin disorders (such as vitiligo, psoriasis, or alopecia), type I diabetes 
mellitus, hypothyroidism only requiring hormone replacement, or conditions not expected 
to recur in the absence of an external trigger are permitted to enroll.
d) Participants 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.
e) Vaccination with live attenuated vaccines within 4 weeks of first study agent 
administration 
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. Participants  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) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following:
i)
Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 
months prior to consent
ii) Uncontrolled or poorly controlled angina within the 3 months prior to consent
iii) Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes)
iv) QTc prolongation > 470 msec
v) history of other clinically significant heart disease (ie, cardiomyopathy, congestive 
heart failure with NYHA functional classification III-IV, pericarditis, significant 
pericardial effusion)
vi) requirement for daily supplemental oxygen therapy
h) Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 
1 second (FEV1) <50% of predicted normal 
i)
Known moderate or severe persistent asthma within the past 2 years, or uncontrolled 
asthma of any classification. Participants who currently have controlled intermittent 
asthma or controlled mild persistent asthma are allowed to participate in the study.
2) Prior/Concomitant Therapy
a) 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.
b) Prior therapy with anti-CD38 monoclonal antibodies.
c) Prior organ allograft. 
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d) Treatment with any chemotherapy, radiation therapy, (except for palliative radiation 
therapy as indicated in inclusion criterion 2.i above), biologics for cancer, or investigational 
therapy within 28 days of first administration of study treatment (participants with prior 
cytotoxic or investigational products < 4 weeks prior to treatment might be eligible after 
discussion between investigator and sponsor, if toxicities from the prior treatment have 
been resolved to Grade 1 (NCI CTCAE version 4).
3) Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
b) Positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS). Testing for HIV must be performed at sites where 
mandated locally.
c) Participants 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 or fusion proteins
c) Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster 
ovary cells or any component of the daratumumab formulation 
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
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6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a screen failure (i.e., participant has not been treated). If re-enrolled, the 
participant must be re-consented.
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). The 
most current result prior to Randomization is the value by which study inclusion will be assessed, 
as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2.-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7.
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
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.
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.
The drugs used in combination therapy during this open-label study qualify as IPs, as per previous 
text, and their description and storage information are described in Table 7.-1.
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Table 7.-1:
Product Description for CA2099GW
Product Description / 
Class and Dosage Form
Potency
IP/Non-IP
Blinded or Open 
Label
Packaging / 
Appearance
Storage Conditions
(per label)
Nivolumab
(BMS-936558-01)
Solution for Injection
100 mg (10 mg/ml) 
and 40 mg (10 
mg/mL)
IP
Open label
Vial
Refer to the label on 
container and/or 
pharmacy manual.
Daratumumab
Solution for Injection 
100 mg
(20mg/mL) and/or 
400 mg (20 mg/mL)
IP
Open label 
Vial
Refer to the label on 
container and/or 
pharmacy manual.
Further instructions with regard to the preparation, handling, and storage for nivolumab and daratumumab will be provided to sites 
separately as Pharmacy preparation instructions or a Pharmacy manual.
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7.1
Treatments Administered
The selection and timing of dose for each participant is presented in Table 7.1-1.
Table 7.1-1:
Study Drug Dosing Schedule
Cohort/Tumor 
Types*
Nivolumab 
+
Daratumumab 
Dose
Frequency of 
administration
Route of 
administration
Duration
A
(n=40)  TNBC 
B
(n=40) NSCLC
C
(n=40) PAC
Nivolumab
240 mg flat 
dose
Every 2 weeks 
starting at Week 3 
30  minutes 
Intravenous 
(IV) infusion
24 months or 
until 
progression, 
toxicity, 
or early 
discontinuation 
from study
480 mg flat 
dose
then every 4 weeks 
starting at Week 25
Daratumumab
16mg/kg
Every week 
(Wks 1-8) then 
every 2 weeks
(Wks 9-24), then 
every 4 weeks 
starting at Week 25
First infusion: 
approximately 8 
hours
Second and 
subsequent 
infusions: 
approximately 4 
hours
Intravenous 
(IV) infusion
* Enrollment in all tumor cohorts is closed.
As of 13-June-2018, only on-study TNBC and PAC participants who are deriving clinical benefit will 
continue to be treated with the nivolumab plus daratumumab combination therapy; NSCLC participants 
will be treated with nivolumab monotherapy.
7.1.1
Nivolumab 
Nivolumab should be administered before daratumumab. There are no pre-medications 
recommended for nivolumab.
Participants will receive nivolumab at a dose of 240 mg as a 30 minute infusion every 2 weeks 
from Week 3 to Week 24, then nivolumab 480 mg every 4 weeks from Week 25 and beyond for 
up to 24 months or until disease progression, occurrence of unacceptable toxicity, withdrawal of 
consent, or the study ends, whichever occurs first.
Nivolumab can be delayed within a 3-day window during the every other week administration 
schedule, as long as the 12-day interval between 2 nivolumab doses is respected. During the every 
4 weeks administration schedule, nivolumab can be delayed within a week, as long as the 21-day 
interval between 2 nivolumab doses is respected. The Week 25 dose (the first dose of the every 4 
week dosing schedule) may be administered no less than 12 days from the previous dose and for 
subsequent doses it should be dosed no less than 21 days from the previous dose. Doses that fall 
outside the allowed window should be skipped.
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Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.1.3.1.
There will be no dose escalations or reductions of nivolumab allowed. Doses of nivolumab may 
be interrupted, delayed, or discontinued depending on how well the participant tolerates the 
treatment.
If the dose of nivolumab is interrupted or discontinued due to a related AE, the treatment with 
daratumumab may continue as scheduled if deemed in their best interest by both the Principal 
Investigator and the BMS medical monitor. Participants must be deriving clinical benefit and the 
AE must clearly not be related to daratumumab. Please consult the BMS Medical Monitor or any 
questions regarding dose interruption or study therapy discontinuation.
7.1.1.1
Nivolumab Dose Delay Due to AEs
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
•
Grade 3 drug-related laboratory abnormality, with the following exceptions:
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8.1)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met. See 
Section 7.1.4. 
7.1.2
Daratumumab
Daratumumab should be administered after nivolumab, and will start no sooner than 30 minutes 
after completion of the nivolumab infusion. All participants will receive pre-infusion and post-
infusion medication for prevention of daratumumab infusion related reactions per the descriptions 
in Section 7.5. Participants should be carefully monitored for infusion reactions during 
daratumumab administration. If an acute infusion reaction is noted, participants should be 
managed according to Section 7.1.3.2.
There will be no dose escalations or reductions of daratumumab allowed. Doses of daratumumab 
may be interrupted, delayed, or discontinued depending on how well the participant tolerates the 
treatment. See Table 7.1.2-1 for guidance on daratumumab dose delay.
If the dose of daratumumab is interrupted or discontinued due to a related AE, the treatment with 
nivolumab may continue as scheduled if deemed in their best interest by both the Principal 
Investigator and the BMS medical monitor. Participants must be deriving clinical benefit and the 
AE must clearly not be related to nivolumab. Please consult the BMS Medical Monitor or any 
questions regarding dose interruption or study therapy discontinuation.
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During the weekly dosing schedule, daratumumab can be delayed within a window of -1 to 
+3 days. During the every other week dosing schedule, daratumumab dosing may be delayed for 
up to 1 week. During the every 4 week dosing schedule, daratumumab can be delayed within a 
21-day window. Doses that fall outside the allowed windows should be skipped.
Table 7.1.2-1:
Daratumumab Dose Delay Guidance
Weeks
Dosing Frequency
Skip dose window
Dosing Resumption
1 -8 
Weekly (QW)
> 3 days
Next planned weekly dosing date
9-24 
Biweekly (Q2W)
> 7 days
Next planned biweekly dosing date
25 and beyond
Every 4 weeks (Q4W)
> 21 days
Next planned every 4 weeks dosing 
date
Doses of daratumumab may be delayed up to 4 weeks during Weeks 1-24 or up to 6 weeks from 
Week 25 and beyond. Any adverse event deemed to be related to daratumumab that requires a 
dose hold longer than those specified above will result in permanent discontinuation of 
daratumumab. If a dose delay occurs, then pharmacokinetic and pharmacodynamic assessments 
should be performed on the actual administration day of daratumumab, not on the original 
scheduled administration day.
7.1.2.1
Daratumumab Dose Delays Due to AEs
The study treatment must be held if any of the following criteria below are met, to allow for 
recovery from toxicity. The criteria for a dose delay are:
•
Grade 4 hematologic toxicity, except for grade 4 lymphopenia
•
Grade 3 or higher thrombocytopenia
•
Febrile neutropenia
•
Neutropenia with infection, of any grade
•
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
−
Grade 3 nausea that responds to antiemetic treatment within 7 days
−
Grade 3 vomiting that responds to antiemetic treatment within 7 days
−
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
−
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
−
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully 
recovered.
If daratumumab administration does not commence within the prespecified window 
(Table 7.1.2-1) of the scheduled administration date, then the dose will be considered a missed 
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dose. Administration may resume at the next planned dosing date. A missed dose will not be made 
up.
7.1.3
Treatment of Study Drug Related Infusion Reactions 
7.1.3.1
Management of nivolumab infusion-related reactions
Since nivolumab is a fully human antibody, it is unlikely to be immunogenic and induce infusion 
or hypersensitivity reactions. However, if such a reaction were to occur, it might manifest with 
fever, chills, rigors, headache, rash, pruritus, 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) guidelines.
Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines,
bronchodilators, and oxygen should be available for use in the treatment of such reactions.
Participants should be carefully observed until the complete resolution of all signs and
symptoms.
Following
an
infusion
reaction,
participants
should
be
premedicated
with
acetaminophen and diphenhydramine for future treatments.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional study drug 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 infusion, begin an IV infusion of normal saline, and treat the participant with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then 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 participant closely. If symptoms recur 
then no further study drug will be administered at that visit. Administer diphenhydramine 50 
mg IV, and remain at bedside and monitor the participant 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 administrations. If 
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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 study drug. Begin an IV infusion of normal saline, and 
treat the participant 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. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. 
•
Nivolumab will be permanently discontinued. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor participant until 
recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine, or corticosteroids).
7.1.3.2
Management of daratumumab infusion-related reactions
Management of Daratumumab Infusion related reactions:
Participants should be carefully observed during daratumumab infusions. Trained study staff at the 
clinic should be prepared to intervene in case of any infusion reactions, and resources necessary 
for resuscitation must be available. Attention to staffing should be considered when multiple 
participants will be dosed at the same time.
For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion and 
manage symptoms. Management of infusion reactions may require further reduction in the rate of 
infusion, or treatment discontinuation of daratumumab. 
Infusion-related reactions of Grade 1 or Grade 2: Once reaction symptoms resolve, resume the 
infusion at no more than half the rate at which the reaction occurred. If the participant does not 
experience any further reaction symptoms, infusion rate escalation may resume at increments and 
intervals as appropriate as outlined in Table 7.5-1.
Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no more 
than half the rate at which the reaction occurred. If the participant does not experience additional 
symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 7.5-1. 
Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently 
discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion-related 
reaction.
Grade 4 (life threatening): Permanently discontinue daratumumab treatment. 
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7.1.4
Criteria to Resume Treatment
Participants may resume nivolumab treatment with study drug when the drug-related AE(s) resolve 
to Grade ≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
•
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8.1.1) should have treatment permanently discontinued. 
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor.
Participants with nivolumab-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor. 
Grade ≥ 3 adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully 
recovered.
7.1.5
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.7
Participants will be permitted to continue treatment beyond initial RECIST 1.1 defined PD, 
assessed by the investigator, as long as they meet the following criteria:
•
Investigator-assessed clinical benefit.
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, central nervous system (CNS) metastases)
•
Participant provides written informed consent prior to receiving additional treatment.  All other 
elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply.
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment.
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If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities in Section 2
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time 
of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the 
diameters of new measurable lesions compared to the time of initial PD. Treatment should be 
discontinued permanently upon documentation of further progression.
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 least15 
mm). Any new lesion considered non-measureable at the time of initial progression may become 
measureable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
7.2
Method of Treatment Assignment
All participants were initially assigned to combination therapy. Enrollment of all tumor types is 
closed, as of 26-May-2018. As of 13-June-2018, only on-study TNBC and PAC participants who 
are deriving clinical benefit will continue to be treated with the nivolumab plus daratumumab 
combination therapy; NSCLC participants will be treated with nivolumab monotherapy.
Study treatment will be dispensed at the study visits as listed in Schedule of Activities: 
Table 2.-2. 
After informed consent has been obtained, the subject must be screened into the study by logging 
into the Interactive Response Technology (IRT) to obtain a subject number. Every subject that 
signs the informed consent form must be assigned a subject number in the IRT. The investigator 
or designee will register the subject for screening by following the screening procedures 
established by BMS. During the screening visit, the IRT will assign a 5-digit participant number 
that will be unique across all sites. Enrolled participants, including those not dosed, will be 
assigned sequential participant numbers starting with 00001, (eg, 00001, 00002, 00003.... 00010). 
The patient identification number (PID) will ultimately be comprised of the site number and 
participant number. For example, the first participant screened (ie, enrolled) at site number 1, will 
have a PID of 0001 00001. Once it is determined that the participant meets the eligibility criteria 
following the screening visit, the investigative site will call the IRT to assign the participant into 
the open dose panel of nivolumab plus daratumumab. Participants who withdraw from the study 
will not be replaced. Specific instructions for using IRT will be provided to the investigational site 
in a separate document.
The following information is required for drug vial assignment:
•
Participant  number
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•
Date of birth
•
Gender at Birth 
7.3
Blinding
This is an open-label study, blinding procedures are not applicable.
7.4
Dosage Modification
There will be no dose adjustments allowed for study drugs with the exception of changes due to
fluctuations in weight for daratumumab. 
7.5
Preparation/Handling/Storage/Accountability
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 participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment 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 treatment arise, the study treatment 
should not be dispensed and BMS should be contacted immediately.
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).
Storage facilities for controlled substances must be securely locked and substantially constructed, 
with restricted access to prevent theft or diversion, as applicable by local regulations. 
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose 
injection) will not be supplied by the sponsor and should be purchased locally if permitted by local 
regulations.
Please refer to the current version of the Investigator Brochure and/or pharmacy manual for 
complete storage, handling, dispensing, and infusion information for nivolumab, and 
daratumumab. 
Nivolumab Preparation and Administration
Please refer to the current version of the IB and/or pharmacy manual for complete storage, 
handling, dispensing, and infusion information for nivolumab. Nivolumab vials must be stored at 
a temperature of 2° to 8°C and should be protected from light and freezing. If stored in a glass 
front refrigerator, vials should be stored in the carton. Recommended safety measures for 
preparation and handling of nivolumab include use of laboratory coats and gloves. For details on 
prepared drug storage and use time of nivolumab under room temperature/light and refrigeration, 
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please refer to the Nivolumab IB: “Recommended Storage and Use Conditions” and/or pharmacy 
manual.
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, or pharmacy manual. Care must be taken to assure sterility of the 
prepared solution because the product does not contain any antimicrobial preservative or 
bacteriostatic agent. 
Daratumumab Preparation and Administration
Daratumumab Infusion solution will be prepared as a 1,000-mL (first dose) or 500-mL (second 
and subsequent doses) dilution of daratumumab in sterile, pyrogen-free 0.9% NaCl. Preparation 
of infusion bags should be done on the day of the planned infusion. Daratumumab must be 
administered as an IV infusion given through a well-functioning IV catheter by using an infusion 
pump. The study drug must be filtered by using an inline filter (0.2 μM) during the infusion. 
Pharmacy manuals with detailed descriptions for preparation and administration of daratumumab 
will be supplied to each pharmacy and site.
Because of this high risk of infusion related reactions daratumumab infusions will be administered 
per the Investigator’s Brochure by a healthcare professional, with immediate access to emergency 
equipment and appropriate medical support to manage infusion reactions if they occur, and all 
participants will receive pre-infusion and post-infusion medication per the descriptions in 
Section 7.5
Before administration the drug product should be stored and prepared as per the instructions in 
pharmacy manual. Daratumumab (dose) will be administered as an IV infusion. All infusions will 
be planned as outpatient visits. Each participant’s dose will be calculated based on the participant’s 
weight at Week 1 rounded to the nearest kilogram. The dose of daratumumab to be administered 
to a participant will be calculated by multiplying the participant’s weight (kg) by 16 mg/kg. The 
dose of daratumumab will remain constant throughout the study, unless the participant’s weight 
changes more than 10% from Week 1. All infusions will be planned as outpatient visits. 
Participants will receive pre-infusion medications and post-infusion medications as detailed in the 
protocol (Section 7.5).
The infusion start and stop time will be recorded in the eCRF. If the infusion is stopped mid-
session for any reason, the stop/start time must be recorded together with an explanation.
The dilution volumes, initial infusion rates, and increment for the first, second, and subsequent 
doses are provided in Table 7.5-1. The first infusion, with a volume of 1,000 mL, takes 
approximately 8 hours; the second and subsequent infusions, with volumes of 500 mL, take 
approximately 4 hours. The maximum infusion rate for all infusions is 200 mL/hour. Additional 
details for administration times and rates, as well as pre-infusion medications, will be provided in 
the pharmacy manual.
Vital signs should be monitored extensively on Week 1 and 2 before, during, and after the first 
infusion of daratumumab. For all other infusions, vital signs should be measured before the start 
of the infusion and at the end of the infusion. If a participant experiences any significant medical 
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event, then the investigator should assess whether the participant should stay overnight for 
observation. If the participant has not experienced a significant medical event but is hospitalized 
overnight only for observation, then the hospitalization should not be reported as a serious adverse 
event.
Table 7.5-1:
Daratumumab Infusion Rates
Dilution Volume
Initial Infusion 
Rate (first hour)
Increments of 
Infusion Rate
Maximum Infusion
Rate
First infusion
1000 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Second infusiona
500 mL
50 mL/hour
50 mL/hour 
every hour
200 mL/hour
Subsequent 
infusionsb
500 mL
100 mL/hour
50 mL/hour 
every hour
200 mL/hour
a Modified rates should only be used if the first infusion of daratumumab was well tolerated as defined by an absence 
of > Grade 1 infusion-related reactions during the first 3 hours.
b Modified rates should only be used if the first 2 infusions of daratumumab were well tolerated as defined by an 
absence of > Grade 1 infusion-related reactions during a final infusion rate of ≥100 mL/hr.
7.5.1
Pre-Infusion Medication for Daratumumab 
Daratumumab will be administered as described in the Schedule of Activities (Table 2.-2). On 
daratumumab infusion days, participants will receive the following medications approximately 
1 hour prior to daratumumab infusion (can be administered before the nivolumab infusion):
•
Paracetamol (acetaminophen) 650-1000 mg IV or PO
•
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of 
promethazine) (see Appendix 8 for list of antihistamines that may be used)
•
Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second 
infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 
60 mg). Substitutions for methylprednisolone are allowed, please refer to Appendix 9. 
•
Leukotriene Inhibitor (optional) on Cycle 1 Day 1: montelukast 10 mg PO, or equivalent.
If necessary, all PO pre-infusion medications may be administered outside of the clinic on the day 
of the infusion, provided they are taken within 3 hours before the infusion.
Pre-infusion medications for daratumumab may be administered before the start of nivolumab 
infusion. Daratumumab should be administered after nivolumab, and will start no sooner than 30 
minutes after completion of the nivolumab infusion.
7.5.2
Post-Infusion medication for Daratumumab 
For the prevention of delayed infusion-related reactions, all participants will receive long- or 
intermediate-acting corticosteroid orally (20 mg methylprednisolone or equivalent in accordance 
with local standards) on the 2 days following all daratumumab infusions (beginning the day after 
the infusion). 
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In the absence of infusion related AEs after the first 3 infusions, post-infusion corticosteroids 
should be administered per investigator discretion.
For participants with a higher risk of respiratory complications (eg, participants with mild asthma 
or participants with COPD who have an FEV1 <80% at screening or developed FEV1 <80% during 
the study without any medical history), the following post-infusion medications should be 
considered:
•
Antihistamine (diphenhydramine or equivalent) 
•
Leukotriene inhibitor (montelukast or equivalent)
•
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
•
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for participants with asthma; long-acting bronchodilators such as tiotropium 
or salmeterol ± inhaled corticosteroids for participants with COPD)
In addition, these at-risk participants may be hospitalized for monitoring for up to 2 nights after an 
infusion. If participants are hospitalized, then their spirometry test (FEV1) should be performed 
before discharge. If these participants are not hospitalized, then a follow-up telephone call should 
be made to monitor their condition within 48 hours after all infusions. If no infusion-related 
reaction has occurred, the follow-up telephone call 48 hours after the infusion is not required. If 
the participant has not experienced a significant medical event but is hospitalized overnight only 
for observation, then the hospitalization should not be reported as a serious adverse event. 
Investigators may prescribe bronchodilators, H1-antihistamines, and corticosteroids that are 
deemed necessary to provide adequate supportive care in the event a bronchospasm occurs after 
participants are released from the hospital/clinic. If an at-risk participant experiences no major
infusion-related reactions, then these post-infusion medications may be waived after 4 doses at the 
investigator’s discretion. 
Any post-infusion medication will be administered after the infusion has completed.
7.6
Treatment Compliance
Study treatment will be administered in the clinical facility by trained medical personnel. 
Treatment compliance will be monitored by treatment accountability, as well as by recording 
administration of each study treatment in the participants’ medical records and eCRF. 
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7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of nivolumab or 
daratumumab is terminated for other reasons, including but not limited to lack of efficacy and/or 
not meeting the study objectives; c) the participant can obtain medication from a government 
sponsored or private health program. In all cases BMS will follow local regulations.
8.
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant ’s request to stop study treatment
•
Any clinical adverse event (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 participant 
•
Documented and confirmed disease progression or clinical deterioration while receiving active 
study therapy
•
Termination of the study by BMS as specified in Section 7.8. 
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
For discontinuation criteria related to nivolumab-and/or daratumumab-related adverse events,
please see below. 
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. Please contact the Sponsor or designee within 24 hours of awareness of 
the pregnancy. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
All participants who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Table 2.-3. The only exception to this requirement is when a participant 
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).
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If study drug is discontinued prior to the participant ’s completion of the study, the reason for the 
discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
Discontinuation of the study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined below or if the investigator 
believes that it is in best interest of the participant.
8.1.1
Nivolumab Discontinuation Criteria
Nivolumab treatment should be permanently discontinued for 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 AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity, 
myocarditis, 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 adrenal insufficiency
requires discontinuation regardless of control with hormone replacement (note:
Hospitalization for diagnostic workup of adrenal insufficiency without severe symptoms
−
should not be considered a Grade 3 event).
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except for the following:
♦Grade 3 drug-related thrombocytopenia lasting > 7 days or associated with bleeding 
requires discontinuation
♦Grade ≥3 drug-related AST, ALT, or Total bilirubin requires discontinuation
♦Concurrent AST or ALT > 3× ULN and total bilirubin > 2× ULN
*In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug(s), a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
•
Any drug-related Grade 4 endocrinopathy and Grade 3 adrenal insufficiency requires 
discontinuation.
•
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or total bilirubin), except for the following events, which do not require 
discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis
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−
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
•
Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed.
−
Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued study drug 
dosing.
8.1.2
Daratumumab Discontinuation Criteria 
Daratumumab treatment should be permanently discontinued for the following reasons:
•
Grade 4 infusion reaction related to daratumumab.
•
The 3rd occurrence of a Grade ≥ 3 daratumumab infusion related reaction
•
Participants experiencing ≥ 8-week delay in all study drugs (nivolumab and daratumumab) due 
to an AE(s) related to study treatment must be discontinued from all study treatment. 
Participants experiencing delays unrelated to study therapy, for example due to palliative 
radiation therapy, may delay study treatment up to 84 days. 
•
Any daratumumab related AE that requires a dose hold of >4 weeks during Weeks 1-24 or >6 
weeks during Week 25 and beyond will result in permanent discontinuation of daratumumab, 
unless, upon consultation with the sponsor and the review of safety and efficacy, continuation 
is agreed upon.
Prior to re-initiating treatment in a participant 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. Periodic study visits to assess safety and laboratory studies should also continue 
as scheduled during such dosing delays.
The assessment for discontinuation of study drug should be made separately considering each 
study drug. If discontinuation criteria are attributed with only 1 drug used in this trial, once the 
participant meets criteria to resume therapy, the participant may continue dosing with the 
remaining study drug not attributed to criteria for discontinuation.
If a participant was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate CRF page.
Refer to the Schedule of Activities (Table 2.-3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
8.1.3
Post Study Treatment Study Follow-up
In this study, PFS is a secondary endpoint. Post-study treatment follow-up is of critical importance 
and is essential to preserving participant safety and the integrity of the study. Participants who 
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discontinue study drug must continue to be followed for collection of outcome follow-up data, as 
required and in line with Table 2.-3, withdrawal of consent, or conclusion of the study.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment 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 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants 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 treatment 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 participant 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.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain 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 participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’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 participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9.
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
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•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the Schedule of Activities.
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 
induced liver enzyme evaluations) 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.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the Nivolumab Investigator Brochure.
•
Some of the assessments referred to in this section 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.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the schedule of activities presented in 
Section 2 and Table 9.1.1-1 and Table 9.1.1-2.
Chest, abdomen, pelvis and all known or suspected sites of disease should be assessed at all time 
points. 
Disease assessment with CT and/or MRI, as appropriate, will be performed at baseline and every 
6 weeks up to 24 weeks, and every 12 weeks thereafter until PD, the completion of follow-up, 
initiation of new therapy, or participant withdraw from the study. Tumor responses will be assessed 
by the investigator as defined by RECIST Version 1.1 (see Appendix 7).
At Screening, MRI of the brain without and with contrast is required for participants with known 
or suspected brain metastases. Participants with a history of brain metastasis should have 
surveillance MRI approximately every 12 weeks, or sooner if clinically indicated.
Participants with a history of bone metastasis may have a bone scan, if clinically indicated.
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9.1.1
Imaging Assessment for the Study
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 Study Investigator as per 
standard medical/clinical judgment.
CT and MRI are an essential part of the work-up to establish recurrence. The following imaging 
assessments should be performed at pre-specified intervals: CT of the chest, CT or MRI of the 
abdomen, pelvis, and other known sites of disease 
•
CT scans should be acquired with slice thickness of 5 mm or less with no intervening gap 
(continuous) 
•
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the 
chest and a contrast enhanced MRI of the abdomen and pelvis and other sites of disease 
may be obtained. MRIs should be acquired with slice thickness of 5 mm or less with no 
gap (continuous).
•
Every attempt should be made to image each participant using an identical acquisition 
protocol on the same scanner for all imaging time points. 
•
PET alone will not be considered for the disease assessment. Complementary CT and/or 
MRI or biopsy must be performed in such cases. 
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 (Appendix 7) 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. 
•
Histology or cytological evidence of recurrence should be attempted in all cases except for 
brain metastases. Cytology and/or histology are mandatory to confirm recurrence in 
solitary or in equivocal lesions, any new lesions occurring in the kidney, and lymph nodes 
unless the lesion is too small to biopsy or the risk of biopsy is substantial (eg, inter-aortal 
node with risk of bleed after biopsy because of close proximity to the aorta and IVC) in 
which case the recurrence must be confirmed with a repeat scan 4 weeks later. 
Study evaluations will take place in accordance with Table 9.1.1-2 and Appendix 7.
Tumor assessments will be completed by the investigator using RECIST (Response Evaluation 
Criteria in Solid Tumors) 1.1 criteria, see Appendix 7.
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Table 9.1.1-1:
Acceptable Imaging Assessment Methods for Different Anatomic 
Regions
Anatomic Region
Preferred Method
Alternative Methods
Chest, abdomen, and pelvis
Note: Scan must cover lung apices 
to diaphragm, diaphragm through 
entire liver, and to below the pubic 
symphysis
CT with IV contrast
For chest:
CT without contrast can be used 
only if the participant has a clinical 
contraindication for iodine-based 
IV contrast (eg, hypersensitivity, 
renal insufficiency)
For abdomen and pelvis:
MRI with gadolinium-based IV 
contrast is the first alternative 
method if the participant has a 
clinical contraindication for iodine-
based IV contrast
CT without contrast can be used as 
the second alternative method only 
if the participant has a clinical 
contraindication for both contrast-
enhanced CT and MRI.
Brain
MRI with IV contrast
CT with IV contrast is the first 
alternative method if IV gadolinium 
is clinically contraindicated. 
MRI without contrast can be used 
as a second alternative method if a 
participant has clinical 
contraindications for both contrast-
enhanced CT and MRI
Bone
Bone scintigraphy
PET (18F-fluoride NaF or FDG) or
99m Technetium SPECT
Notes:
1)
CT scans must be performed with slice thickness of ≤5 mm. The reconstruction interval should be equal to slice 
thickness to avoid gap. 
2)
The same modality for a given anatomical coverage and the same scanning procedure (most importantly: 
reconstruction slice thickness, anatomic coverage, use of IV contrast) should be consistent between baseline and 
all subsequent follow-up scanning. If possible, the same scanner or an equivalent scanners should be used 
throughout the study. 
3)
For abdomen and pelvis CT scans, oral contrast is recommended as per institutional standards. 
4)
MRI should include both T1 and T2-weighted sequences with T1-weighted both  pre- and post-contrast. 
5)
If bone scan shows hotspots indicative of metastases, further investigation with X-ray, CT, or MRI is warranted. 
6)
All scans generated should be exportable in electronic format (DICOM) to enable secure and rapid electronic 
transmission to the designated central imaging laboratory. No longer required per Revised Protocol 03.
Imaging restrictions and precautions are described in Section 7.7.2.6.
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Table 9.1.1-2:
Schedule of Spiral CT/MRI Tumor Assessments for advanced and 
Metastatic Cohorts
Tumor Assessment Frequency
Assessment Window
Tumor assessment at screening (within 28 days of first dose), and then every 
6 weeks thereafter up to 24 weeks 
± 1 week
Tumor assessment at week 24 and beyond will be every 12 weeks until PD.
± 2 weeks
For the 3 advanced metastatic tumor cohorts a baseline tumor assessments will be performed 
within 28 days prior to the start of treatment. Participants will then be evaluated for tumor response 
beginning 6 weeks from the date of first dose (± 1 week.), then every 6 weeks (± 1 week.) 
thereafter up to 24 weeks, then it will be every 12 weeks (+/- 2 weeks) until disease progression is 
documented, regardless of early treatment discontinuation due to reasons other than PD, or 
subsequent therapy is initiated (whichever occurs first).
Confirmation Scans are required as follows:
•
Verification of Response: Confirmation of PR and/or CR is required after at least 4 weeks to 
ensure responses identified are not the result of measurement error.
•
Verification of Progression: When not clinically burdensome to the participant, confirmation 
of PD is required after at least 4 weeks to ensure responses identified are not the result of 
measurement error.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until 100 
days after the last treatment, at the timepoints specified in the Schedule of Activities (Section 2). 
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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 participants.
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 participant’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. For participants assigned to treatment and never treated with study drug, 
SAEs should be collected for 30 days from the date of treatment assignment. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure (e.g., 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.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment 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.
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After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant 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 
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 Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner (e.g., 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 24 
hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
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 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
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disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value).
9.2.7
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 (see Section 9.2 and Appendix 3 for reporting 
details).
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.
9.2.8
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.
9.3
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 an SAE (see Section 9.2).
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9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
9.4.1
Physical Examinations
Refer to Schedule of Activities: Section 2.
9.4.2
Vital signs
Refer to Schedule of Activities: Section 2.
9.4.3
Electrocardiograms
Refer to Schedule of Activities: Section 2.
9.4.4
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
A local laboratory will perform the analyses and will provide reference ranges for these tests. 
Results of clinical laboratory tests performed on Day -1 must be available prior to dosing.
•
Results of all laboratory tests required by this protocol must be provided to BMS, recorded 
either on the laboratory pages of the CRF or by another mechanism, as agreed upon between 
the investigator and BMS (eg, provided electronically). If the units of a test result differ from 
those printed on the CRF, the recorded laboratory values must specify the correct units. Any 
abnormal laboratory test result considered clinically significant by the investigator must be 
recorded on the appropriate AE page of the CRF.
The laboratory tests that will be performed for study participants are shown in Table 9.4.4-1
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Table 9.4.4-1:
Clinical Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Blood type (ABO, Rh, and indirect antiglobulin testing) (screening only)
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatininea
Blood Urea Nitrogen (BUN) or serum urea level
Glucose, Phosphate
Albumin
Sodium
Potassium
Chloride
Calcium
Magnesium
Creatinine clearance (CLcr)- screening only
Carbon Dioxide or Bicarbonateb
Amylase and lipase: only for participants with 
pancreatic adenocarcinoma
Urinalysis
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity
pH
Microscopic examination of the sediment if blood, protein or leukocytes esterase are positive on the dipstick
Thyroid Function Tests
TSH (reflex to free T3 and free T4 if abnormal result)
Serology
Hepatitis B surface antigen (HBV sAg, Australia antigen), and hepatitis C antibody (HCV Ab) or HCV 
ribonucleic acid (RNA)HIV-1 and -2 antibody (screening only)
Other Analyses
Pregnancy test (WOCBP only: screening, predose, discharge).
Follicle stimulating hormone (FSH) (screening only for women only) 
a Creatinine clearance measured by 24-hour urine collection or estimated from serum creatinine by the Cockcroft-
Gault formula.
b To be done in sites where this is a standard part of the chemistry panel. In sites where testing for CO2/HCO3 is not 
standard, the test is optional.
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9.4.4.1
Blood Typing 
Blood Type, Rh factor, and Indirect Antiglobulin Test (IAT) should be done before the first dose 
of daratumumab. Participant RBC phenotyping (standard or extended) is an alternative option to 
the IAT test, if locally required.  Either method must be completed prior to first daratumumab 
infusion. Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed  
to identify a patient’s antibodies to minor antigens so that suitable donor blood can be given for 
transfusion. Daratumumab does not interfere with ABO/RhD typing.  CD38 is expressed at very 
low levels on erythrocytes.  Daratumumab binds to the CD38 on erythrocytes, which results in a 
positive IAT (Indirect Coombs Test). This positive result masks the detection of antibodies to 
minor antigens and may prevent or delay blood banks from issuing donor blood for transfusion.  
This effect occurs during daratumumab treatment and for up to 6 months after treatment ends.  
Participants will receive a Participant Alert Card (PAC) for the study that includes the blood profile 
(ABO, Rh, and IAT or phenotyping) determined before the first infusion of daratumumab along 
with information on the IAT interference for healthcare providers/blood banks. Participant are to 
carry the PAC throughout the treatment period and for at least 6 months after treatment ends.  
Blood banks can eliminate the daratumumab IAT interference with IAT by treating reagent RBCs 
with dithiothreitol (DTT).122
Possible methods for blood banks to provide safe RBCs for transfusion to participants receiving 
daratumumab include:
a) Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
b) Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is needed 
emergently as per local blood bank practice. Despite daratumumab binding to CD38 on 
erythrocytes, no indication of clinical significant hemolysis has been observed in daratumumab 
studies.
9.4.5
Safety Assessment
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include signs and symptoms, weight, ECOG Performance Status, 
BP, HR, temperature, and respiratory rate should be performed within 14 days prior to first dose 
except where noted in Table 2.-1. Concomitant medications will also be collected within 14 days 
prior to first dose and through the study treatment and follow-up periods. (See Table 2.-2 and Table 
2.-3). 
Baseline safety laboratory assessments should be done within 14 days prior to the first dose (see
Table 2.-1). Pregnancy testing for WOCBP (done locally) to be done within 24 hours prior to first 
dose, and then every 4 weeks (+/– 1 week) regardless of dosing schedule, and at each safety follow 
up visit.  
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Determination of safety lab results is required prior to dosing. If there are delays with obtaining 
results for certain tests, please contact the medical monitor to determine clinical significance.
Participants will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be performed continuously during the treatment phase. During the safety follow-up phase (see 
Table 2.-3) toxicity assessments should be done in person. 
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.
On treatment vital signs should be monitored extensively on Week 1 and 2 before, during, and
after the first infusion of daratumumab as follows: immediately before the start of the infusion, at 
30 minutes, 1 hour, 90 minutes, 2 hours, and 3 hours 30 minutes after the start of the infusion; at 
the end of the infusion, and 30 minutes, 1 hour, and 2 hours after the end of the infusion. For all 
other cycles, measure vital signs prior to administration of premedication of daratumumab, and 
pre-nivolumab and daratumumab and after the end of the infusion. The start and stop time of the 
nivolumab and daratumumab infusions should be documented. Physical examinations are to be 
performed at treatment visits 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.
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.
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.
9.5
Pharmacokinetic
As of Revised Protocol 03, the collection of pharmacokinetic samples was discontinued. 
 
 
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9.8.2
Immunogenicity Assessments 
As of Revised Protocol 03, the collection of immunogenicity samples is discontinued.
10.
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
Sample size determination is not based on statistical power calculation.
40 participants were to be enrolled to each cohort; enrollment to the NSCLC cohort was closed 
before this target was attained. In this study, an ORR in excess of 10% will be considered of clinical 
interest for TNBC and PAC cohort. An ORR in excess of 20% will be considered of clinical 
interest for NSCLC cohort. 
Assuming the true ORR is 25%, 40 participants in each tumor type can provide approximately 
79.8% power to reject the null hypothesis that the ORR is 10%, considering a 2-sided alpha of 5%.
Assuming the true ORR is 40%, 40 participants in each tumor type can provide approximately 
83.7% power to reject the null hypothesis that the ORR is 20%, considering a 2-sided alpha of 5%.
Table 10.1-1 shows the precision of the estimation of ORR based on the two sided 95% exact CI 
using Clopper-Pearson methods based on 4, 8, 12, 16 and 20 responders out of 40 participants. At 
observed more than or equal to 9 responders, i.e., ORR ≥ 22.5%, the lower bound of the 95% CI 
excludes 10%. At observed more than or equal to 14 responders, i.e., ORR ≥ 35%, the lower bound 
of the 95% CI excludes 20%.
Table 10.1-1:
Two-sided 95% exact CI using Clopper-Pearson Method Based on 
the Number of Observed Responses from 40 participants
Number of 
Observed 
Responses
4
8
12
16
20
Observed 
Response Rate
4/40 (10.0%)
8/40 (20.0%)
12/40 (30.0%)
16/40 (40.0%)
20/40 (50.0%)
95% exact CI 
(%)
(2.8, 23.7 )
(9.1, 35.6)
(16.6, 46.5)
(24.9, 56.7)
(33.8, 66.2)
A sample size of 40 can also detect, with more than 87% probability, a safety event that occurs at 
an incident rate of 5%.
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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
All Treated
All enrolled participants who received at least one dose of study 
drug. This will be both efficacy and safety population.
Safety
All treated participants who received at least one dose of study 
treatment. Participants will be included in the treatment group 
that they actually received
Pharmacokinetic 
Participants
All participants who receive at least one dose of study drug and 
have available serum concentration data
Immunogenicity 
Participants
All treated participants with baseline and at least one post-
baseline immunogenicity assessment for nivolumab or 
daratumumab. 
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
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10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
NA
Secondary
ORR as defined as proportion of participants who achieved a best overall 
response (BOR) of CR or PR before taking any subsequent anti-cancer 
therapy, will be computed in each cohort along with the exact 95% CI using 
Clopper-Pearson method. 
BOR is defined as the best response designation recorded between the date of 
first dose and the date of the initial objectively documented tumor progression 
per investigator assessment using RECIST 1.1 criteria or the date of 
subsequent therapy, whichever occurs first
Duration of response (or complete response) in each cohort will be estimated 
using KM product-limit method for participants who achieve PR or CR (or 
CR only). Median values along with two-sided 95% CI will be calculated.
Investigator-assessed progression free survival (PFS) is defined as the time 
from first dosing date to the date of the first documented tumor progression, 
as determined by investigators (per RECIST 1.1), or death due to any cause. 
Participants who die without a reported progression will be considered to 
have progressed on the date of their death. Participants who did not progress 
or die will be censored on the date of their last tumor assessment. Participants 
who did not have any on study assessments and did not die will be censored 
on the randomization date. A participant who initiates a subsequent anti-
cancer therapy will be censored on the date of last tumor assessment prior or 
on the start date of their subsequent anti-cancer therapy. 
The PFS curve, median and PFS rate at appropriate time points for each 
cohort will be estimated using the Kaplan-Meier product-limit method. Two 
sided, 95% confidence intervals for median PFS will be computed by 
Brookmeyer and Crowley method. A two-sided, 95% confidence interval for 
the PFS rates will be computed by Greenwood method for variance derivation 
and on log-log transformation applied on the survivor function S(t).
10.3.2
Safety Analyses
Safety analyses will be performed in all treated participants. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4.0. All on-study AEs, treatment-related, AEs, SAEs and 
treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v4.0 criteria by 
system organ class and MedDRA preferred term. On-study lab parameters including hematology, 
chemistry, liver function, thyroid function, and renal function will be summarized using worst 
grade per NCI CTCAE v4.0 criteria.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ADA
antidrug antibody 
ADCC
antibody-dependent cellular cytotoxicity
ADCP
antibody-dependent cellular phagocytosis
ADP
adenosine diphosphate
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
AI_AUC
AUC Accumulation Index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax Accumulation Index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
AIDS
acquired immunodeficiency syndrome
ALK
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
APC
anaphase-promoting complex.
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
β-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
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Term
Definition
%BE
percent biliary excretion
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BRCA
breast cancer 1, early onset
Bregs
regulatory B cells
BRt
Total amount recovered in bile
%BRt
Total percent of administered dose recovered in bile
BUN
blood urea nitrogen
C
Celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
CDC
complement-dependent cytotoxicity
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLD
dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
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Term
Definition
CLT/F/fu 
or 
CLT/fu
apparent clearance of free drug or clearance of free if (if IV)
Cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
minimum observed concentration
CMV
cytomegalovirus
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CR
complete response
CRC
Clinical Research Center
CRF
Case Report Form, paper or electronic
CT
computerized tomography
Ct
Expected concentration at a certain time, usually at the end of an 
expected future dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctau
Concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
Trough observed plasma concentration
CV
coefficient of variation
CYP
cytochrome p-450
DCC
detected in colon cancer
D/C
discontinue
DEHP
di(2-ethylhexyl)phthalate
DILI
Drug Induced Liver Injury 
dL
deciliter
DMC
Data monitoring committee
DOR
duration of response
DRt
total amount recovered in dialysate
%DRt
total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
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Term
Definition
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
Eg
exempli gratia (for example)
EGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ER
estrogen receptor
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
%FE
percent fecal excretion
FEV1
forced expiratory volume in 1 second
FFPE
formalin-fixed, paraffin-embedded
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
Foxp3
forkhead box P3 transcription factor
FRt
total amount recovered in feces
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone
Fu
fraction of unbound drug
G
gram
GC
gas chromatography
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
H
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
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Term
Definition
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCO3
bicarbonate
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HPV
human papillomavirus
HR
heart rate
HRT
hormone replacement therapy
IASLC
International Association for the Study of Lung Cancer
IAT
IB
Investigator’s Brochure
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
Ie
id est (that is)
IEC
Independent Ethics Committee
IFN-γ
interferon-γ
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
iNOS
inducible nitric oxide synthase
IP
Investigational product
IRB
Institutional Review Board
IRC
Independent Review Committee
IRRs
infusion related reactions
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
Kg
kilogram
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Term
Definition
λσz
terminal disposition rate constant
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
LDH
lactate dehydrogenase
Ln
natural logarithm
Lz_Start
The time point starting the log-linear elimination phase defining the 
terminal half life
Lz_End
The time point ending the log-linear elimination phase defining the 
terminal half life
Lz_N
Number of time points in the log-linear elimination phase defining the 
terminal half life
MDSCs
myeloid-derived suppressor cells
Mg
milligram
Mg++
magnesium
MI
myocardial infarction
MIC
minimum inhibitory concentration
Min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
MM
multiple myeloma
mmHg
millimeters of mercury
MoA
multiple mechanisms of action
MR
medical research
MR_AUC(0-T)
Ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
MR_AUC(INF)
Ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
Ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
Ratio of metabolite Cmax to parent Cmax, corrected for molecular 
weight
MR_Ctau
Ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
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Term
Definition
MRI
magnetic resonance imaging
MRT
mean residence time
MS
mass spectrometry
MST
medical safety team
MTD
maximum tolerated dose
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
Ng
nanogram
NIMP
non-investigational medicinal products 
NK
natural killer
NKT
natural killer T 
NO
nitric oxide 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PAC
pancreatic adenocarcinoma
PARP
poly ADP ribose polymerase
pAUCe
Extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PBMC
peripheral blood mononuclear cell
PCP
Pneumocystis carinii pneumonia
pCR
complete pathological response
PD
pharmacodynamics; progressive disease
PD-L1
programmed death-ligand 1 
PD-L2
Programmed death-ligand 2
PFS
promising clinical outcomes???  progression-free survival
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Term
Definition
PID
patient identification number 
PK
Pharmacokinetics
PO
per os (by mouth route of administration)
PPK
population PK
PR
progesterone receptor; partial response
PT
prothrombin time
PTT
partial thromboplastin time
Pu
percent of unbound drug
PVC
polyvinyl chloride
QC
quality control
QD, qd
quaque die, once daily
R2
coefficient of determination
RBC
red blood cell
RCC
renal cell carcinoma
ROS
of reactive oxygen species
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation; stable disease
SOP
Standard Operating Procedures
sp.
Species
Subj
Subject
SUSAR
Suspected, Unexpected Serious Adverse Reaction
T
Temperature
T
Time
T3
tri-iodothyronine
T4
thyroxine
TAO
Trial Access Online, the BMS implementation of an EDC capability
TCR
T-cell receptor
T-HALF
Half life
T-HALFeff_AUC
Effective elimination half life that explains the degree of AUC 
accumulation observed
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Term
Definition
T-HALFeff_Cmax
Effective elimination half life that explains the degree of Cmax
accumulation observed)
TIA
transient ischemic attack
TID, tid
ter in die, three times a day
TIL
tumor-infiltrating lymphocytes
TKI
tyrosine kinase inhibitor
Tmax, TMAX
time of maximum observed concentration
TME
tumor microenvironment
TNBC
triple-negative breast cancer
TPC
treatment of physician’s choice
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
Tregs
regulatory T cells
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
%URt
total percent of administered dose recovered in urine
UV
Ultraviolet
Vss/F (or Vss)
apparent volume of distribution at steady state
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
Washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
x g
times gravity
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APPENDIX 2
STUDY GOVERANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee 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 (e.g., loss of medical licensure, debarment). 
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, participant recruitment materials (e.g., 
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, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) 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 relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (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).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
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 participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (i.e., 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:
•
Provide a copy of the consent form and written information about the study in the language 
in which the participant is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the 
participant's legally acceptable representative and by the person who conducted the 
informed consent discussion. 
•
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.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant'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 participant records. 
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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SOURCE DOCUMENTS
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. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
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If
Then
Supplied by BMS (or its vendors):
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 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (e.g., 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.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.   
These records should include:
•
label identification number or batch 
number 
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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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 Sponsor or designee 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 electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee.
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. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. 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 Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee 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.
In addition, the study may be evaluated by Sponsor or designee 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.
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The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) 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 or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g.,
cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
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It is the investigator’s or designee’s responsibility to arrange for disposal, 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. 
The following minimal standards must be 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, i.e., 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.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
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
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (e.g., among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (e.g., 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 Sponsor or designee. 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 
Sponsor or designee 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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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant 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.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant 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)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
o
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)
o
elective surgery, planned prior to signing consent
o
admissions as per protocol for a planned medical/surgical procedure
o
routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)
o
medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases
o
admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason)
o
admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols)
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 participant or may require intervention [e.g., 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 9.2.7 for the definition of potential DILI.) 
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Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment 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 9.2.5
for reporting pregnancies).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (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. 
Follow-up of AEs and SAEs
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, the SAE report must be updated and submitted within 24 
hours to BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
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.
o
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. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state 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.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment. 
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
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•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
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•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
ECOG PERFORMANCE STATUS CRITERIA 
0 
Fully active; able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
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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 other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion.
1.4
Specifications by methods of measurements
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 30 days before the 
beginning of the 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.
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.
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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 by both 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 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.
1.4.2.6
Tumor markers 
Tumor markers alone cannot be used to assess objective tumor response. 
1.4.2.7
Cytology, histology
The results of cytology or histology may be utilized to inform individual timepoint response
assessments. 
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.
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 
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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 record form (e.g. ‘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
Special notes on the assessment of target lesions
3.1.1.1
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.
3.1.1.2
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 (e.g. 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:
•
if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 
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•
if the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).   
3.1.1.3
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 may be maintained that would aid in obtaining 
maximal diameter measurements of each 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).
3.2.1
Special notes on assessment of non-target lesions
The concept of progression of non-target disease requires additional explanation as follows:
Fluid Collections:
Effusions and Ascites: At each time point, radiologists will check for the presence or absence 
of effusions/ascites.  Pleural effusions, pericardial effusions and ascites will not be followed 
as target or non-target lesions and will not contribute to response or progression.
3.2.1.1
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. 
3.2.1.2
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. 
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•
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: i.e. 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. 
3.2.1.3
Tumor markers
Tumor markers alone cannot be used to assess objective tumor responses.
3.3
New lesions  
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal: i.e. 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 pre-existing 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 report 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.
3.3.1
FDG-PET evaluation
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of the qualitative assessment of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible ‘new’ disease). New lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm: 
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
•
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
−
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
−
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
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occurring at that site (if so, the date of PD will be the date of the initial positive FDG-PET 
scan).
−
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.
4.
RESPONSE CRITERIA
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline Table 1 provides a summary of the overall 
response status calculation at each time point.
Table 1:
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.
4.1.1
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 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.
•
Confirmation of PR and CR is required after at least 4 weeks to ensure responses identified 
are not the result of measurement error.  
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4.1.2
Confirmation Scans
•
Verification of Response: Confirmation of PR and/or CR is required after at least 4 weeks to
ensure responses identified are not the result of measurement error.
•
Verification of Progression: When not clinically burdensome to the subject, confirmation of
PD is required after at least 4 weeks to ensure responses identified are not the result of
measurement error.
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4.2
Best overall response: All timepoints
The best overall response is determined once all the data for the subject is known. It is the best 
response recorded from the start of the study treatment until the end of treatment taking into 
account any requirement for confirmation. The subject’s best overall response assignment will 
depend on the findings of both target and non-target disease and will also take into consideration 
the appearance of new lesions. 
Best response is defined as the best response across all time points with subsequent confirmation. 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later). 
In this circumstance, the best overall response can be interpreted as specified in Table 2. When SD 
is believed to be best response, it must meet the protocol specified minimum time from baseline.
Measurements must have met the SD criteria at least once after study entry at a minimum interval 
that is defined in the study protocol.
Table 2:
Best overall response when confirmation of CR 
and PR IS required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SDb
duration met, otherwise, PD
CR
PD
SD provided minimum criteria for SDb
duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SDb
duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
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Table 2:
Best overall response when confirmation of CR 
and PR IS required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time 
point
PR
PD
SD provided minimum criteria for SDb
duration met, otherwise, PD
PR
NE
SD provided minimum criteria for SDb
duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
b Minimum criteria for SD duration is 5 weeks (35 days).
4.3
Duration of response
The duration of overall response is measured from the time measurement criteria are first met for
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is
objectively documented (taking as reference for progressive disease the smallest measurements
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are
first met for CR until the first date that recurrent disease is objectively documented.
4.3.1
Duration of overall response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
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4.3.2
Duration of stable disease  
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
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