A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Nivolumab or Nivolumab Plus Cisplatin, in Combination With Radiotherapy in Participants With Cisplatin Ineligible and Cisplatin Eligible Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Phase: PHASE3
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: Bristol-Myers Squibb



Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Revised Protocol No.: 03
Date: 16-Nov-2018
2
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions. 
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Revised Protocol No.: 03
Date: 16-Nov-2018
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 03
16-Nov-2018
•
Enrollment in the study was closed as of 15-Oct-2018. Revised Protocol 
03 covers the changes implemented to the protocol post study enrollment 
closure: study treatment unblinding, removal of placebo treatment, and 
removal of analysis of efficacy end-points and efficacy follow-up. 
Revised 
Protocol 02
21-Feb-2018
•
Added exclusion of participants with active interstitial lung disease (ILD) 
/ pneumonitis or with a history of ILD / pneumonitis requiring steroids.
•
Aligned thyroid testing to study visits.
•
Added guidance for premedications for cetuximab if necessary.
Revised 
Protocol 01
01-Nov-2017
Update to questionnaire administration updated to align with dosing cycles.  
Outcome research assessment and endpoints redefined updated to align with 
analysis planned.  TNM Staging clarified for high and intermediate risk 
definition.  Other minor corrections, clarifications
Original 
Protocol
15-Aug-2017
Not applicable
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12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 6 TNM STAGING ACCORDING TO AJCC VERSION 8 .................... 
APPENDIX 7 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 8 COUNTRY SPECIFIC APPENDIX..................................................... 
APPENDIX 9 NECK DISSECTION GUIDELINES ................................................... 
APPENDIX 10 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
APPENDIX 11 HEAD AND NECK SQUAMOUS CELL CARCINOMAS 
CLASSIFIED AS FOLLOWS: ............................................................................... 
APPENDIX 12 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
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Clinical Protocol
BMS-936558
CA2099TM
nivolumab
Revised Protocol No.: 03
Date: 16-Nov-2018
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
•
HPV p16 test result available (performed locally or centrally) for participants with 
oropharyngeal disease
•
Patients must be of intermediate or high risk categories*:
•
High risk:
Oral cavity, hypopharynx, larynx, oropharynx (p16 negative): Stage III/ IV
Oropharynx (p16 positive): Stage III (T4 any N or T1-3 N3) - irrespective of smoking status.
•
Intermediate risk:
−
Oropharynx (p16 positive): T3 N0-2 or T1-3 N2 disease if smoking > 20 pack year history.
*TNM clinical staging according to AJCC version 8
Cohort 1 (cisplatin-ineligible participants) Specific Inclusion Criteria (Arm A and Arm B)
•
Physician assesses participant to be non-eligible for treatment with platinum based combined 
CRT. This must be for one or more of the following reasons:
−
Age ≥70 years at enrolment
−
Creatinine clearance < 60mL/min and > 30mL/min (using the Cockcroft and Gault 
formula– see below**)
−
Severe hearing loss (minimal hearing threshold of 80 dB or more in either ear)
Cohort 2 (cisplatin-eligible participants) Specific Inclusion Criteria (Arm C and Arm D)
•
Adequate renal function within 28 days prior to randomization as follows:
−
Creatinine clearance ≥60 mL/min. as determined by 24 hour collection or estimated by 
Cockcroft-Gault formula:
CCr={((140–age in years) x weight in Kg)/(72 x serum creatinine in mg/dL)}
(for females, multiply the result by 0.85)**
**Participants aged ≥ 70 years may enter either Cohort 1 or 2 dependent on whether the physician’s assessment is that 
the participant is eligible for cisplatin (Cohort 2) or ineligible for cisplatin (Cohort 1) based on their age. It is 
anticipated that in the majority of cases, patients aged ≥ 70 years will be considered ineligible for cisplatin and 
enter cohort 1.  If the subject has poor renal function as one of the acceptable inclusion criteria, the subject will 
be enrolled under inclusion criteria 3) ii) and must meet the requirement for Creatinine clearance < 60 mL/min 
and > 30mL/min (using the Cockcroft and Gault formula).
Key Exclusion Criteria:
•
Carcinoma originating in the nasopharynx or paranasal sinus, squamous cell carcinoma that 
originated from the skin and salivary gland or non-squamous histology (eg, mucosal 
melanoma), squamous cell carcinoma of unknown primary
•
Clinical or radiological evidence of metastatic disease
•
Prior radiotherapy that overlaps with radiation fields
Revised Protocol No.: 03
Date: 16-Nov-2018
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
•
Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair the 
ability of the participant to receive protocol therapy, or interfere with the interpretation of study 
results
•
Active unstable angina and/or congestive heart failure
•
Myocardial infarction within 6 months prior to randomization
•
Participants who have a weight loss of > 10% of body weight between screening and 
randomization will be considered a screen failure. 
•
Participants with an active, known or suspected autoimmune disease. Participants with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such 
as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected 
to recur in the absence of an external trigger are permitted to enroll.
•
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
•
Participants with active interstitial lung disease (ILD) / pneumonitis or with a history of ILD / 
pneumonitis requiring steroids.
Objectives and Endpoints: Not Applicable per Revised Protocol 03
Overall Design: Study CA2099TM was a randomized, double-blinded, placebo-controlled, phase 
3 study of nivolumab or nivolumab plus cisplatin, in combination with radiotherapy in participants 
with cisplatin ineligible and cisplatin eligible locally advanced squamous cell carcinoma of the 
head and neck (LAD SCCHN).
As of 15-Oct-2018, enrollment into the study was closed. At implementation of Revised Protocol 
03, the study will be unblinded. Placebo treatments will no longer be given. 
Participants will be stratified by risk group (intermediate versus high risk SCCHN). 
•
Intermediate risk participants will be defined as those with p16-positive oropharyngeal cancer 
with T3 N0-2 or T1-3 N2 disease if smoking > 20 pack year history.
•
High risk participants are defined as participants with tumors arising in the oral cavity, larynx, 
hypopharynx, or p16-negative oropharynx and Stage III/IV or Oropharynx (p16 positive): 
Stage III (T4 any N or T1-3 N3) - irrespective of smoking status. 
All staging will be according to AJCC 8 guidelines. 
See study design schematic below.
Number of Participants: Per Revised Protocol 03, sample size will be limited to participants that 
have signed an informed consent as of 15-Oct-2018. 
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Date: 16-Nov-2018
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Number of Events and Power: Not applicable per Revised Protocol 03. No analyses of efficacy 
will be conducted. 
Treatment Arms and Duration:
Study treatment: 
Study Drug for CA2099TM
Product Description / Class and 
Dosage Form
Potency 
IP/Non-IP 
Nivolumab Solution for Injectiona
10 mg/mL – 100 mg fill volume
IP
Cetuximab Solution for Infusionb
5 mg/mL - 500 mg fill volume
IP
Cisplatin Concentrate for Solution for 
infusionb
1 mg/mL – 100 mg fill volume
IP
a May be labeled as either “BMS-936558-01” or “Nivolumab.”
b These products may be obtained by the investigational sites as local commercial product in certain countries if 
allowed by local regulations. In these cases, products may be a different pack size/potency than listed in the table. 
These products should be prepared/stored/administered in accordance with the package insert or summary of 
product characteristics (SmPC) or according to institutional standards.
Revised Protocol No.: 03
Date: 16-Nov-2018
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Study Design Schematic for CA2099TM:
*As of 15-Oct-2018, enrollment in the study is closed. Participants with signed informed consent as of that date will be permitted to be randomized, and participants 
currently on treatment may continue. All participants should be reconsented under the current Revised Protocol 03. Only safety assessments will be conducted.
Upon approval and implementation of Revised Protocol 03, placebo treatments will no longer be given. 
Abbreviations: C=cycle; Cis=cisplatin; CRCL=creatinine clearance; d=day; ECOG PS= Eastern Cooperative Oncology Group performance status; IMRT=
Intensity-modulated radiation therapy; Int.=Intermediate; IV=intravenous; PD-L1= Programmed death-ligand 1; Q1W=every week; Q2W=every 2 weeks; q21 
days=every 21 days; Q3W=every 3 weeks, Q4=every 4 weeks; SCCHN= squamous cell carcinoma of the head and neck; w or W=week
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Participants in Cohort 1 (cisplatin ineligible) will be randomized 1:1 to either Arm A or Arm B:
•
Arm A will be administered nivolumab 240 mg for a single dose at w1d1 (C1 of cohort 1) then 
nivolumab 360 mg every 3 weeks for a total of 3 doses starting at w3d1 (C3, C6, C9 of cohort 
1). Then, participants will be administered nivolumab 480 mg every 4 weeks for a total of 6 
doses.
•
Arm B will be administered cetuximab 400 mg/m2 as a single dose at w2d1 (C2 of cohort 1) 
then 250 mg/m2 IV every week for a total of 7 doses starting at w3d1 (C3 to C9 of cohort 1) 
with IMRT.
Participants in Cohort 2 (cisplatin eligible) will be randomized 1:1 to either Arm C or Arm D.
•
Arm C will be administered nivolumab 240 mg for a single dose at w1d1 (C1 of cohort 2) then 
nivolumab 360 mg every 3 weeks for a total of 3 doses starting at w3d1 (C2, C3, C4 of cohort 
2). In addition, participants will be administered cisplatin 100 mg/m2 every 21 days for 3 doses 
starting at w3d1 (C2 of cohort 2) with IMRT. Then, participants will be administered 
nivolumab 480 mg every 4 weeks for a total of 6 doses.
•
Arm D will be administered cisplatin 100 mg/m2 every 21 days for 3 doses starting at w3d1 
(C2 of cohort 2) with IMRT. 
Participants in Cohort 1 (cisplatin ineligible) and Cohort 2 (cisplatin eligible) will receive RT to a 
total dose of 70 Gy in 35 fractions which will be administered in daily doses of 2 Gy, typically on 
a 5 days on / 2 days off schedule as appropriate, over 7 weeks by Intensity Modulated Radiation 
Therapy (IMRT) starting at w3d1. Alternate fractionation schemes are not allowed.
Participants who are randomized to a placebo arm do not need to delay the start of radiotherapy. 
For subjects randomized to Cohort 1 Arm B, cetuximab may be administered at w1d1 and 
radiotherapy at w2d1. For participants randomized to Cohort 2 Arm B, cisplatin and radiotherapy 
may begin at w1d1.
Imaging will occur at baseline (within 28 days prior randomization. Per Revised Protocol 03, 
subsequent imaging assessments should be performed according to the timing of local standard of 
care. 
The Follow-up stage begins when protocol specific treatment with nivolumab is completed or the 
decision to discontinue a participant from study therapy is made (no further treatment with study 
therapy). Participants will have the first follow-up visits (FU1 and FU2) approximately 30 days 
and 100 days, respectively, from the last dose of study therapy or coinciding with the date of 
discontinuation and AEs will be followed until the toxicities resolve, return to baseline, or are 
deemed irreversible.
All participants should continue to have tumor scans per local standards of care. .
A Data Monitoring Committee (DMC) will be utilized to provide general study oversight, to 
monitor safety on an on-going basis.
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Date: 16-Nov-2018
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Participants MUST discontinue study treatment for 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.
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2099TM)
Effective as of 15-Oct-2018, enrollment in the study is closed. Participants who have already signed an informed consent as of 15-Oct-2018 will have 
the option to begin treatment (see Section 3.1.1)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
A participant is considered enrolled only when a protocol specific informed consent is signed.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed and confirmed prior to randomization.
Medical History
X
Include any history (e.g., toxicities, allergies, tobacco use, pre-study testing, and documented hearing loss 
as applicable) relevant to the participant’s current state of health and the disease under study. Also, any 
history related to previous treatments.
Abbreviated Comprehensive 
Geriatric Assessment (aCGA) –G-8
(for Cohort 1 only)
X
For cohort 1 only. Prior to randomization. See Section 5.1.
Tumor Tissue Sample 
(for stratification by PD-L1 tumor 
expression and HPV p16)
X
A tumor sample prior to therapy is mandatory for PD-L1 testing (to be shipped to central lab) and HPV p-
16 testing for participants with oropharyngeal CA (sample either tested locally or shipped to Central Lab).
If a recent tumor sample (obtained within 3 months of enrollment) is not available at screening, a fresh 
biopsy will be taken prior to randomization. Sufficient tumor tissue should be submitted - either two full 
block or minimum of 25 slides preferred, obtained from core biopsy, punch biopsy, excisional biopsy or 
surgical specimen. Biopsies of bone lesions that do not have a soft tissue component are unacceptable for 
submission. See Section 9.8.2. As of 15-Oct-2018, and approval and implementation of Revised Protocol 
03, tumor samples will not be collected from any participant still in the screening period.
Radiological Tumor Assessment
(i.e., neck, chest, abdomen, pelvis)
X
Performed within 28 days prior to randomization. See Section 9.1.1.
TNM staging according to AJCC version 8 (Appendix 6).
Brain Imaging
X
Performed at screening for all participants to rule out brain metastasis. See Section 9.1.1.
Head and Neck Examination
X
For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror and/or fiber 
optic and/or direct procedure) prior to randomization is required, unless the participant cannot tolerate or 
refuses.
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099TM)
Effective as of 15-Oct-2018, enrollment in the study is closed. Participants who have already signed an informed consent as of 15-Oct-2018 will have 
the option to begin treatment (see Section 3.1.1)
Procedure
Screening
Visita
Notes
Multidisciplinary Case Evaluation
X
Multidisciplinary case evaluation, should include radiation oncology, medical oncology and ENT/head 
and neck surgeon or equivalent functions prior to randomization.
Creatinine Clearance Assessment
X
Using Cockroft and Gault formula within 28 days prior to randomization See Section 9.4.1.
Safety Assessments
Physical Examination
X
Includes height, weight, and ECOG Performance Status (Appendix 7) within 14 days prior to 
randomization.
Vital Signs
X
Temperature, blood pressure and heart rate within 14 days prior to randomization.
ECG (for Cohort 1 only)
X
For cohort 1 only. Within 14 days prior to randomization.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Concomitant Medication Use
X
Within 14 days prior to randomization.
Serious Adverse Events Assessment
X
Begins at the time of consent. See Section 9.2.1.
Laboratory Tests
X
See Section 9.4.1 for additional details on tests required. Must be performed within 14 days prior to 
randomization:
•
Complete Blood Cell (CBC) with differential
•
Chemistry panel 
•
Thyroid panel including TSH, free T4, free T3
Hepatitis B and C Testing
X
See Section 9.4.1 for additional details on tests required. Hepatitis B surface antigen (HBV sAg), hepatitis 
C antibody (HCV Ab) or Hepatitis C RNA (HCV RNA) within 28 days prior to randomization.
HIV Testing
X
Testing for HIV must be performed at sites where mandated locally. See Section 9.4.1 and Appendix 8.
Pregnancy Test 
X
WOCBP only: Serum or urine test (minimum sensitivity 25 IU/L or equivalent units of HCG) to be done 
at screening visit and repeated within 24 hours of first dose. See Section 9.4.1.
a 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.
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CA2099TM
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline for Cohort 1 Arms A and B (CA2099TM)
Effective as of 15-Oct-2018, enrollment in the study is closed. Participants who have already signed an informed consent as of 15-Oct-2018 will have 
the option to begin treatment. Per Revised Protocol 03, placebo treatment will no longer be given. 
Procedurea
Cycles 1 to 9 each = 1 weekb
C10 to C15b
(each cycle=4 
weeks)
Visit at the 
start of the 
cycle
Notes
Procedures must be done within 72 hrs. prior to dosing 
unless otherwise specified
Study visits to occur at the start of each cycle, weekly up to 
and including C9 for cohort 1 (± 3 days) then every 4 
weeks from C10 to C15 for cohort 1 (± 7 days). C10 for
cohort 1 to start 3 weeks after the start of C9.
Cycles will differ between Cohorts.
C1
C2
C3
C4 -
C5
C6
C7 -
C8
C9
Safety Assessments
Informed Consent
Following study closure, participants already enrolled in the study will require re-consent upon implementation of Revised 
Protocol 03.
Targeted Physical 
Examination
X
X
X
X
X
X
X
X
Should be performed by a qualified professional guided by the 
examiner’s observations and/or participant complaints on new 
or changed conditions, symptoms, or concerns. Includes 
height, weight and ECOG performance status (Appendix 7). 
The dosing calculations should be based on the body weight. 
If the participant’s weight on the day of dosing differs by 
> 10% from the weight used to calculate the dose, the dose 
must be recalculated. All doses should be rounded to the 
nearest milligram.
Vital Signs
X
X
X
X
X
X
X
X
Temperature, blood pressure and heart rate
Assessment of Signs and 
Symptoms
X
X
X
X
X
X
X
X
Concomitant Medication 
Use
X
X
X
X
X
X
X
X
Serious Adverse Events 
Assessment
X
X
X
X
X
X
X
X
Adverse Events 
Assessment
X
X
X
X
X
X
X
X
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Clinical Protocol
CA2099TM
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline for Cohort 1 Arms A and B (CA2099TM)
Effective as of 15-Oct-2018, enrollment in the study is closed. Participants who have already signed an informed consent as of 15-Oct-2018 will have 
the option to begin treatment. Per Revised Protocol 03, placebo treatment will no longer be given. 
Procedurea
Cycles 1 to 9 each = 1 weekb
C10 to C15b
(each cycle=4 
weeks)
Visit at the 
start of the 
cycle
Notes
Procedures must be done within 72 hrs. prior to dosing 
unless otherwise specified
Study visits to occur at the start of each cycle, weekly up to 
and including C9 for cohort 1 (± 3 days) then every 4 
weeks from C10 to C15 for cohort 1 (± 7 days). C10 for
cohort 1 to start 3 weeks after the start of C9.
Cycles will differ between Cohorts.
C1
C2
C3
C4 -
C5
C6
C7 -
C8
C9
Radiotherapy (RT)
X
X
X
X
X
IMRT: 70 Gy, 35 fractions over 7 weeks from w3d1 (C3 for 
cohort 1). Alternate Fractionation Schemes are not permitted.
The first fraction of RT should be delivered on a Monday or 
Tuesday, but this may vary according to local treatment plan. 
Five fractions should be delivered a week. Randomization and 
dosing should be timed such that the first dose of nivolumab 
occurs 14 days ± 3 days prior to the start of RT. See Section 
7.1.4.
Abbreviations: c or C=cycle; d or D=day; IV=intravenous; Q1W=every week; Q3W=every 3 weeks; Q4W=every 4 weeks; w or W=week
a 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.
b If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
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BMS-936558
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Table 2-3:
On Treatment Procedural Outline for Cohort 2 Arms C and D (CA2099TM)
Procedurea
Cycle 1 
(C1)
(cycle=2 
weeks)
C2 - C4 b
(each cycle= 
3 weeks)
C5 to C10b
(each 
cycle=4 
weeks)
Notes
Procedures must be done within 72 hrs. prior to dosing unless otherwise 
specified
Study visits to occur at the start of each cycle [i.e., for C2 to C4 for cohort 
2 (± 3 days) and for C5 to C10 for cohort 2 (± 7 days).
Cycles will differ between Cohorts.
Effective as of 15-Oct-2018, enrollment in the study is closed. Participants who have already signed an informed consent as of 15-Oct-2018 will have 
the option to begin treatment. Per Revised Protocol 03, placebo treatment will no longer be given.
Safety Assessments
Informed Consent
Following study closure, participants already enrolled in the study will require re-consent upon implementation of Revised 
Protocol 03.
Targeted Physical 
Examination
X
X
X
Should be performed by a qualified professional guided by the examiner’s 
observations and/or subject complaints on new or changed conditions, 
symptoms, or concerns. Includes height, weight and ECOG performance status 
(Appendix 7). 
The dosing calculations should be based on the body weight. If the 
participant’s weight on the day of dosing differs by > 10% from the weight 
used to calculate the dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram.
Vital Signs
X
X
X
Temperature, blood pressure and heart rate
Assessment of Signs and 
Symptoms
X
X
X
Concomitant Medication Use
X
X
X
Serious Adverse Events 
Assessment
X
X
X
Adverse Events Assessment
X
X
X
Laboratory Tests
X
X
X
CBC with differential and Chemistry panel. See Section 9.4.1 for additional 
details on tests required. 
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BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline for Cohort 2 Arms C and D (CA2099TM)
Procedurea
Cycle 1 
(C1)
(cycle=2 
weeks)
C2 - C4 b
(each cycle= 
3 weeks)
C5 to C10b
(each 
cycle=4 
weeks)
Notes
Procedures must be done within 72 hrs. prior to dosing unless otherwise 
specified
Study visits to occur at the start of each cycle [i.e., for C2 to C4 for cohort 
2 (± 3 days) and for C5 to C10 for cohort 2 (± 7 days).
Cycles will differ between Cohorts.
Administer Cisplatin (for 
Cohort 2 only)
X
For cohort 2 only, administer cisplatin 100 mg/m2 every 21 days x 3 doses in
C2, C3, and C4. See Section 7.
Radiotherapy (RT)
X
IMRT: 70 Gy, 35 fractions over 7 weeks from w3d1 (C2). Alternate 
Fractionation Schemes are not permitted).
The first fraction of RT should be delivered on a Monday or Tuesday, but this 
may vary according to local treatment plan. Five fractions should be delivered 
a week. Randomization and dosing should be timed such that the first dose of 
nivolumab occurs 14 days ± 3 days prior to the start of RT. See Section 7.1.4.
Abbreviations: c or C=cycle; d or D=day; IV=intravenous; Q1W=every week; Q3W=every 3 weeks; Q4W=every 4 weeks; w or W=week
a 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.
b If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
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3
INTRODUCTION
CA2099TM was a randomized, double blind, placebo controlled, Phase 3 study of nivolumab or 
nivolumab plus cisplatin, in combination with radiotherapy in participants with cisplatin ineligible 
and cisplatin eligible locally advanced squamous cell carcinoma of the head and neck (SCCHN).
The study consists of two independent cohorts: 
•
Cohort 1 will randomize participants who are ineligible for cisplatin chemotherapy based 
either on age (≥70 years), and/or poor renal function (Creatinine clearance < 60 mL/min),
and/or have documented hearing loss (minimal hearing threshold of 80 dB or more in either 
ear) to receive nivolumab in combination with radiotherapy (RT) or cetuximab in combination 
with RT.
•
Cohort 2 will randomize participants who are eligible to receive cisplatin based therapy to 
receive nivolumab or placebo in combination with cisplatin and RT. 
As of 15-Oct-2018, enrollment into the study was closed (see Section 3.1.1). Participants who have 
signed an informed consent as of 15-Oct-2018 and are in the screening period will be able to be 
randomized. All participants receiving treatment will have the option to continue treatment under 
the updated Revised Protocol 03. At approval and implementation of Revised Protocol 03, all 
enrolled participants must be re-consented prior to continuing treatment on the study. Under 
Revised Protocol 03 only safety assessments will be conducted as part of study procedures.
Participants will be monitored until 100 days post-last dose. 
 
 
 
 
 
 
 
 
 
 
 
 
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participants with cisplatin ineligible and cisplatin eligible locally advanced squamous cell 
carcinoma of the head and neck (LAD SCCHN).
As of 15-Oct-2018, enrollment into the study was closed. At implementation of Revised Protocol 
03, the study will be unblinded. Placebo treatments will no longer be given. 
For Cohort 1 (cisplatin ineligible), participants must be either age ≥70 years, and/or have 
creatinine clearance < 60 mL/min, and/or have documented hearing loss (minimal hearing 
threshold of 80 dB or more in either ear). There is no minimum or maximum number of participants 
that must fulfill any of these criteria. For Cohort 2 (cisplatin eligible), participants eligible for 
cisplatin based CRT must have cisplatin eligible disease. 
Participants will be stratified as follows:
•
Cohort 1 (cisplatin ineligible), participants will be stratified by PD-L1 tumor expression (≥1% 
vs < 1% or indeterminate), risk category (intermediate vs. high risk), and Eastern Cooperative 
Oncology Group performance status (ECOG PS [0 vs 1]) and randomized in a 1:1 ratio to one 
of the study arms (Arms A or B). 
•
Cohort 2 (cisplatin eligible), participants will be stratified by PD-L1 tumor expression (≥1% 
vs < 1% or indeterminate) and risk category (intermediate vs. high risk), and ECOG PS [0 vs 
1]) and randomized in a 1:1 ratio to one of the study arms (Arms C or D). 
HPV p16 testing can be performed locally or centrally and is required for entry into the study for 
participants with oropharyngeal disease. For subjects with oropharyngeal cancer, sites are defined 
in Appendix 11.
After participants sign an informed consent, a tumor sample collection is mandatory for PD-L1 
testing (shipped to a central lab). Sufficient, recent tumor tissue obtained within < 3 months prior 
to enrollment from a primary tumor lesion which has not been previously irradiated (formalin-
fixed paraffin-embedded block or minimum of 25 slides preferred, obtained from core biopsy, 
punch biopsy, excisional biopsy or surgical specimen) must be received by a central lab. If the 
archival tissue is > 3 months old, a fresh biopsy must be obtained from core biopsy, punch biopsy, 
excisional biopsy or surgical specimen to obtain sufficient tissue sample for PD-L1 testing (two
block or minimum of 25 slides preferred). Fine needle aspiration cytology is not acceptable. 
Biopsies of bone lesions that do not have a soft tissue component are unacceptable for submission.
Participants should not have received any systemic anticancer therapy after the date that the 
submitted tumor tissue was obtained. The PD-L1 analysis must be processed with an available 
result prior to randomization..
A multidisciplinary case evaluation, including input from radiation oncology, medical oncology 
and ENT/head and neck surgeon or equivalent functions is required prior to randomization
(patients should have been seen by each of these groups or discussed at a multidisciplinary tumor 
board meeting). For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy 
(mirror and/or fiber optic and/or direct procedure) prior to randomization is required unless the 
participant cannot tolerate or refuses.
 
 
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The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic for CA2099TM*
*As of 15-Oct-2018, enrollment in the study is closed. Participants who have signed an informed consent as of that date will be permitted to be randomized, and 
participants currently on treatment may continue. All participants should be re-consented under the current Revised Protocol 03. Only safety assessments will 
be conducted.
Upon approval and implementation of Revised Protocol 03, placebo treatments will no longer be given. 
Abbreviations: C=cycle; Cis=cisplatin; CRCL=creatinine clearance; d=day; ECOG PS= Eastern Cooperative Oncology Group performance status; IMRT=
Intensity-modulated radiation therapy; Int.=Intermediate; IV=intravenous; PD-L1= Programmed death-ligand 1; Q1W=every week; Q2W=every 2 weeks; q21 
days=every 21 days; Q3W=every 3 weeks, Q4=every 4 weeks; SCCHN= squamous cell carcinoma of the head and neck; w or W=week
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Participants in Cohort 1 (cisplatin ineligible) will be randomized 1:1 to either Arm A or Arm B:
•
Arm A will be administered nivolumab 240 mg for a single dose at w1d1 (C1 of cohort 1) then 
nivolumab 360 mg every 3 weeks for a total of 3 doses starting at w3d1 (C3, C6, C9 of cohort 
1). Then, participants will be administered nivolumab 480 mg every 4 weeks for a total of 6 
doses.
•
Arm B will be administered cetuximab 400 mg/m2 as a single dose at w2d1 (C2 of cohort 1) 
then 250 mg/m2 IV every week for a total of 7 doses starting at w3d1 (C3 to C9 of cohort 1)
with IMRT.
Participants in Cohort 2 (cisplatin eligible) will be randomized 1:1 to either Arm C or Arm D.
•
Arm C will be administered nivolumab 240 mg for a single dose at w1d1 (C1 of cohort 2) then 
nivolumab 360 mg every 3 weeks for a total of 3 doses starting at w3d1 (C2, C3, C4 of cohort 
2). In addition, participants will be administered cisplatin 100 mg/m2 every 21 days for 3 doses 
starting at w3d1 (C2 of cohort 2) with IMRT. Then, participants will be administered 
nivolumab 480 mg every 4 weeks for a total of 6 doses.
•
Arm D will be administered cisplatin 100 mg/m2 every 21 days for 3 doses starting at w3d1 
(C2 of cohort 2) with IMRT. 
Participants in Cohort 1 (cisplatin ineligible) and Cohort 2 (cisplatin eligible) will receive RT to a 
total dose of 70 Gy in 35 fractions which will be administered in daily doses of 2 Gy, typically on 
a 5 days on / 2 days off schedule as appropriate, over 7 weeks by Intensity Modulated Radiation 
Therapy (IMRT) starting at w3d1. Alternate fractionation schemes are not allowed. Sites must be 
equipped and qualified to deliver standard of care radiotherapy in combination to the specified 
systemic agents. Radiotherapy will be subject to a Quality Assurance (QA) process. This will 
involve site qualification/credentialization and real time review of radiotherapy plans with real 
time feedback to sites. On completion of radiotherapy all data must be submitted for final analysis. 
The radiotherapy requirements and QA processes will be the subject of a separate manual. QA 
services will be provided by an external vendor. 
After randomization, participants must commence systemic treatment within 3 days. Participants 
should not delay starting systemic treatment in order to complete radiotherapy QA. Following 
initial systemic treatment, sites have 14 days to complete radiotherapy planning and QA before 
starting RT at w3d1.
Participants who are randomized to a placebo arm do not need to delay the start of radiotherapy. 
For subjects randomized to Cohort 1 Arm B, cetuximab may be administered at w1d1 and 
radiotherapy at w2d1. For participants randomized to Cohort 2 Arm B, cisplatin and radiotherapy 
may begin at w1d1.
Imaging will occur at baseline (within 28 days prior randomization. Per Revised Protocol 03, 
subsequent imaging assessments should be performed according to the timing of local standard of 
care. 
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The Follow-up stage begins when protocol specific treatment with nivolumab is completed or the 
decision to discontinue a participant from study therapy is made (no further treatment with study 
therapy). Participants will have the first follow-up visits (FU1 and FU2) approximately 30 days 
and 100 days, respectively, from the last dose of study therapy or coinciding with the date of 
discontinuation and AEs will be followed until the toxicities resolve, return to baseline, or are 
deemed irreversible.
All participants should continue to have tumor scans per local standards of care. .
5.1.1
Data Monitoring Committee and Other External Committees
5.1.1.1
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be utilized to provide general oversight and safety 
considerations for this study, CA2099TM. The DMC will provide advice to the Sponsor regarding 
actions the committee deems necessary for the continuing protection of subjects enrolled in this 
study. The DMC will be charged with assessing such actions in light of an acceptable safety profile 
for nivolumab. The DMC will act in an advisory capacity to BMS and will monitor subject safety 
data for the study. The DMC will be advisory to the clinical study leadership team. The clinical 
study leadership will have responsibility for overall conduct of the study including managing the 
communication of study data. The group will be responsible for promptly reviewing the DMC 
recommendations, for providing guidance regarding the continuation or termination of the study, 
and for determining whether amendments to the protocol or changes to the study conduct are 
required.
Details of the DMC responsibilities and procedures will be specified in the DMC charter.
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
5.1.2
Radiotherapy Quality Assurance
Radiation Therapy (RT) QA for this study consists of 3 components.  
1) Sites will undergo radiation therapy credentialing prior to enrolling patients on study. 
2) The RT treatment plans for all patients will have a pre-treatment central review prior to the 
start of radiation therapy. Feedback will be provided to the treating site within 72 hours of 
receipt of the treatment plan.
3) At the completion of radiation therapy documentation of the course of treatment delivered will 
be submitted for central review. A summary of the delivered radiation therapy and compliance 
with protocol requirements will be provided to BMS for the participant record.
Qualification of site for delivery of radiotherapy will be based on ongoing radiation quality 
assurance activities, including site credentialing and rapid review of radiotherapy plans. The RT 
QA data submission requirements and protocol compliance criteria are detailed in the RT QA 
Manual.
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5.2
Number of Participants
Per Revised Protocol 03, enrollment in this study was closed as of 15-Oct-2018. 
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last visit or scheduled procedure shown in the Schedule of Activities (SOA) for the 
last participant. Study completion is defined as the final date on which data is collected for this 
study. The total duration of the study will be determined by the last safety follow-up visit for the 
last participant after stopping treatment (i.e. 100 days from the last dose of study treatment).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
Per Revised Protocol 03, enrollment in the current study was closed as of 15-Oct-2018. 
Participants that have signed an informed consent as of that date will be permitted to be 
randomized. All study participants must be re-consented at implementation of Revised Protocol 
03.
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, 
and laboratory testing.
2) Type of Participant and Target Disease Characteristics
a) Histologically proven squamous cell carcinoma of the head and neck (SCCHN) from one 
of the following primary sites: oral cavity, oropharynx, hypopharynx, and larynx
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b) Locally advanced disease which is unresectable, or resectable but suitable for an organ 
sparing approach
c) No previous radiotherapy or systemic treatment for SCCHN
d) Eastern cooperative oncology group (ECOG) score of 0-1 (Appendix 7)
e) Measurable disease by RECIST1.1 (Appendix 10) criteria, and tumor assessment 
performed prior to randomization
f)
Sufficient sample of fresh or archival (< 3 months from informed consent date) formalin-
fixed, paraffin-embedded (FFPE) tissue block, or unstained tumor tissue sections, with an 
associated pathology report, must be submitted for biomarker evaluation for PD-L1 status.
Central lab must provide Interactive Response Technology (IRT) with confirmation of 
receipt of evaluable tumor tissue prior to randomization. Biopsy should be excisional, 
incisional or core needle. Fine needle or aspiration is unacceptable for submission. PD-L1 
status must be available prior to randomization. Not applicable after 15-Oct-2018. 
g) HPV p16 test result available (performed locally or centrally) for participants with 
oropharyngeal disease 
h) Patients must be of intermediate or high risk categories*:
i)
High risk:
(1) Oral cavity, hypopharynx, larynx, oropharynx (p16 negative): Stage III/IV
(2) Oropharynx (p16 positive): Stage III (T4 any N or T1-3 N3) - irrespective of 
smoking status.
ii) Intermediate risk:
(1) Oropharynx (p16 positive): T3 N0-2 or T1-3 N2 disease if smoking > 20 pack year 
history
*TNM clinical staging according to AJCC version 8 (Appendix 6).
3) Cohort 1 (cisplatin ineligible) Specific Inclusion Criteria (Arms A and Arm B)
a) Physician assesses participant to be non-eligible for treatment with platinum based 
combined CRT. This must be for one or more of the following reasons:
i)
Age ≥70 years at enrolment
ii) Creatinine clearance < 60mL/min and > 30mL/min (using the Cockcroft and Gault 
formula– see below**)
iii) Severe hearing loss (minimal hearing threshold of 80 dB or more in either ear)
4) Cohort 2 (cisplatin eligible) Specific Inclusion Criteria (Arm C and Arm D)
a) Adequate renal function within 28 days prior to randomization as follows:
i)
Creatinine clearance ≥60 mL/min. as determined by 24 hour collection or estimated 
by Cockcroft-Gault formula:
CCr={((140–age in years) x weight in Kg)/(72 x serum creatinine in mg/dL)}
(for females, multiply the result by 0.85)**
**Participants aged ≥ 70 years may enter either Cohort 1 or 2 dependent on whether the physician’s assessment is that 
the participant is eligible for cisplatin (Cohort 2) or ineligible for cisplatin (Cohort 1) based on their age. It is 
anticipated that in the majority of cases, patients aged ≥ 70 years will be considered ineligible for cisplatin and 
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enter cohort 1.  If the subject has poor renal function as one of the acceptable inclusion criteria, the subject will 
be enrolled under inclusion criteria 3) ii) and must meet the requirement for Creatinine clearance < 60 mL/min 
and > 30mL/min (using the Cockcroft and Gault formula)
5) Age and Reproductive Status
a) Males and Females ≥ages 18 or age of majority 
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) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 
5 months after the last dose of study treatment {i.e., 30 days (duration of ovulatory cycle) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}. 
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment with nivolumab and 
7 months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) 
plus the time required for the investigational drug to undergo approximately five half-
lives.}. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
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 on the use of highly effective methods of contraception (Appendix 4) 
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
Per Revised Protocol 03, enrollment in the current study was closed as of 15-Oct-2018. 
Participants that have signed an informed consent as of that date will be permitted to begin 
treatment.
1) Medical Conditions
a) Carcinoma originating in the nasopharynx or paranasal sinus, squamous cell carcinoma 
that originated from the skin and salivary gland or non-squamous histology (e.g., mucosal 
melanoma), squamous cell carcinoma of unknown primary
b) Clinical or radiological evidence of metastatic disease
c) Prior radiotherapy that overlaps with radiation fields
d) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the participant to receive protocol therapy, or interfere with the interpretation 
of study results
e) Active unstable angina and/or congestive heart failure
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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 randomized in the study/included in the analysis population. 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.
6.4.1
Retesting During Screening or Lead-In Period
As of 15-Oct-2018, enrollment in this study was closed, as of enrollment closure this section is not 
applicable. 
This study permits the re-enrollment of a participant that has discontinued the study as a pre-
treatment failure (i.e., participant has not been randomized). 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. 
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following (see 
Table 7-1 for additional details):
•
BMS-936558-01 (Nivolumab) Solution for Injection
•
Cetuximab solution for Infusion
•
Cisplatin solution for Infusion
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Note: At the approval and implementation of Revised Protocol 03 study treatments will be 
unblinded, and no further placebo medication will be given.
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.
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Table 7-1:
Study Treatments for CA2099TM
Product Description / Class and 
Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
Nivolumab Solution for Injectiona
10 mg/mL –
100 mg fill 
volume
IP
Open Labelb
Vials
Refer to the label or container 
and/or pharmacy manual
Cetuximab Solution for Infusionc
5 mg/mL -
500 mg fill 
volume
IP
Open Labelb
Vials
Refer to the label or container 
and/or pharmacy manual 
Cisplatin Concentrate for Solution 
for Infusionc
1 mg/mL – 100 
mg fill volume
IP
Open Labelb
Vials
Refer to the label or container 
and/or pharmacy manual. 
a May be labeled as either “BMS-936558-01” or “Nivolumab”
b The term “open label” refers to the medication as it is upon receipt at the pharmacy. Per Revised Protocol 03, the study will be unblinded, and placebo treatment 
will no longer be administered.
c These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC) or according to institutional standards.
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative sites if available and permitted by local regulations. 
Solutions used as diluent or placebo (i.e., 0.9% Sodium Chloride Injection or 5% Dextrose Injection) should also be sourced by investigative sites if available and 
permitted by local regulations.
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7.1
Treatments Administered 
The selection and timing of dose for each participant is as follows in Table 7.1-1. Dosing schedule 
by cycle for Cohort 1 and 2 are shown in Table 7.1-2and Table 7.1-3, respectively.
Table 7.1-1:
Selection and Timing of Dose
Arm
Study 
Treatment
Dosage level(s) and 
Formulation
Frequency of Administration
Route of 
Administration
A
Nivolumab
240 mg IV x 1 dose then 
360 mg IV x 3 doses then 
480 mg IV x 6 doses
Single dose at w1d1 (C1 of cohort 1) 
then every 3 weeks (Q3W) for 3 
doses starting w3d1 then every 4 
weeks (Q4W) for 6 doses
IV
B
Cetuximab
400 mg/m2 IV x 1 dose 
then 250 mg/m2 IV x 7 
doses
Single dose at w2d1 (C1 of cohort 1) 
then every week (Q1W) for 7 doses
IV
C
Nivolumab
240 mg IV x 1 dose then 
360 mg IV x 3 doses then 
480 mg IV x 6 doses
Single dose at w1d1 (C1 of cohort 2) 
then every 3 weeks (Q3W) for 3 
doses starting w3d1 then every 4 
weeks (Q4W) for 6 doses
IV
Cisplatin
100 mg/m2 IV x 3 doses
Every 21 days (q21days) starting at 
w3d1
IV
D
Cisplatin
100 mg/m2 IV x 3 doses
Every 21 days (q21days) starting at 
w3d1
IV
Abbreviations: C=cycle; d=day; IV=intravenous; Q1W=every week; q21 days= every 21 days; Q3W=every 3 weeks; 
Q4W=every 4 weeks; w=week
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Table 7.1-2:
Dosing Schedule by Cycle for Cohort 1 Arms A and B
Drug
Cycle 1
(cycle=1 
week)
Cycle 2
(cycle=1 
week)
Cycle 3
(cycle=1 
week)
Cycle 4 and 
Cycle 5
(cycle=1 
week)
Cycle 6
(cycle=1 
week)
Cycle 7 and 
Cycle 8
(cycle=1 
week)
Cycles 9
(cycles=1 
week)
Cycles 10 to 15a
(cycles=4 weeks)
Cohort 1
Arm A
Nivolumab
Nivolumab 
240 mg IV x 
1
--
Nivolumab 
360 mg IV 
--
Nivolumab 
360 mg IV 
--
Nivolumab 
360 mg IV
Nivolumab 480 mg 
IV at the start of 
the cycle
Per Revised Protocol 03, no placebo will be administered. 
Cohort 1
Arm B
Per Revised Protocol 03, no placebo will be administered. 
Cetuximab
--
Cetuximab 
400 mg/m2
IV x 1
Cetuximab 
250 mg/m2
IV 
Cetuximab 
250 mg/m2
IV each 
cycle 
Cetuximab 
250 mg/m2
IV
Cetuximab 
250 mg /m2
IV each 
cycle
Cetuximab 
250 mg/m2
IV
--
Abbreviations: C=cycle; IV=intravenous
a Cycle 10 to start after 2 weeks off after the end of Cycle 9.
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Table 7.1-3:
Dosing Schedule by Cycle for Cohort 2 Arms C and D
Cycle 1
(cycle=2 weeks)
Cycle 2
(cycle=3 weeks)
Cycle 3
(cycle=3 weeks)
Cycle 4
(cycle=3 weeks)
Cycles 5 to 10
(cycles=4 weeks)
Cohort 2
Arm C
Nivolumab 
240 mg IV 
Nivolumab 
360 mg IV 
+
Cisplatin 
100 mg/m2 IV 
Nivolumab 
360 mg IV 
+
Cisplatin 
100 mg/m2 IV 
Nivolumab 
360 mg IV 
+
Cisplatin 
100 mg/m2 IV 
Nivolumab 480 mg 
IV at the start of the 
cycle
Cohort 2
Arm D
Cisplatin 
100 mg/m2 IV 
Cisplatin 
100 mg/m2 IV 
Cisplatin 100
mg/m2 IV 
Abbreviations: C=cycle; IV=intravenous
The infusion duration of nivolumab is 30 minutes and for cetuximab is infusion duration is over 2 
hours for 400 mg/m2 and 1 hour for the 250 mg/m2, see Section 7.1.2. The start and stop times of 
the infusions should be documented. 
7.1.1
Nivolumab Dosing
Participants should begin study treatment within 3 calendar days of treatment assignment. 
Participants should receive nivolumab as a 30-minute infusion starting on Day 1 Cycle 1 at 240 
mg, then after 2 weeks (-2/+3 days) 360 mg for 3 doses Q3W (± 3 days), then at 480 mg for 6 
doses Q4W. Cycles differ between Cohorts. Refer to Table 7.1-2 for Cohort 1 and Table 7.1-3 for 
Cohort 2 when nivolumab is administered by cycle.
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 12 days from the previous dose during Q2W cycles. For the Q3W (360 mg nivolumab) 
dosing, participants may be dosed no less than 18 days from the previous dose. For Q4W dosing 
cycles, participants may be dosed within a ± 7 day window. Premedications are not recommended 
for the first dose of nivolumab. Refer to Table 7.1-2 for details on dosing schedule for 
administration of nivolumab in Cohort 1 and Table 7.1-3 for Cohort 2.
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 7.4.7.
Doses of nivolumab may be interrupted, delayed (Section 7.4.1), or discontinued (Section 8.1.1)
depending on how well the participant tolerates the treatment.
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/mL (10 mg/mL) is to be administered 
as an IV infusion through a 0.2-micron to 1.2-micron pore size, low-protein binding in-line filter 
at the protocol-specified doses. It is not to be administered as an IV push or bolus injection. When 
the dose is based on patient weight (i.e., mg/kg), nivolumab injection can be infused undiluted 
(10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
to protein concentrations as low as 0.35 mg/mL. When the dose is fixed (e.g., 240 mg flat dose), 
nivolumab injection can be infused undiluted or diluted so as not to exceed a total infusion volume 
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of 120 mL. Nivolumab infusion must be promptly followed by a saline flush to clear the line. 
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, or pharmacy reference sheet. Care must be taken to assure sterility of 
the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent.
On cycles where nivolumab and cetuximab or cisplatin needs to be administered on the same day,
nivolumab should be administered first using separate infusion bags and filters. The infusion of 
cetuximab or cisplatin should occur no earlier than 30 minutes after the completion of the 
nivolumab infusion.
7.1.2
Cetuximab
For countries in which BMS is providing packaged/labeled cetuximab, please refer to package 
insert, summary of product characteristics (SmPC), or similar document for details regarding drug 
preparation, administration and use time.
For countries where local sourcing of cetuximab is permitted, product should be stored, prepared 
and administered in accordance to the package insert, summary of product characteristics (SmPC) 
or similar document.
For participants in Cohort 1, cetuximab initial dose of 400 mg/m2 (over 2 hour infusion) is given 
on Day 1 Cycle 2, then weekly (± 3 days) at 250 mg/m2 (over 1 hour infusion) for 7 weeks (C3 to 
C9 in cohort 1). Refer to Table 7.1-2 for when cetuximab is administered by cycle.
7.1.2.1
Cetuximab supportive care
CAUTION: Infusion reactions may occur during or following cetuximab administration. 
Most infusion reactions occur with the first infusion of cetuximab, but some patients’ first 
infusion reactions have been reported following subsequent doses. The infusion reaction may 
occur during the infusion or be delayed until any time after the infusion.
All patients will be premedicated with diphenhydramine hydrochloride, 50 mg, (or an equivalent 
antihistamine) by IV 30-60 minutes prior to the first dose of cetuximab in an effort to prevent an 
infusion reaction. For the initial dose of cetuximab of 400 mg/m2, the dose may be split to observe 
for signs of an infusion reaction. An initial dose of 100 mg/m2 may be given and if no signs of an 
infusion reaction are observed 30 minutes after the end of the infusion, the remaining 300 mg/m2
may be given.
The routine use of systemic steroids for premedication is not necessary and may interfere with anti 
PD-1 activity. If considered absolutely necessary, systemic high dose steroids are allowed as 
premedication for the first dose of cetuximab and only as clinically indicated for the subsequent 
doses. Topical steroids are acceptable.
For cetuximab, the recommended premedication is with an H1 antagonist (e.g., 50 mg 
Diphenhydramine) IV 30-60 minutes prior to the first dose; for subsequent doses, premedication 
should be administered based upon clinical judgement and presence/severity of prior infusion 
reactions in accordance with local institutional standard of practice. 
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It is recommended that the medical staff closely observe participants for treatment-related adverse 
events, especially infusion reactions (see Section 7.4.2.4 for management) during the cetuximab 
infusion per local institutional standards.
For subsequent infusions, it is recommended that the participants be observed for 1 hour post-
infusion.
Doses of cetuximab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. For more details see Sections dose delays (7.4.2), dose 
reductions (7.4.2), resuming treatment (7.4.4), and 8.1 discontinuation.
Participants should be carefully monitored for infusion reactions. If an acute infusion reaction is 
noted, participants should be managed according to Section 7.4.2.4.
7.1.3
Cisplatin
For participants in Cohort 2, cisplatin (100 mg/m2 IV) will begin dosing on Day 1 Cycle 2 and 
then every 21 days (± 3 days); participants are expected to receive 3 doses but must have minimum 
2 doses. Individual investigators may use institutional guidelines for the administration of 
cisplatin. Refer to Table 7.1-3 to when cisplatin is administered by cycle.
Doses of cisplatin may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. For more details, see Sections 7.4.3 (dose delays), 7.4.3.1 (dose 
reductions), 7.4.4 (resuming treatment), and 8.1 (discontinuation).
7.1.3.1
Cisplatin supportive care
Institutional or National Comprehensive Cancer Network (NCCN) guidelines or local guidance 
should be followed for cisplatin supportive care. Hydration guidelines may be modified at the 
discretion of the treating physician provided adequate pre- and post-cisplatin hydration is achieved, 
and renal function remains adequate. One suggested regimen consists of administering cisplatin in 
500 cc to 1000 cc of IV fluids following adequate hydration and the establishment of adequate 
urinary output. It is suggested the pre-cisplatin hydration consist of NS at 500 cc/hr. x 1 liter and 
post-cisplatin hydration consist of 1/2 NS + 10 meq KCl/liter + 1 gram magnesium sulfate/liter + 
25 grams mannitol/liter at 500 cc/hr. for at least one hour, followed by additional hydration at the 
discretion of the investigator.
It is suggested that participants receive antiemetic therapy, acute and delayed, including 
dexamethasone, 5-HT3 serotonin receptor antagonists. However, the specifics of the regimen are 
at the discretion of the treating investigator, provided adequate control is achieved. One potential 
regimen consists of 20 mg of oral or IV dexamethasone and a high dose of oral or IV 5-HT3 
antagonist (such as 2 mg oral or 10 mcg/kg IV granisetron, or 32 mg oral or IV ondansetron) on 
the day of cisplatin administration. Followed by additional anti-emetics consisting of oral 
dexamethasone and scheduled 5-HT3 serotonin receptor antagonists on days 2-5. For example, 
8 mg orally, twice daily for days 2 and 3, and then 4 mg orally, twice daily for days 4 and 5, 
especially if an aprepitant is not given. On the day of chemotherapy administration, the dose of 
dexamethasone must be reduced by 50%, if an aprepitant is given.
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For cisplatin, the recommended premedications are dexamethasone (dosing according to local 
standard; an equivalent dose of another corticosteroids may be substituted) and a 5-HT3 receptor 
antagonist (type per investigator discretion and local standards of care) prior to each dose. 
Additional use of emetics premedication may be employed at the discretion of the investigator. 
Refer to the local product label for more detail.
7.1.4
Radiotherapy
All participating institutions must be credentialed for head and neck IMRT prior to enrolling 
participants in this study. See Section 5.1.2 for details.
Intensity Modulated Radiation Therapy (IMRT) is mandatory for this study. Proton therapy is not 
permitted.
IMRT will be given in 35 fractions over 7 weeks beginning at Day 1 Cycle 3 for Cohort 1 or Day 
1 Cycle 2 for Cohort 2, 5 fractions per week (both corresponding to (w3d1). 
Full details of radiation therapy are provided in an accompanying radiation therapy manual. 
The first fraction of RT should be delivered on a Monday or Tuesday, but this may vary according 
to local treatment plan. Five fractions should be delivered a week. Randomization and dosing 
should be timed such that the first dose of nivolumab occurs 14 ± 3 days prior to the start of 
radiotherapy. 
7.2
Method of Treatment Assignment
All participants will be assigned to treatment using an Interactive Response Technology (IRT). 
Users will receive log in information and directions on how to access the IRT. Study treatment 
will be dispensed at the study visits as listed in Schedule of Activities (Section 2).
As of 15-Oct-2018, enrollment in the study is closed. Participants with signed informed consent 
as of the 15-Oct-2018 may be randomized to treatment. 
7.3
Blinding
Per approval and implementation of Revised Protocol 03, the study will be unblinded.
7.4
Dosage Modification
7.4.1
Nivolumab Dose Delay 
If adverse events prevent the administration of nivolumab, the participant should continue to 
receive other study therapies.
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
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•
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8.1.1)
•
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.
In case of RT delay due to technical issues (instrument breakdown), continue systemic treatment 
as planned.
7.4.1.1
Rescheduling Nivolumab Treatment After Dose Delay
•
If nivolumab is delayed during the combined radiotherapy phase, radiotherapy should 
continue unless there is a specific reason to discontinue both nivolumab and 
radiotherapy. It is anticipated that the majority of immune related AEs that require 
nivolumab delay or discontinuation will not require delay or discontinuation of 
radiotherapy
•
If nivolumab is delayed, the criteria for restarting nivolumab should be adhered to 
independent of whether the participant is receiving concurrent radiotherapy
•
In the event of delay of nivolumab dosing during combined radiotherapy/nivolumab 
treatment, participants should receive 480 mg Q4W as soon after completion of radiotherapy 
as possible (at the earliest week 10), i.e., patients may receive fewer than 3 doses of 360 mg 
Q3W
•
In the event of dose delay during nivolumab maintenance dosing, all 6 doses of nivolumab 
480 mg Q4W should be given, up to a maximum duration of 40 weeks
•
In the event of delay to radiotherapy requiring radiotherapy beyond week 11, 480 mg IV
Q4 dosing should be substituted with 240 mg IV Q2 dosing until the radiotherapy is 
complete
7.4.2
Cetuximab Dose Modifications and Delay 
If adverse events prevent the administration of cetuximab, the participant should continue to 
receive radiation therapy.
In the event of cetuximab treatment delay, there will be no reloading cetuximab infusion. Resume 
at the appropriate dose as indicated in Table 7.4.2-1.
Table 7.4.2-1:
Cetuximab Dose Levels
Starting Dose
Dose Level–1
Dose Level–2
Cetuximab
400 mg/m2 (first week only)
Cetuximab
250 mg/m2 (weekly)
200 mg/m2 (weekly)
150 mg/m2 (weekly)
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Note: If a weight change of ≥ 10% occurs, the cetuximab dose should be adjusted.
7.4.2.1
Cetuximab Dose Modifications for Hematologic Adverse Events
Cetuximab will not be dose reduced or held for hematologic adverse events, such as neutropenia, 
neutropenic fever, or thrombocytopenia.
7.4.2.2
Cetuximab Dose Modifications for Non-Hematologic Adverse Events
See Table 7.4.2.2-1.
See Section 7.4.2.5 for instructions for rash.
Table 7.4.2.2-1:
Cetuximab Dose Modifications for Non-Hematologic Adverse Event
Toxicity Grade 
(CTCAE, v. 4)
Cetuximab Dosea
Renal-Calculated 
Creatinine Clearance*
≥ 50 mL/min 
Maintain dose levels
< 50 mL/min
Maintain dose levels
Fatigue (Asthenia)
≥ Grade 3
Maintain dose levels
Nausea/Vomiting
≤ Grade 2 with maximal 
medical management
≥ Grade 3 with maximal 
medical management
Maintain dose levels
Hold drug until ≤ grade 2, then resume at same dose level 
Other Non-hematologic
Adverse Eventsb,c
Grade 3- 4, if possibly related to cetuximab, or 
likely to be exacerbated by continuation of 
cetuximab, e.g., diarrhea, except for weight loss or 
mucositis
Hold drug until < grade 3, then resume at 1 dose level 
reduction
Any grade 1-2
Maintain dose levels
a Dose levels are relative to the previous dose.  Dose reductions of cetuximab below the –2 dose level will not be 
allowed. If a dose reduction below the -2 dose is mandated by the toxicity grade, cetuximab will be permanently 
discontinued. In any case of cetuximab treatment delay, there will be no re-loading infusion, and all subsequent 
treatment will be at the assigned dose level.
b With the exception of infusion reaction;
c For depressed K or Mg, administer replacement therapy. Chemotherapy should continue at the discretion of the 
treating physician (see table below for management of hypomagnesemia).
*For subjects with normal renal function.
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7.4.2.3
Cetuximab Dose Modifications for Hypomagnesemia
Table 7.4.2.3-1:
Cetuximab Dose Modifications for Hypomagnesemia
CTCAE, 
v. 4 Grade
Serum Magnesium
Guidelines for management
Action
mg/dL
mmol/L
1
< LLN – 1.2
< LLN – 0.5
Consider replacement with IV 
magnesium sulfate 2-5 g in normal saline 
or D5W. Infusion schedule based on 
institutional guidelines. 
Maintain dose and schedule
2
< 1.2 – 0.9
< 0.5 – 0.4
As above for grade 1 and consider 
prophylactic weekly infusion of 
magnesium and/or oral magnesium 
supplementation (e.g., magnesium oxide) 
if grade 2 of higher hypomagnesemia 
persists.
Maintain dose and schedule
3
< 0.9 – 0.7
< 0.4 – 0.3
As above for grades 1 and 2
Hold cetuximab until 
recovery to < grade 2, then 
resume at same dose level 
4
< 0.7
< 0.3
As above for grades 1 and 2
Hold cetuximab until 
recovery to < grade 2, then 
reduce by 1 dose level
7.4.2.4
Cetuximab Infusion Reaction Management
See Section 7.1.2.1 for additional information on cetuximab supportive care.
Table 7.4.2.4-1:
Cetuximab Infusion Reaction Management
CTCAE, v. 4
Adverse Event Grade
Treatment Guidelinesa
Grade 1: 
Mild transient reaction;
infusion interruption not 
indicated; intervention not 
indicated
For mild infusion reactions, slow the infusion rate for cetuximab by 50% 
when the drug is restarted. For reactions manifesting only as delayed drug 
fever, consider administering prophylactic antihistamine medications for 
subsequent doses.  Maintain the cetuximab dose.  Acetaminophen or a non-
steroidal anti-inflammatory drug (NSAID) may be administered prior to 
subsequent cetuximab infusions, if not otherwise contraindicated in 
participants.
Grade 2:
Therapy or infusion interruption 
indicated but responds promptly 
to symptomatic treatment (eg, 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hrs
For moderate infusion reactions, slow the infusion rate for cetuximab by 50% 
when the drug is restarted and consider administering antihistamine 
medications and/or steroidal medications. Maintain the cetuximab dose.  
Acetaminophen or a non-steroidal anti-inflammatory drug (NSAID) may be 
administered prior to subsequent cetuximab infusions, if not otherwise 
contraindicated in participants.
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Table 7.4.2.4-1:
Cetuximab Infusion Reaction Management
CTCAE, v. 4
Adverse Event Grade
Treatment Guidelinesa
Grade 3:
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief
interruption of infusion); 
recurrence of symptoms 
following initial improvement;
hospitalization indicated for
clinical sequelae
NO FURTHER STUDY DRUG THERAPY. Severe infusion reactions 
require immediate interruption of cetuximab infusion and permanent 
discontinuation from further treatment with cetuximab. Appropriate medical 
therapy including epinephrine, corticosteroids, diphenhydramine, 
bronchodilators, and oxygen should be available for use in the treatment of 
such reactions. Patients should be carefully observed until the complete 
resolution of all signs and symptoms.
a Study Therapy Retreatment Following Infusion Reactions: Once a cetuximab infusion rate has been decreased due 
to an infusion reaction, it will remain decreased for all subsequent infusions. If the participant has a second infusion 
reaction > grade 2 with the slower infusion rate, the infusion should be stopped, and the patient should receive no 
further cetuximab treatment. If a patient experiences a Grade 3 or 4 infusion reaction at any time, the patient should 
receive no further cetuximab treatment. If there is any question as to whether an observed reaction is an infusion 
reaction of Grades 1-4, the Study Director and Medical Monitor should be contacted immediately to discuss and 
grade the reaction.
7.4.2.5
Cetuximab Related Rash
Manifestations: Rash associated with EGFR-inhibitors is a relatively new dermatologic condition. 
It appears to be “acneiform” but it is NOT considered a form of acne; rather, it is a form of 
folliculitis. Skin changes may be manifested in a number of ways: erythema; follicle based papules, 
which may ulcerate; pain; itching; cosmetic disturbance; and/or nail disorders. The rash may 
become infected and transform into cellulitis.
Grading of Cetuximab-induced Rash: According to physician judgment, if a participant
experiences ≥ Grade 3 rash (according to either the “outside of the radiation field” or the “inside 
of the radiation field” definitions below), cetuximab treatment adjustments should be made 
according to the Cetuximab Dose Modification tables (Table 7.4.2.5-1 and Table 7.4.2.5-2). In 
participants with mild and moderate skin adverse events, cetuximab should continue without 
adjustment.
NOTE: Rash intensity (i.e., the size and number of papules or the level of discomfort and extent 
of erythema) may be an important consideration. However, the absolute number of lesions, 
without associated physical discomfort, does not necessarily constitute a basis for a dose 
reduction or delay. Rash considered “intolerable” (because of pain, itching, or appearance) or that 
has failed to respond to symptomatic management may be considered Grade 3 and thus prompt 
dose reduction or delay of cetuximab. The clinical judgment of the treating physician is critical 
to grading and will ultimately dictate dose modification.
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Acute Skin Changes: 
•
Rash Occurring Outside of the Radiation Field: Should be graded using the following CTCAE, 
v. 4 terms. A rash complicated by secondary infection or cellulitis should be graded per 
additional CTCAE terms (see Table 7.4.2.5-1).
•
Rash Occurring Inside the Radiation Field: Acute radiation dermatitis may be exacerbated by 
cetuximab or chemotherapy. The severity of such rash should be graded using CTCAE,  v. 4 
criteria for radiation dermatitis (see Table 7.4.2.5-2). 
•
Late Skin Changes: A potential late change of interest is consequential scarring/pock marking 
in or out of the radiation field. This may be reported by using the MedDRA code, “Skin and 
subcutaneous tissue disorders - Other, specify” with the following protocol-specific grading 
scale as guidance:
−
Grade 1: Mild (seen only on close inspection)
−
Grade 2: Moderate (scarring, intervention or cosmetic coverage/intervention indicated)
−
Grade 3: Severe (significant disfigurement, deep scarring, or ulceration)
−
Grade 4: Deep cratering/scarring, skin necrosis, or disabling
Table 7.4.2.5-1:
Rash Occurring Outside of the Radiation Field
1
2
3
4
Pruritus* 
Mild or localized
Intense or widespread
Intense or 
widespread and 
interfering with 
ADL
-
Rash/acneiform*
Papules and/or 
pustules covering 
< 10% BSA, which 
may or may not be 
associated with 
symptoms of 
pruritus or 
tenderness
Papules and/or pustules 
covering 10-30% BSA, 
which may or may not be 
associated with symptoms 
of pruritus or
tenderness; associated 
with psychosocial impact; 
limiting
instrumental ADLI
Papules and/or 
pustules covering 
> 30% BSA, which 
may or may not be 
associated with 
symptoms of 
pruritus or 
tenderness; 
limiting self -care 
ADL; associated 
with local 
superinfection with 
oral antibiotics 
indicated
Papules and/or 
pustules
covering any % 
BSA, which may 
or may not be 
associated
with symptoms of 
pruritus or
tenderness and are 
associated
with extensive 
superinfection
with IV 
antibiotics 
indicated; life 
threatening
consequences
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Table 7.4.2.5-1:
Rash Occurring Outside of the Radiation Field
1
2
3
4
Paronychia*
Nail fold edema or 
erythema; disruption 
of the cuticle
Localized intervention 
indicated; oral 
intervention indicated 
(e.g., antibiotic, 
antifungal, antiviral);
nail fold edema or 
erythema with pain; 
associated with discharge 
or nail plate
separation; limiting 
instrumental ADL
Surgical 
intervention or IV 
antibiotics 
indicated; limiting 
self
care ADL
-
*Onset of grade 3 will require modification. See the Table 7.4.2.5-3, Cetuximab Dose Modification Guidelines for 
Dermatologic Changes.
Table 7.4.2.5-2:
Rash Occurring Inside the Radiation Field
1
2
3
4
Radiation recall 
reaction 
(dermatologic); 
Dermatitis 
radiation
Faint erythema or 
dry desquamation
Moderate to brisk 
erythema; patchy 
moist desquamation, 
mostly confined to 
skin folds and creases; 
moderate edema
Moist desquamation 
other than skin folds 
and creases; bleeding 
induced by minor 
trauma or abrasion
Life-threatening 
consequences;
skin necrosis or 
ulceration of full
thickness dermis; 
spontaneous
bleeding from 
involved site; skin
graft indicated
Table 7.4.2.5-3:
Cetuximab Dose Modification Guidelines for Dermatologic 
Changes (≥ Grade 3)
Cetuximab
Outcome
Cetuximab Dose Modification
1st occurrence
Delay infusion 1 to 2 
weeks
Improvement to 
≤Grade 2
Resume at 250 mg/m2
No Improvement; 
remains grade 3
Discontinue cetuximab
2nd occurrence
Delay infusion 1 to 2 
weeks 
Improvement to 
≤Grade 2
Resume at Dose Level-1 
(200 mg/m2)
No Improvement; 
remains grade 3
Discontinue cetuximab
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Table 7.4.2.5-3:
Cetuximab Dose Modification Guidelines for Dermatologic 
Changes (≥ Grade 3)
Cetuximab
Outcome
Cetuximab Dose Modification
3rd occurrence
Delay infusion 1 to 2 
weeks
Improvement to 
≤Grade 2
Resume at Dose Level-2 
(150 mg/m2)
No Improvement; 
remains grade 3
Discontinue cetuximab
4th occurrence
Discontinue cetuximab
Drug-Related Rash Management: Participants developing dermatologic adverse events while 
receiving cetuximab should be monitored for the development of inflammatory or infectious 
sequelae, and appropriate treatment of these symptoms initiated. Below are suggestions for 
managing cetuximab-induced rash75:
•
Antibiotics: The benefit of routine antibiotics in uncomplicated (uninfected) rash is unclear, 
though the early use of tetracycline based antibiotics early is encouraged. Prophylactic used is 
also permissible. Rash complicated by cellulitis should be treated with appropriate antibiotics 
based on clinical judgment or microbial sensitivity analysis.
•
Antihistamines: Benadryl or Atarax may be helpful to control itching.
•
Topical Steroids: The benefit of topical steroids is unclear.
•
Retinoids: No data to support use. Use is not advised.
•
Benzoyl peroxide: Should NOT be used as this may aggravate rash.
•
Makeup: Rash can be covered with makeup; this should not make it worse (use a 
dermatologist-approved cover-up, e.g., Dermablend®, or any other type of foundation). 
Remove makeup with a skin-friendly liquid cleanser, e.g., Neutrogena®, Dove®, or Ivory Skin 
Cleansing Liqui-Gel®.
•
Moisturizers: Use emollients to prevent and alleviate the skin dryness, e.g., Neutrogena®
Norwegian Formula Hand Cream® or Vaseline Intensive Care Advanced Healing Lotion®.
•
Sunlight: It is recommended that participants wear sunscreen and hats and limit sun exposure
while receiving cetuximab as sunlight can exacerbate any skin reactions that may occur.
•
Over-the-counter medications: Over-the-counter acne vulgaris medications (e.g., benzoyl 
peroxide) are not advised. This rash is not like acne vulgaris and these treatments could make 
it worse.
7.4.2.6
Treatment Of Isolated Drug Fever
In the event of isolated drug fever, the investigator must use clinical judgment to determine if the 
fever is related to the study drug or to an infectious etiology.
If a participant experiences isolated drug fever, for the next dose, pre-treat with acetaminophen or 
non-steroidal anti-inflammatory agent (investigator discretion), repeat antipyretic dose 6 and 12 
hours after cetuximab infusion. The infusion rate will remain unchanged for future dose. If a 
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participant experiences recurrent isolated drug fever following pre-medication and post-dosing 
with an appropriate antipyretic, the infusion rate for subsequent dosing should be 50% of previous 
rate. If fever recurs following infusion rate change, the investigator should assess the participant’s 
level of discomfort with the event and use clinical judgment to determine if the patient should 
receive further cetuximab.
7.4.2.7
Rescheduling Cetuximab Treatment After Dose Delay
Weekly cetuximab will continue if radiation therapy is being held. If cetuximab is omitted for 
more than 4 consecutive infusions for adverse events due to cetuximab, or for an intercurrent 
illness (e.g., infection) requiring interruption of therapy, the participant should be discontinued 
from further cetuximab therapy. If adverse events prevent the administration of cetuximab, the 
participant may continue to receive nivolumab/placebo and radiation therapy. 
If a dose of cetuximab is omitted, it will not be made up or added to the end of treatment. The 
omitted dose and the reason for the omission should be recorded in the site’s source documentation.
7.4.3
Dose Modifications And Delay For Cisplatin
Note: If adverse events prevent the administration of cisplatin, the participant should continue to 
receive nivolumab and radiation therapy.
Cisplatin should be delayed for the following:
•
Presence of febrile neutropenia or neutropenia < 1500 cells/mm3 for greater than one week 
despite the use of growth factors
•
Any Grade > 2 non-skin, drug-related adverse event, except for alopecia, fatigue or laboratory 
abnormalities
•
Any Grade 3 drug-related laboratory abnormality, with the following exceptions:
−
Grade 3 lymphopenia does not require a dose delay
−
Delay if total bilirubin >1 x ULN or if AST and/or ALT > 1.5 x ULN occurs concomitant 
with alkaline phosphatase > 2.5 x ULN
•
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants skipping the dose of study medication.
Subsequent dose reductions may be required as per Section 7.4.3.1. Participants may receive 
growth factors (including G-CSF and erythropoietin) at the discretion of the investigator.
A dose given more than 3 days after the intended dose date will be considered a dose delay.
A maximum delay of 6 weeks between doses is allowed. Longer delays may be allowed following 
discussion with the Medical Monitor.
7.4.3.1
Dose Reductions for cisplatin
A maximum of 2 dose reductions are permitted; if additional reductions are required, cisplatin 
must be discontinued. Once a dose has been decreased, it should remain reduced for all subsequent 
dosing unless dose is further reduced. No dose escalations will be allowed. Participants who 
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discontinue cisplatin may, at the investigators discretion, continue administration of the other study 
drugs in the regimen.  
Recommendations for dose modifications for cisplatin should be considered with local institutional 
standards. The dose levels for cisplatin are listed in Table 7.4.3.1-1.
Table 7.4.3.1-1:
Dose Levels for Cisplatin
Toxicity Grade 
(CTCAE, v. 4)
Cisplatin Dose
Stating Dose
Dose Level -1
Dose Level -2
100 mg/m2
75 mg/m2
56 mg/m2
7.4.3.2
Recommended Cisplatin Dose Modifications for Hematologic Toxicity
Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration. Dose level adjustments are relative to that of the preceding administration and are 
described in Table 7.4.3.2-1.
Table 7.4.3.2-1:
Cisplatin Dose Modifications for Hematologic Toxicitya
Drug Related Toxicity
Cisplatin
Neutrophils (ANC) < 500/mm3 lasting ≥5 days
Decrease 1 dose level
Febrile neutropenia (body temperature ≥38.5°C and ANC 
< 1,000/mm3)
Decrease 1 dose level
Platelets < 25,000/mm3
Decrease 1 dose level
Platelets < 50,000/mm3 with significant bleeding or requiring 
blood transfusion
Decrease 1 dose level
Grade 4 hemoglobin (< 6.5 g/100 mL)
Decrease 1 dose level
a If considered in the best interest of the participant, and consistent with local practice, investigators may decide to 
use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. 
Also, if toxicity can clearly be attributed to one of the drugs, the investigator may choose to only dose reduce the 
cytotoxic.
7.4.3.3
Recommended Dose Modifications for Non-Hematologic Toxicity
Dose adjustments for non-hematologic toxicity during treatment are described in Table 7.4.3.3-1. 
All dose modifications should be made based on the worst grade toxicity per CTCAE v4.0. 
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7.4.7
Treatment of Nivolumab Related Infusion Reactions
As nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if a reaction occurs, it 
may manifest as fever, chills, rigors, headache, rash, pruritus, arthralgias, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion reactions
should be reported within 24 hours to the BMS Study Medical Monitor and reported as an SAE if 
it meets the criteria. Infusion reactions should be graded according to NCI CTCAE (Version 4) 
guidelines.
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 acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administration.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for ≤ 24 
hours):
•
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/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 nivolumab will be not be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (e.g., renal impairment, 
pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
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1:1000 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. Study drug will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., oral 
antihistamine or corticosteroids).
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 contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (e.g., required diluents, administration sets).
Infusion-related supplies (e.g., 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 (IB) and/or pharmacy manual for 
complete storage, handling, dispensing, and infusion information for nivolumab, cetuximab,
cisplatin, and matching placebo. The pharmacy manual will refer to the current SmPC for 
non-BMS investigational products. These products may be obtained by the investigational sites as 
local commercial product in countries where it is allowed by local regulations. Non-BMS 
investigational products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC) or according to institutional standards.
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
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7.7.2.2
Imaging Restriction and Precautions
Per Revised Protocol 3, imaging will be performed according to local standard of care. 
It is the local imaging facility’s responsibility to determine, based on participant attributes (e.g., 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered in 
this assessment. Participants with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. If CT is 
contraindicated for a participant because of an iodinated contrast allergy, then a contrast enhanced 
MRI of the neck, chest, abdomen and pelvis will be performed.
Specific to MRI, participants with severe renal insufficiency (i.e., estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this participant population. Certain surgically-implanted devices 
(pacemaker, deep brain stimulator, metallic implants, etc.) are incompatible with MRI imaging. 
The local imaging facility and investigator should determine the appropriate precautions or 
guidelines that should be instituted for participants with tattoos, body piercings or other body art.
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee.
. 
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration specified 
in protocol Section 7.1. Study treatment will be provided via an extension of the study, a rollover 
study requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of the nivolumab 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. 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 
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consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
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
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
•
Documented investigator-assessed progression by RECIST v1.1
Refer to the Schedule of Activities (Table 2-4) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
during a clinical trial, the study treatment must be discontinued immediately. 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. If the investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. 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 (i.e., is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment 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.
8.1.1
Nivolumab Dose Discontinuation
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 adverse event 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
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−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
♦Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x 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 Grade 4 drug-related adverse event 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 lasting ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. 
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 
every 6 weeks or more frequently if clinically indicated during such dosing delays.
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 nivolumab dosing.
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8.1.2
Criteria to Resume Nivolumab Treatment
Participants may resume 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 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor. Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
8.1.3
Nivolumab Treatment Beyond Disease Progression
Treatment beyond investigator assessed progression will not be permitted on this study. The 
radiotherapy given in combination with nivolumab/cisplatin/cetuximab are intended to be 
definitive treatment and any recurrence is likely to represent genuine progression of the disease, if 
that recurrence/progression is non equivocal. In cases where progression is equivocal based on 
imaging findings, it is recommended that a biopsy is performed to further investigate radiological 
findings.
8.1.4
Cetuximab Dose Discontinuation
Specific details of AEs requiring discontinuation can be found in section 8.1 and Section 7.4.2. 
8.1.5
Cisplatin Dose Discontinuation
See Section 8.1 and Section 7.4.3 for criteria for discontinuation of study treatment.
8.1.6
Post Study Treatment Study Follow-up
Per Revised Protocol 03, overall survival follow up is not required. Participants will be followed 
for assessment of safety through 100 days post last dose of study treatment. 
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (Section 2). At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
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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
After 15-October-2018, follow-up is restricted to safety assessments through the 100 days after 
the last day of dosing. 
•
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 (Section 2).
•
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (e.g., 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 (e.g.. 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 BMS-936558 (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
9.1.1
Imaging Assessment for the Study
Per Revised Protocol 03, imaging assessments will be conducted per the schedule of local standard 
of care. Tumor imaging assessments for ongoing study treatment decisions will be completed by 
the investigator using RECIST v1.1 criteria (see Appendix 10)
Screening (baseline) tumor assessments of neck, chest, abdomen, and pelvis are to be performed 
within 28 days prior to randomization. 
If the investigator assesses there to be progression, study treatments must discontinue; treatment 
beyond progression is not permitted in this protocol.
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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). 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (e.g., 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.
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. 
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 and 
continue during the treatment period and for a minimum of 100 days following discontinuation of 
study treatment, at the time points specified in the Schedule of Activities (Section 2). 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.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized/assigned to treatment and never treated with 
study drug, SAEs should be collected for 30 days from the date of randomization.
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.
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.
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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
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
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.
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).
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 
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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.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized/assigned to treatment and never treated with 
study drug, SAEs should be collected for 30 days from the date of randomization.
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.
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 
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
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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.
In the event of an overdose, the investigator should:
1) Contact the Medical Monitor immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities 
3) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant/
For details of regarding overdose with cetuximab or cisplatin can be found in the local product 
information.
Overdoses meeting the regulatory definition of an SAE must be reported as an SAE (see Appendix 
3).
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9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities in Section 2.
9.4.1
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin (T Bili)
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or serum urea 
level
Glucose
Albumin (Screening only)
Sodium (Na)
Potassium (K)
Chloride (Cl)
Calcium (Ca)
Phosphate (P)
Magnesium (Mg)
Creatinine clearance (CrCl) 
Serology
Hepatitis C antibody (HCV Ab), Hepatitis C RNA (HCV RNA)- screening only
Hepatitis B surface antigen (HBV sAg)- screening only
HIV, if mandated locally- screening only (See Appendix 8)
Other Analyses
Thyroid stimulating hormone (TSH) with free thyroxine (fT3) and free triiodothyronine (fT4)-
screening only; TSH with reflexive fT3 and fT4 during study and follow up
Pregnancy test (WOCBP only)- screening and during study
Follicle stimulating hormone (FSH)- screening only for women under 55 years old to confirm 
menopause as needed
9.4.2
Imaging Safety Assessment
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.
9.5
Pharmacokinetics and Immunogenicity
Not applicable per Revised Protocol 03. Samples collected for PK and immunogenicity analysis 
will be discarded and not analyzed. 
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Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
•
Residual whole blood (DNA), serum, plasma blood, PBMCs, and tumor biopsy collections 
(See Table 9.8.1-1) will be retained for additional research purposes.
Samples kept for future research will be stored at the BMS Biorepository in Hopewell, NJ, USA 
or an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be participant to the recipient’s 
agreement to establish similar storage procedures.
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Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the laboratory
procedure manual.
Table 9.8.1-1:
Residual Sample Retention for Additional Research 
Schedulea
Sample Type
Time points for which residual samples will be retained
Serum/Plasma
All
Whole Blood (DNA)
All
PBMC
All
Tumor Biopsy
All
a Samples collected prior to 15-Oct-2018, may be retained for additional research. 
9.8.2
Tumor Tissue Specimens
Screening Biopsies
The screening tumor biopsy tissue needs to be shipped to the central laboratory and the PD-L1 
analysis and HPV p-16 testing (if needed) must be processed with an available result prior to 
randomization. In the event the tumor sample is deemed unevaluable due to insufficient tumor 
content, the medical monitor may request the site to send another specimen, if available. The 
presence of either an archival or a fresh biopsy specimen is an inclusion criterion and hence a 
prerequisite for full eligibility of a participant. An archived biopsy prior to therapy is acceptable if 
the fresh biopsy cannot be obtained and if the archived tissue meets the defined criteria as stated 
below.
•
Obtained within 3 months of enrollment
•
An archived biopsy (block or slides) must contain tumor tissue
•
If archived blocks are not available, ≥25 slides (preferred) containing tumor are available for 
exploratory use.
9.8.2.1
Tumor sample collection details
In revised protocol 03 tumor samples are no longer required to be collected. 
A minimum of 5 formalin-fixed paraffin embedded (FFPE) unstained sections (preferred) are 
required for assessment of PD-L1 status. Specimens should contain a minimum of 100 evaluable 
tumor cells.
9.9
Medical Resource Utilization and Health Economics HEOR
Not applicable per Revised Protocol 03. 
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10
STATISTICAL CONSIDERATIONS
Per Revised Protocol 03, efficacy analyses will not be conducted (Section 3.1.1).
10.1
Sample Size Determination 
Per Revised Protocol 03, sample size will be limited to the patients enrolled as of October 15, 
2018.
This trial is made up of two cohorts, the first comprised of cisplatin ineligible participants and the 
second of cisplatin eligible participants. Each will be sized and analyzed separately.
The sample size and power calculations that follow were conducted assuming exponential time to 
even distributions, using East software, version 6.3.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.2
Populations for Analyses
Per Revised Protocol 03 this section is not applicable
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Analyses will be done by cohort. Key analysis populations for each cohort are defined as follows:
Table 10.2-1:
Analysis Populations
Population
Description
Enrolled
All participants who signed an informed consent form and were 
registered into the IRT.
Treated
All randomized participants who received at least one dose of study drug. 
This is the dataset for safety evaluation.
10.3
Endpoints
Per Revised Protocol 03, only safety assessments will be collected. 
•
Safety and tolerability will be measured by the incidence of deaths, adverse events, serious 
adverse events, adverse events leading to discontinuation, immune-mediated adverse events, 
select adverse events, adverse events leading to dose delay, and specific laboratory 
abnormalities (worst grade). Toxicities will be graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
•
Time to onset and time to resolution of immune-related AEs
10.4
Statistical Analyses
A description of the participant population will be included in the statistical output reported, 
including subgroup of age, gender, and race.
 
10.4.2
Safety Analyses
Analyses of safety will be conducted by cohort. They will be restricted to treated participants.
Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0, by treatment arm. The frequency and 
percentage of worst grade AEs, AEs leading to discontinuation and SAEs, without regard to cause
and drug-related, will be presented by system organ class and preferred term. On-study lab 
parameters including hematology, coagulation, chemistry, liver function and renal function will 
be summarized using worst grade per NCI CCAE v 4.0 criteria.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
Ab
Antibody
aCGA
Abbreviated Comprehensive Geriatric Assessment
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALP
Alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
anti-HCV
hepatitis C antibody
APM
antigen processing machinery 
AR
additional research 
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AT
Aminotranferase
BA/BE
bioavailability/bioequivalence
Bcl-xL
B-cell lymphoma-extra large
%BE
percent biliary excretion
BICR
Blinded Independent Central Review 
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BRt
Total amount recovered in bile
%BRt
Total percent of administered dose recovered in bile
BTLA
B- and T-lymphocyte attenuator
BUN
blood urea nitrogen
C or C
Cycle
CA
Cancer
Ca
Calcium
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Term
Definition
Cavg
average concentration
CBC
Complete Blood Cell
Cexpected-tau
expected concentration in a dosing interval
CD-28
Cluster of Differentiation 28
CFR
Code of Federal Regulations 
aCGA
Abbreviated Comprehensive Geriatric Assessment
CI
confidence interval
C1-
Chloride
CrCl
creatinine clearance
Cmaxss
steady-state maximum observed concentration
CMH
Cochran-Mantel-Haenszel 
CMV
Cytomegalovirus
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form, paper or electronic
eCRF
Electronic Case Report Form
CRT
chemoradiotherapy
CT
computed tomography
CTAg
Clinical Trial Agreement
CTCAE
Common Terminology Criteria for Adverse Events 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
d or D
Day
DILI
Drug induced liver injury
DLRC
Duration of locoregional control
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DMC
Data monitoring committee
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
DLRC
Duration of loco-regional control
EC50
Half maximal effective concentration
ECG
Electrocardiogram
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Term
Definition
ECOG
Eastern Cooperative Oncology Group 
ECOG PS
Eastern Co-operative Oncology Group performance status
EFS
event free survival
Eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
EORTC
European Organisation for the Research and Treatment of Cancer 
EORTC QLQ-
H&N35
EORTC head and neck cancer–specific module
FDA
Food and Drug Administration
FDG PET
fluorodeoxyglucose-positron emission tomography 
FFPE
formalin-fixed paraffin embedded 
FISH
fluorescent in-situ hybridization
FOXp3
forkhead box P3
FSH
follicle stimulating hormone
FU
follow up
GBM
glioblastoma multiforme
Hr
Hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV Ab
hepatitis C antibody
HCV RNA
hepatitis C RNA
HIV
Human Immunodeficiency Virus
HLA
human leukocyte antigen
HPV
Human papilloma virus
HR
heart rate
HR
hazard ratio 
HRQoL
Health-related quality of life
HSV
herpes simplex virus 
IB
Investigator Brochure 
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Term
Definition
IC
investigator’s choice 
ICAM
Intercellular Adhesion Molecule 1
ICOS
inducible T-cell costimulator
Ie
id est (that is)
IEC
Independent Ethics Committee
IFN-γ
Interferon gamma
IGRT
Image-Guided Radiation Therapy
IHC
immuno-histochemistry
IL
Interleukin
ILD
Interstitial lung disease
IMP
investigational medicinal products
IMRT
intensity modulated radiotherapy
IND
Investigational New Drug Exemption
IO
Innumo-oncology
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
K+
Potassium
Kg
Kilogram
L
Liter
LAD
locally advanced
LAD SCCHN
locally advanced squamous cell carcinoma of the head and neck
LDH
lactate dehydrogenase
Mg
Milligram
Mg++
Magnesium
MHC
Major histocompatibility complex
Min
Minute
mL
Milliliter
MLR
mixed lymphocyte reaction 
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Term
Definition
MNA
Mini Nutritional Assessment
MRI
magnetic resonance imaging
MS
mass spectrometry
MTD
maximum tolerated dose
N
number of subjects or observations
Na+
Sodium
N/A
not applicable
Ng
Nanogram
nM
Nanomolar
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute 
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small-cell lung cancer
OPC
Oropharynx
OPSCC
oropharyngeal squamous cell carcinoma
OS
Overall survival
PBMC
peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PD
Pharmacodynamics
PD-1
Programmed death-1
PDILI
Potential Drug Induced Liver Injury 
PD-L1
Programmed death-ligand 1
pembro
pembrolizumab
PET/CT
positron emission tomography/computed tomography
PFS
Progression free survival
PGIC
patient global impression of change 
PGIS
Patient global impression of severity
PK
Pharmacokinetics
PPK
population Pharmacokinetics
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Term
Definition
PO
per os (by mouth route of administration)
PRO
patient reported outcomes 
PS
Performance status
Q1W
every week
Q2W
Every 2 week
Q3W
every 3 week
Q4W
every 4 week
QA
Quality Assurance
QD, qd
quaque die, once daily
QLQ-C30
Quality of Life Questionnaire–Core 30
QoL
quality of life
RCC
renal cell carcinoma
R&D
Research and development
RNA
ribonucleic acid
RO
Receptor occupancy
RT
Radiation Therapy
RTOG
Radiation Therapy Oncology Group
SAE
serious adverse event
SAP
statistical analysis plan 
SCCHN
squamous cell carcinoma of the head and neck
SD
Standard deviation
SNPs
single nucleotide polymorphisms 
SmPC
summary of product characteristics
SOA
Schedule of Activities
Subj
Subject
SUSAR
Suspected, Unexpected Serious Adverse Reaction
TCR
T-cell receptor
fT3
free thyroxine
fT4
free thyroxine
TAO
Trial Access Online, the BMS implementation of an EDC capability
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Term
Definition
T.Bili
Total bilirubin
T-HALF
Half life
TID, tid
ter in die, three times a day
Tmax, TMAX
time of maximum observed concentration
TMB
Tumor mutation burden
TRAE
treatment-related adverse events
TRSAEs
treatment-related serious adverse events
TSH
Thyroid stimulating hormone
ULN
upper limit of normal 
VAS
visual analogue scale 
W
Week
WBC
white blood cell
WOCBP
women of childbearing potential
WNOCBP
women not of childbearing potential
RT
Radiotherapy
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APPENDIX 2
STUDY GOVERNANCE 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:
•
consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 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 for 
•
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. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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), 
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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.
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.
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BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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 .Certain CRF pages and/or electronic files may serve as the source 
documents:
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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.
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 treatment
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 treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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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: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
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.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
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 treatment 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 treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
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 weeks 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 6
TNM STAGING ACCORDING TO AJCC VERSION 8
The American Joint Committee for Cancer (AJCC) TNM Staging System is based on the extent 
of the tumor (T), the extent of spread to the lymph nodes (N), and the presence of metastasis (M). 
Adapted from Amin, M.B., Edge, S., Greene, F., Byrd, D.R., Brookland, R.K., Washington, M.K., 
et al. (Eds.) (2017). AJCC Cancer Staging Manual, 8th Edition. Switzerland:Springer International 
Publishing.
LARYNX
Table -1:
Supraglottis Tumor Staging (Definition of Primary Tumor)
Supraglottis
T Category
T Criteria
TX
Primary tumor cannot be assessed
Tis
Carcinoma in situ
T1
Tumor limited to one subsite of supraglottis with normal vocal cord mobility
T2
Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region 
outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) 
without fixation of the larynx
T3
Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid 
area, preepiglottic space, paraglottic space, and/or inner cortex of the thyroid cartilage
T4
Moderately advanced or very advanced
T4a
Moderately advanced local disease
Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the 
larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap 
muscles, thyroid, or esophagus)
T4b
Very advanced local disease
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
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Table -2:
Glottis Tumor Staging (Definition of Primary Tumor)
Glottis
T Category
T Criteria
TX
Primary tumor cannot be assessed
Tis
Carcinoma in situ
T1
Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal 
mobility
T1a
Tumor limited to one vocal cord
T1b
Tumor involves both vocal cords
T2
Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility
T3
Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or 
inner cortex of the thyroid cartilage 
T4
Moderately advanced or very advanced
T4a
Moderately advanced local disease
Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the 
larynx (e.g., trachea, cricoid cartilage, soft tissues of neck including deep extrinsic muscle of the 
tongue, strap muscles, thyroid, or esophagus)
T4b
Very advanced local disease
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures 
Table -3:
Subglottis Tumor Staging (Definition of Primary Tumor)
Subglottis
T Category
T Criteria
TX
Primary tumor cannot be assessed
Tis
Carcinoma in situ
T1
Tumor limited to the subglottis
T2
Tumor extends to vocal cord(s) with normal or impaired mobility
T3
Tumor limited to larynx with vocal cord fixation and/or invasion of paraglottic space and/or 
inner cortex of the thyroid cartilage
T4
Moderately advanced or very advanced
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Table -3:
Subglottis Tumor Staging (Definition of Primary Tumor)
Subglottis
T Category
T Criteria
T4a
Moderately advanced local disease
Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., 
trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, 
thyroid, or esophagus)
T4b
Very advanced local disease
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures 
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Table -4:
Definition of Regional Lymph Nodes (N)
Clinical N (cN)
N Category
N Criteria
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(-)
N2
Metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in greatest 
dimension and ENE);
or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension 
and ENE(-);
or metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE(-)
N2a
Metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in greatest 
dimension and ENE(-)
N2b
Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-)
N2c
Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension 
and ENE(-)
N3
Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(-);
or metastasis in any lymph node(s) with clinically overt ENE(+)
N3a
Metastasis in a lymph node, larger than 6 cm in greatest  dimension and ENE(-)
N3b
Metastasis in any lymph node(s) with clinically overt ENE(+)
Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of 
the cricoid (U) or below the lower border of the cricoid (L).
Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+)
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Table -5:
AJCC Prognostic Stage Groups
When T is...
And N is...
And M is..
Then the stage group is...
Tis
N0
M0
0
T1
N0
M0
I
T2
N0
M0
II
T3
N0
M0
III
T1,T2,T3
N1
M0
III
T4a
N0,1
M0
IVA
T1,T2,T3,T4a
N2
M0
IVA
Any T
N3
M0
IVB
T4b
Any N
M0
IVB
Any T
Any N
M1
IVC
LIP AND ORAL CAVITY
Table -6:
Tumor Staging (Definition of Primary Tumor)
T Category
T Criteria
TX
Primary tumor cannot be assessed
Tis
Carcinoma in situ
T1
Tumor is ≤ 2 cm, ≤ 5 mm depth of invasion (DOI)
DOI is depth of invasion and not tumor thickness
T2
Tumor ≤ 2 cm, DOI > 5 mm and ≤ 10 mm
or tumor > 2 cm but ≤4 cm, and ≤ 10 mm DOI
T3
Tumor > 4 cm 
or any tumor > 10 mm DOI
T4
Moderately advanced or very advanced local disease
T4a
Moderately advanced local disease
(lip) Tumor invades through cortical bone or involves the inferior alveolar nerve, floor of mouth, 
or skin of face (i.e., chin or nose)
(oral cavity) Tumor invades adjacent structures only (e.g. through cortical bone of the mandible or 
maxilla, or involves the maxillary sinus or skin of face )
Note: Superficial erosion of the bone/tooth socket (alone) by a gingival primary is not sufficient 
classify a tumor as T4
T4b
Very advanced local disease
Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid 
artery
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Table -7:
Definition of Regional Lymph Nodes (N)
Clinical N (cN)
N Category
N Criteria
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(-)
N2
Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest 
dimension and ENE(-);
or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and 
ENE(-);
or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and 
ENE(-)
N2a
Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest 
dimension and ENE(-)
N2b
Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-)
N2c
Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension,
and ENE(-)
N3
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-);
or metastasis in any node(s) and clinically overt ENE(+)
N3a
Metastasis in a lymph node larger than 6 cm in greatest  dimension and ENE(-)
N3b
Metastasis in any node(s) and clinically overt ENE(+)
Note: A designation of “U” or “L” ma be used for any N category to indicate metastasis above the lower border of the 
cricoid (U) or below the lower border of the cricoid (L).
Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+)
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Table -8:
AJCC Prognostic Stage Groups
When T is...
And N is...
And M is..
Then the stage group is...
T1
N0
M0
I
T2
N0
M0
II
T3
N0
M0
III
T1,2,3
N1
M0
III
T4a
N0,1
M0
IVA
T1,2,3,4a
N2
M0
IVA
Any T
N3
M0
IVB
T4b
Any N
M0
IVB
Any T
Any N
M1
IVC
OROPHARYNX (P16+)
Table -9:
Tumor Staging (Definition of Primary Tumor)
T Category
T Criteria
T0
No primary identified
T1
Tumor 2 cm or smaller in greatest dimension
T2
Tumor larger than 2 cm but not larger than 4 cm in greatest dimension
T3
Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis
T4
Moderately advanced local disease
Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible 
or beyond*
*Mucosal extension of lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does 
not constitute invasion of the larynx.
Table -10:
Definition of Regional Lymph Nodes (N)
Clinical N (cN)
N Category
N Criteria
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
One or more ipsilateral lymph nodes, none larger than 6 cm
N2
Contralateral or bilateral lymph nodes, none larger than 6 cm
N3
Lymph node(s) larger than 6 cm
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Table -11:
AJCC Prognostic Stage Groups
When T is...
And N is...
And M is...
Then the stage group is...
T0, T1 or T2
N0 or N1
M0
I
T0, T1 or T2
N2
M0
II
T3
N0, N1 or N2
M0
II
T0, T1, T2, T3 or T4
N3
M0
III
T4
N0, N1, N2 or N3
M0
III
Any T
Any N
M1
IV
OROPHARYNX (P16-) AND HYPOPHARYNX
Table -12:
Oropharynx (P16-)Tumor Staging (Definition of Primary Tumor)
Oropharynx (P16-)
T Category
T Criteria
TX
Primary tumor cannot be assessed
Tis
Carcinoma in situ
T1
Tumor 2 cm or smaller in greatest dimension
T2
Tumor larger than 2 cm but not larger than 4 cm in greatest dimension
T3
Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis
T4
Moderately advanced or very advanced local disease
T4a
Moderately advanced local disease
Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard plate or mandible*
T4b
Very advanced local disease
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or 
encases carotid artery
*Note: Mucosal extension of lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula 
does not constitute invasion of the larynx
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Table -13:
Hypopharynx Tumor Staging (Definition of Primary Tumor)
Hypopharynx
T Category
T Criteria
TX
Primary tumor cannot be assessed
Tis
Carcinoma in situ
T1
Tumor limited to one subsite of hypopharynx and/or 2 cm or smaller in greatest dimension
T2
Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures larger than 
2 cm but not larger than 4 cm in greatest dimension without fixation of hemilarynx 
T3
Tumor larger than 4 cm in greatest dimension or with fixation of hemilarynx or extension to 
esophagus
T4
Moderately advanced or very advanced local disease
T4a
Moderately advanced local disease
Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft 
tissue*
T4b
Very advanced local disease
Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures
*Note: Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat
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Table -14:
Definition of Regional Lymph Nodes (N)
Clinical N (cN) - Oropharynx(P16-) and Hypopharynx
N Category
N Criteria
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE(-)
N2
Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest 
dimension and ENE(-);
or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and 
ENE(-);
or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and 
ENE(-)
N2a
Metastasis in a single ipsilateral node larger than 3 cm but not larger than 6 cm in greatest 
dimension and ENE(-)
N2b
Metastasis in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(-)
N2c
Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension 
and ENE(-)
N3
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE(-);
or metastasis in any node(s) and clinically overt ENE(+)
N3a
Metastasis in a lymph node larger than 6 cm in greatest  dimension and ENE(-)
N3b
Metastasis in any node(s) and clinically overt ENE(+)
Note: A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of 
the cricoid (U) or below the lower border of the cricoid (L).
Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+)
Table -15:
AJCC Prognostic Stage Groups
When T is...
And N is...
And M is..
Then the stage group is...
Tis
N0
M0
0
T1
N0
M0
I
T2
N0
M0
II
T3
N0
M0
III
T1,T2,T3
N1
M0
III
T4a
N0,1
M0
IVA
T1,T2,T3,T4a
N2
M0
IVA
Any T
N3
M0
IVB
T4b
Any N
M0
IVB
Any T
Any N
M1
IVC
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APPENDIX 7
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS a
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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APPENDIX 8
COUNTRY SPECIFIC APPENDIX
Argentina, Czech Republic, France, Germany, Italy, Spain
Criterion to exclude HIV positive participants in countries listed above
Country-specific language
Section 2 Flow
Chart/Time and Events
Schedule, Table 2-1: 
ScreeningAssessments-
LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 1.a
“Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
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APPENDIX 9
NECK DISSECTION GUIDELINES 
Abbreviations: HPV= human papillomavirus; PRND=post radiation neck dissection; RT=Radiotherapy; SCCHN=squamous cell carcinoma of the head and neck
Source: Huang SH, et al. Temporal Nodal Regression and Regional Control After Primary Radiation Therapy for N2-N3 Head-and-Neck Cancer Stratified by HPV 
Status. International Journal of Radiation Oncology 87, 2013.
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APPENDIX 10
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
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/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
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.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-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 (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
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 above, 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.
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’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
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.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. 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
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
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retroperitoneum; however, if a lymph node is believed to be present and is 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). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
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. Similarly, 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’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group 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 (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, 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 qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
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2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’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.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). 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 patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued 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. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
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possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. 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 occurring at that site (if so, the 
date of PD will be the date of the initial abnormal 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.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’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. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients 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
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Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
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APPENDIX 11
HEAD AND NECK SQUAMOUS CELL CARCINOMAS 
CLASSIFIED AS FOLLOWS:
•
oral cavity: 
−
anterior two thirds of the tongue 
−
tongue unspecified, 
−
lip 
−
gum 
−
floor of the mouth 
−
hard palate 
−
palate unspecified 
−
other oral cavity—including buccal mucosa and retromolar area 
−
oral cavity unspecified 
•
oropharynx: 
−
base of the tongue 
−
soft palate 
−
tonsil 
−
uvula 
−
other parts of the oropharynx 
−
Waldeyer’s ring   
−
oropharynx unspecified
•
larynx: 
−
glottis
−
supraglottis
−
subglottis 
−
other and unspecified larynx subsites 
−
Hypopharynx cases are classified as belonging to the larynx, including pyriform sinus
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