REPORT; REirradiation and PD-1 Blockade On Recurrent Squamous Cell Head and Neck Tumors
Phase: PHASE1
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: Oslo University Hospital

 
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TITLE:  
 
REPORT; REirradiation and PD-1 blockade On Recurrent 
squamous cell head and neck Tumors  
 
 
 
 
SPONSOR:   
 
Oslo University Hospital 
The Norwegian Radium Hospital 
Department of Oncology 
Ullernchausseen 70 
0379 Oslo 
Norway 
 
 
 
 
 
 
EudraCT NUMBER: 
2016-005240-42 
 
 
 
PROTOCOL CODE: 
CA209-686_REPORT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol version no.:  
1.2 
Protocol date: 
 
16 May 2017 

 
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TABLE OF CONTENTS 
Contact details ......................................................................................................................... 6 
1.0 
TRIAL SUMMARY .................................................................................................... 7 
2.0 
BACKGROUND AND RATIONALE ....................................................................... 8 
2.1 
Rationale for study therapy ....................................................................................... 8 
2.2 
Nivolumab ................................................................................................................. 9 
2.3 
Rationale for Dose Selection ..................................................................................... 9 
2.4 
Risk/benefit considerations ....................................................................................... 9 
3.0 
Safety Monitoring Committee .................................................................................... 9 
4.0 
OBJECTIVEs & HYPOTHESES ............................................................................ 10 
4.1 
Objectives ................................................................................................................ 10 
4.2 
Hypotheses .............................................................................................................. 10 
5.0 
METHODOLOGY .................................................................................................... 11 
5.1 
Entry Criteria ........................................................................................................... 11 
5.1.1 Subject Inclusion Criteria .................................................................................... 11 
5.1.2 Subject Exclusion Criteria ................................................................................... 11 
5.2 
Study treatment ....................................................................................................... 12 
5.2.1 Study drug ........................................................................................................... 12 
5.3 
Dose schedule and modification ............................................................................. 14 
5.3.1 Nivolumab Schedule ........................................................................................... 14 
5.3.2 Dose Modifications for Nivolumab ..................................................................... 14 
5.4 
Concomitant Treatments ......................................................................................... 18 
5.4.1 Prohibited and/or Restricted Treatments ............................................................. 18 
5.4.2 Permitted Therapy ............................................................................................... 18 
5.5 
Subject Withdrawal/Discontinuation Criteria ......................................................... 19 

 
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5.6 
Clinical Criteria for Early Trial Termination .......................................................... 20 
6.0 
OUTCOME MEASURES ........................................................................................ 20 
6.1 
Primary Outcome Measures .................................................................................... 20 
6.2 
Secondary Outcome Measures ................................................................................ 20 
7.0 
TRIAL FLOWCHART ............................................................................................ 21 
8.0 
TRIAL PROCEDURES ............................................................................................ 23 
8.1 
Trial Procedures ...................................................................................................... 23 
8.1.1 Administrative Procedures .................................................................................. 23 
8.1.2 Clinical Procedures/Assessments ........................................................................ 25 
8.1.3 Other Procedures ................................................................................................. 28 
8.2 
End of study ............................................................................................................ 29 
9.0 
Adverse Events .......................................................................................................... 29 
9.1 
Management of adverse events ............................................................................... 30 
9.2 
Serious Adverse Events........................................................................................... 30 
9.2.1 Serious Adverse Event Collection and Reporting ............................................... 31 
9.3 
Nonserious Adverse Events .................................................................................... 32 
9.3.1 Nonserious Adverse Event Collection and Reporting ......................................... 32 
9.4 
Laboratory Test Result Abnormalities .................................................................... 32 
9.5 
Pregnancy ................................................................................................................ 32 
9.6 
Overdose ................................................................................................................. 33 
9.7 
Potential Drug Induced Liver Injury (DILI) ........................................................... 33 
9.8 
Dose Limitied Toxicity (DLT) ................................................................................ 33 
9.9 
Other Safety Considerations ................................................................................... 34 
9.9.1 Evaluating Adverse Events ................................................................................. 34 
9.10 
Sponsor Responsibility for Reporting Adverse Events ........................................... 34 
10.0 
COLLATERAL RESEARCH. ................................................................................. 36 

 
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10.1 
Biobanking: ............................................................................................................. 36 
10.2 
Plans for translational research addressing exploratory endpoints ......................... 36 
11.0 
STATISTICAL ANALYSIS PLAN ......................................................................... 37 
11.1 
Statistical Analysis Plan Summary ......................................................................... 37 
12.0 
Ehical considerations ................................................................................................ 38 
12.1 
Compliance with Laws and Regulations ................................................................. 38 
12.2 
Informed Consent .................................................................................................... 38 
12.3 
Ethics Committee .................................................................................................... 38 
12.4 
Confidentiality ........................................................................................................ 39 
13.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 39 
13.1 
Study Documentation .............................................................................................. 39 
13.2 
Protocol Adherence ................................................................................................. 39 
13.3 
Monitoring .............................................................................................................. 39 
13.4 
Audit and Inspections .............................................................................................. 40 
13.5 
Data Management ................................................................................................... 40 
13.6 
Publication Policy ................................................................................................... 40 
14.0 
LIST OF REFERENCES ......................................................................................... 41 
15.0 
Abbreviations ............................................................................................................. 42 
16.0 
APPENDICES ........................................................................................................... 44 
16.1 
ECOG Performance Status ...................................................................................... 44 
16.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ..................... 44 
16.3 
Response Evaluation Criteria in Solid Tumors ....................................................... 44 
16.3.1 Measurability of tumor at baseline ...................................................................... 44 
16.3.2 Target lesions: specifications by methods of measurements .............................. 46 
16.3.3 Tumor response evaluation ................................................................................. 47 
16.4 
Immune-modified Response Evaluation Criteria in Solid Tumors ......................... 53 

 
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16.4.1 Definitions of measurable/non-measurable lesions ............................................. 54 
16.4.2 Tumor response evaluation ................................................................................. 56 
16.5 
Methods of contraception ........................................................................................ 60 
17.0 
SIGNATURES ........................................................................................................... 62 
17.1 
Sponsor's Representative ......................................................................................... 62 
17.2 
Investigator .............................................................................................................. 62 
 

 
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CONTACT DETAILS 
Sponsor: 
Stein Kaasa, MD PhD 
Department of Oncology 
Oslo University Hospital 
Ph: +47 22934000 
Principal Investigator: 
Åse Bratland, MD PhD 
Oslo University Hospital, The Norwegian 
Radiumhospital 
Nydalen Postbox 4950 
Oslo, 0424 Norway 
Ph:+47 4024 3735/+47 2293 5942 
BRT@ous-hf.no 
Principal Investigator:  
Jon Amund Kyte, MD PhD 
Oslo University Hospital, The Norwegian 
Radiumhospital 
Nydalen Postbox 4950 
Oslo, 0424 Norway 
Ph:+47 9756 9619/+47 2293 4000 
Jon.amund.kyte@rr-research.no 
Statistical adviser 
 
 
 
 
 
Eva Skovlund, Professor 
Department of Public Health and General Practice 
NTNU  
PO Box 8905  
Trondheim, 7491 Norway 
Ph:+47 7359 7536 
eva.skovlund@ntnu.no 
 
Project manager 
Ismail Abdi,  
Department of Oncology 
Oslo University Hospital 
Ph:+47 2293 5177/+47 2302 6824 
Ismabd@ous-hf.no 
 
 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
REPORT  
Full title 
REirradiation and PD-1 blockade On Recurrent squamous cell head and 
neck Tumors 
Trial Phase 
Phase I/II 
Clinical Indication 
Head and neck squamous cell carcinoma (HNSCC) 
Trial Type 
Exploratory 
Type of control 
NA 
Route of administration 
Intravenous 
Trial Blinding 
Open-label 
Treatment Groups  
Nivolumab, intravenous every 2nd week (1 cycle = 2 weeks), dose 
escalation schedule (1.0, 3.0 mg/kg), for a maximum of 12 months or 
until disease progression. In addition radiotherapy (RT) will be given to 
a total dose of 60 Gy (1,5 Gy fractions twice daily) for a total period of 4 
weeks  
Number of trial subjects 
20 
Estimated enrollment period 
Q2 2017 – Q4 2018 
Estimated duration of trial 
The sponsor estimates that the trial will require approximately 2.5 years 
from the time the first subject signs the informed consent until the last 
subject’s last on-treatment visit. Follow-up will continue 4 years after 
end of study therapy.  
Duration of Participation 
Each subject will participate in the trial until death, drop out, or loss-to 
follow-up from the time the subject signs the Informed Consent Form 
(ICF) through the final contact. After a screening phase of up to 28 days, 
each eligible subject will receive nivolumab. Two weeks after start of 
nivolumab the patients will receive radiotherapy (RT) to a total dose of 
60 Gy, given as 1.5 Gy fractions twice daily for a total period of 4 
weeks. Treatment with nivolumab will continue until disease 
progression, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, Investigator’s decision to 
withdraw the subject, noncompliance with trial treatment or procedures 
requirements, subject receives nivolumab for 12 months, pregnancy, or 
administrative reasons. 
After the end of treatment, each subject will be followed for 30 days for 
adverse event monitoring (serious adverse events [SAEs] will be 
collected for 90 days after the end of treatment). Patients without disease 
progression will have follow-up visits for 4 years after end of study 
therapy. 
 
 
 
 
 
 

 
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2.0 BACKGROUND AND RATIONALE 
2.1 
Rationale for study therapy 
Radiotherapy (RT) is a main treatment modality across different cancer forms and is 
administered to approximately 50 % of all cancer patients. Radiation therapy is not curative in 
most cases, and the need for adjuvants is evident and unmet. There has emerged compelling 
evidence that radiotherapy is capable of inducing immunogenic cell death, which serves as a 
trigger for the immune system (“in situ vaccine”). Recently published preclinical and clinical 
data indicate that localized radiotherapy can evoke and/or modulate tumor-associated immune 
responses, resulting in systemic anti-tumor activity(1). There is generally a high expression of 
PDL-1 in HNSCC(2), and the expression is enhanced by RT. HNSCC is among the most 
radiation sensitive cancers, while also considered immunogenic, partly due to the high and 
increasing frequency of tumors infected with human papiloma virus (HPV)(2). Moreover, 
HNSCC with T-cell infiltration is more sensitive to radiotherapy. 
 
In this study, the aim is to release the brake on the immune response by use of nivolumab, an 
inhibitory antibody against PD-1. Importantly, the immune response may not only boost local 
tumor control, but lead to eradication of metastatic disease and hence bring patients to a curative 
situation. Nivolumab has previously been shown to be effective in phase III trials in melanoma, 
lung cancer and renal cell carcinoma.  Recently the results from a phase III study in HNSCC 
was reported(3). This was, an open-label, randomized study of nivolumab versus investigator’s 
choice of therapy in previously treated patients with HNSCC. The patients had tumor 
progression on or within 6 months of platinum therapy in the primary, recurrent, or metastatic 
setting. The trial randomized 361 patients 2:1 to receive either nivolumab 3 mg/kg intravenously 
every two weeks or investigator’s choice (cetuximab/methotrexate/docetaxel) until documented 
disease progression or unacceptable toxicity. The primary endpoint was OS. The study was 
stopped early due to positive interim results in favour of nivolumab.  At the interim analysis, 
which was conducted after 218 events, patients assigned to nivolumab were found to have a 30 
percent reduction in risk of death compared with those assigned therapy of investigator’s choice. 
Median overall survival was 7.5 months for those assigned nivolumab versus 5.1 months for 
those assigned therapy of investigator’s choice. At 12 months, 36 percent of the patients treated 
with nivolumab were alive compared with 17 percent of those assigned therapy of investigator’s 
choice. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-
therapy group. The safety profile for nivolumab was favorable compared to the investigator´s 
choice therapy, and consistent with prior studies. Treatment-related adverse events of grade 3 or 
4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the 
standard-therapy group 
 
Despite aggressive multimodal treatment with chemoradiotherapy, hypoxic-modulators and 
surgery to cure HNSCC patients, recurrent and second primary tumors in previous irradiated 
area (>46 Gy) are a common clinical challenge. Re-irradiation to doses of 60 Gy or more is a 
possible treatment option, offering long-term survival for selected patients. However, the re-
irradiation is complicated with serious acute and late toxicity.  Recurrent disease is also 
associated with a high risk of developing systemic disease. There is a need for new treatment 
approaches and combinations to improve tumor control and reduce toxicity. 
 
Radiotherapy is a powerful inducer of inflammation, and the expression of PD1-L1 is known to 
be enhanced by inflammatory cytokines, including IFNg. Experimental evidence from mice 

 
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models have shown that radiotherapy induces increased PD-L1 expression in tumor tissue. 
Moreover, there is evidence suggesting that HNSCC with T-cell infiltration is more sensitive to 
radiotherapy. There is thus a strong rationale for combing PD-1 inhibitors with radiotherapy. 
However, this potential remains largely unexplored in humans. We consider that head-and-neck 
cancer is a particularly attractive entity for investigating this therapeutic combination, because 
of i) the high radiosensitivity of this cancer form ii) the clinical efficacy of PD-1 inhibitors as 
monotherapy in early clinical trials iii) the availability of tumor  biopsies for 
translational/biomarker research.  
 
2.2 
Nivolumab 
Nivolumab is a fully human monoclonal antibody that binds to PD-1 with nanomolar affinity 
and a high degree of specificity, thus precluding binding of PD-1 to its ligands PD-L1 and PD-
L2. Nivolumab does not bind other related family members, such as BTLA, CTLA-4, ICOS, or 
CD28. Nivolumab has been approved by FDA and EMA for treatment of metastatic melanoma, 
renal cell carcinoma (RCC) and NSCLC, based on phase III trials showing improved survival. 
Clinical trials have also demonstrated clinical activity of nivolumab against HNSCC (see above) 
and other cancers. Please refer to the Investigator’s Brochure (IB)/approved labeling for detailed 
background information on nivolumab. 
 
2.3 
Rationale for Dose Selection  
Nivolumab is safe and well tolerated up to 10 mg/kg Q2W dose level (see IB). The RT given in 
the present study gives considerable side effects, related to inflammation that may be enhanced 
by PD1 blockade. Nivolumab has shown efficacy and mild toxicity when given as monotherapy 
for HNSCC at a dose of 3.0 mg/kg Q2W, which is the target dose in the present trial(3). To 
assess the toxicity, the following dosing schedule has been chosen: Nivolumab, intravenous 
every 2nd week (1 cycle = 2 weeks), dose escalation schedule (1.0, 3.0 mg/kg), for a maximum 
of 12 months or until disease progression. RT will be given to a total dose of 60 Gy (1.5 Gy 
fractions twice daily) for a total period of 4 weeks. We expect that any increased toxicity will be 
observed within 2 weeks after end of RT and thus allow for a 3.0 mg/kg Q2W dose level 
therafter. If a drug-related toxicity is observed, the guidelines outlined below will apply. 
2.4 
Risk/benefit considerations 
The benefit-risk relationship has been carefully considered in the planning of the trial. Based on 
the preclinical and clinical data (see IB, (3) and above), the conduct of this trial is considered 
justifiable. Even though subjects in phase I/II clinical trials generally cannot expect to receive 
direct benefit, we believe the rationale for conducting this trial is sound, and it is a realistic 
chance that some patients could benefit from nivolumab in combination with radiotherapy. The 
routine treatment (i.e. radiotherapy or palliative chemotherapy alone) is not of major benefit for 
many patients in this group. The dose escalation schedule included in our trial design, and the 
moderate maxium dose of 3.0 mg/kg, mean that the risk of SAE related to nivolumab is limited. 
We thus consider that the risk-benefit ratio is favourable. Additional details regarding specific 
benefits and risks for subjects participating in this clinical trial may be found in the 
accompanying Investigators Brochure (IB) and Informed Consent documents. 
 
3.0 SAFETY MONITORING COMMITTEE  
A safety monitoring committee (SMC) will monitor safety on a periodic basis. Members of the 

 
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SMC will be experienced clinicians. The SMC will meet approximately every 6 months from 
the point of first patient in (FPI) to review safety and study conduct data. The safety data will 
include demographic data, adverse events and relevant laboratory data. In addition the SMC will 
meet after finalization of each dose cohort (i.e. three patients has completed minimum 8 weeks 
of treatment), and in case DLT is experienced. See section 8.8 for definitions.  
Following each data review, the SMC will provide recommendations to the Study Leadership as 
to whether the study should continue or be amended, or whether the study should be stopped on 
the basis of safety (i.e., evidence of harm). The Study Leadership will make a decision on the 
basis of the SMC recommendations.  
Any outcomes of these safety reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of the Institutional Review Boards/Ethics 
Committees (IRBs/ECs).  
 
No interim efficacy analysis is planned. 
 
4.0 OBJECTIVES & HYPOTHESES 
4.1 
Objectives 
Primary objectives: 
1) To determine the safety and tolerability of nivolumab when administered concomitant 
with high dose (60 Gy) re-irradiation in patients with locally advanced recurrent or 
second primary HNSCC 
2) To determine a safe dose of  nivolumab when administered concomitant with high dose 
(60 Gy) re-irradiation in patients with locally advanced recurrent or second primary 
HNSCC 
 
Secondary objectives: 
1) To evaluate progression-free survival after 12 months 
2) To evaluate objective response rate (ORR) and duration of response (DOR), by RECIST 
v1.1 as primary method and immune-related RECIST (irRECIST) as secondary method 
3) To evaluate overall survival 
 
Exploratory objectives: 
4) To investigate the immunological response, tumor evolution and dynamics in the tumor 
micrenvironment induced by the study therapy 
5) To investigate biomarkers for development of clinical response, toxicity and immune 
response 
 
 
4.2 
Hypotheses 
- 
Anti-PD1 mAb can safely be administered concomitant with re-radiation in HNSCC. 

 
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- 
The combination therapy can induce clinical response, immune response and dynamics 
in the tumor microenvironment.  
- 
Genetical and immunological profiling of pre-treatment samples may identify 
biomarkers for predicting which patients will benefit from the therapy 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Subject Inclusion Criteria 
 Age >18 years 
 Recurrent or secondary primary squamous cell carcinoma originating from the oral 
cavity, oro/hypo-pharynx or larynx 
 Prior radiotherapy (46-70Gy) 
 Adequate newly obtained core or excisional biopsy of a recurrent tumor lesion  
 Measurable disease 
 Lesion available for biopsy during study treatment 
 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
 Life expectancy > 12 months 
 A minimum of 6 months since prior radiotherapy in the same area or minimum 4 weeks 
(28 days) since previous other cancer treatment   
 Both HPV positive and HPV negative disease allowed  
 Distant metastases allowed 
 Adequate organ function based on clinical examination and lab values 
 Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of study drug 
 Women must not be breastfeeding 
 WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus 
the time required for nivolumab to undergo five half-lives) after the last dose of 
investigational drug 
 Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the 
time required for the investigational drug to undergo five half-lives. The terminal half-
life of nivolumab is up to 25 days 
 
5.1.2 Subject Exclusion Criteria 
 History of other prior malignancy, with the exception of curatively treated basal cell or 
squamous cell carcinoma of the skin, cervical cancer stage IB and stage I prostate cancer 
considered not necessary to treat 
 Disease suitable for curative salvage surgery 
 Treatment with any investigational medicinal product (IMP) that may interfere with the 
study treatment, within 4 weeks prior to first administration of study drug.  

 
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 Significant cardiac, pulmonary or other medical illness that would limit activity or 
survival 
 Pregnancy or lactation. 
 Known hypersensitivity to any of the components of the investigational product 
 Patients who test positive for hepatitis B, C or HIV.  
 Diagnosis of immunodeficiency or medical condition requiring systemic steroids or 
other forms of immunosuppressive therapy 
 Autoimmune disease that has required systemic therapy within the past 2 years 
 Any reason why, in the opinion of the investigator, the patient should not participate  
 
5.2 
Study treatment 
The study will include 20 patients. The following treatment will be used: 
 Radiotherapy (RT) to a total dose of 60 Gy, given as 1.5 Gy fractions twice daily for a 
total period of 4 weeks, will be delivered to the target volumes determined by PET-CT 
scan. Definition of target volumes and organs at risk will follow the Dahanca guidelines 
2013 (published on www.dahanca.dk ). The dose deliverd to organs at risk, determined 
by PET-CT scan, will also be calculated. 
 
 Nivolumab administered intravenous every two weeks, starting two weeks (Cycle 1, Day 
1) before start of radiotherapy. Nivolumab will be given for a maximum of 12 months or 
until disease progression. 
 
 Nivolumab will be administered according to a dose escalation schedule (1.0 and 3.0 
mg/kg), as shown in Figure 1. Three patients will be included at each dose level. During 
the dose escalation part the subsequent patient will start therapy with nivolumab 6 weeks 
after the previous to allow time to observe the possibility for acute toxicity. If no dose 
limiting toxicity (DLT) is observed at the first dose level, additional three patients will 
be included at the next dose level. If DLT is experienced see section 8.8 for details. The 
remaining patients will we treated at the maximum tolerated dose.     
 
 The nivolumab dose will be adjusted to 3.0 mg/kg (standard dose used in 
NCT02105636) for all patients from Cycle 5, Day 1 (2 weeks after end of radiotherapy), 
irrespective of starting dose.     
            
 
The study treatment is outlined in Table 1. Trial treatment should begin within 28 days of first 
interventional screening assessments. Details on preparation and administration of nivolumab 
are provided in the IB.  
5.2.1 Study drug 
The product storage manager at the local pharmacy should ensure that the study drug is stored in 
accordance with the environmental conditions (temperature, light, and humidity) as determined 
by BMS. If concerns regarding the quality or appearance of the study drug arise, the study drug 
should not be dispensed and contact BMS immediately. 
Investigational product documentation  must be maintained. That includes all processes required 
to ensure drug is accurately administered. This includes documentation of drug storage, 

 
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administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets). 
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% 
dextrose injection) will not be supplied by the sponsor and should be purchased locally if 
permitted by local regulations. 
 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
Please refer to the current version of the Investigator Brochure (IB) and/or pharmacy reference 
sheets for complete storage, handling, dispensing, and infusion information for nivolumab. 
The infusion will be administrated by nurses with experience in treatment with immunotherapy.  
 
Table 1  Study Treatment 
Drug 
Dose/Potency Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Nivolumab 
1,0 mg/kg 
Q2W 
IV infusion 
Day 1 of each 2 week 
cycle 
Experimental, 
Dose level 1 
Nivolumab 
3,0 mg/kg 
Q2W 
IV infusion 
Day 1 of each 2 week 
cycle 
Experimental, 
Dose level 2 
Radiotherapy 
1,5 Gy 
BID 
 
5 days a week, 4 
weeks (Cycle 2 and 
3) 
Standard 
 
Figure 1  
     
    
 
 
 
 
 
            
Dose-escalation part of study: 
1st dose level 
N=3 
Nivolumab; 1,0 
mg/kg, C1-C4-6 
Radiation; 1,5 Gy 
b.i.d., C2-C3 
2nd dose level 
N=3 
Nivolumab; 3,0 
mg/kg, C1-C46 
Radiation; 1,5 Gy 
b.i.d., C2-C3 
DLT 
No DLT 
See protocol section 8.8. 

 
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5.3 
Dose schedule and modification 
5.3.1 Nivolumab Schedule 
Continuation of nivolumab treatment with suspected progression is permitted, see Section 
5.3.2.4. Treatment will continue for a maxiumum of 12 months, or discontinuation from study 
treatment due to any of the criteria listed in section 5.5. 
 
If required, subjects may receive nivolumab up to 3 days before or after the scheduled date. A 
dose given more than 3 days after the intended dose date will be considered a delay. Subsequent 
dosing should be based on the actual date of administration of the previous dose of drug. 
Subjects should be monitored for infusion reactions during nivolumab administration. If an 
acute reaction is noted, subjects should be managed according to Section 5.3.2.6. Doses of 
nivolumab may be interrupted, delayed or discontinued as needed. 
5.3.2 Dose Modifications for Nivolumab 
Dose modification is only allowed in case of Dose Limited Toxiticity (DLT). See section 8.8 for 
instructions. For dose delay, see 5.3.2.1 
5.3.2.1 Dose Delay Criteria for Nivolumab 
Dose delay criteria apply for all drug-related AEs. A treatment delay up to 4 weeks, i.e. 6 weeks 
calculated from the last dose, is allowed. A treatment delay beyond this must be discussed with 
the Study leadership. A treatment delay beyond 10 weeks is not allowed. 
 
Tumor assessments should continue per protocol schedule, even if dosing is delayed. 
 
Nivolumab administration should be delayed for the following reasons: 
 
Any Grade ≥ 2 non-skin drug-related adverse event, except for fatigue and laboratory 
abnormalities 
 
Any Grade 3 skin drug-related adverse event 
 
Any Grade 3 drug-related laboratory abnormality  
 
Any adverse event, laboratory abnormality, intercurrent illness or other reason which, in the 
judgment of the investigator, warrants delaying the dose of study medication. 
 
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated. Nivolumab dosing can be resumed on the established dosing schedule when 
retreatment criteria are met (Section 5.3.2.2). 
 
5.3.2.2 Criteria to Resume Dosing for Nivolumab 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤ 
1 or baseline value, with the following exceptions: 
 
Subjects may resume treatment in the presence of grade 2 fatigue 
 
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed.  
 
Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 

 
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 
Subjects who received systemic corticosteroids for management of any drug-related toxicity 
must be off corticosteroids or have tapered down to an equivalent dose of prednisone ≤ 10 
mg/day. 
 
5.3.2.3 Treatment Discontinuation Criteria for Nivolumab 
Nivolumab treatment should be permanently discontinued for the following:  
 
Any grade 4 drug-related toxicity  
 
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment. 
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies: 
o 
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation 
o 
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation 
o 
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 
 
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
o 
AST or ALT > 5 x ULN for 2 weeks 
o 
AST or ALT >5 x ULN 
o 
Total bilirubin > 3 x ULN 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events which do not require discontinuation: 
o 
Grade 4 neutropenia ≤ 7 days 
o 
Grade 4 lymphopenia or leukopenia 
o 
Isolated Grade 4 amylase or lipase abnormalities that is not associated with symptoms 
or clinical manifestations of pancreatitis. The Study leadership should be consulted for 
Grade 4 amylase or lipase abnormalities. 
o 
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 
o 
Grade 4 drug-related endocrinopathy adverse events, such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or 
are adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Study leadership. 
 
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
o 
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. 
o 
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed, if approved by the Study leadership. 

 
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o 
Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 weeks, the 
Study leadership 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 subject with continued nivolumab 
dosing. 
 
For deailed information see the IB for nivolumab. 
 
 
5.3.2.4 Continuing Nivolumab with Suspected Progression 
Accumulating evidence indicates that a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of disease progression, eg, due to inflammatory 
reaction simulating progression (“tumor flare” or pseudoprogression). Subjects may, at 
investigator discretion and agreement with the Study leadership, continue nivolumab in the 
setting of suspected progression until progression is confirmed. If the investigator believes that 
the subject continues to derive clinical benefit by continuing treatment, the subject should 
continue monitoring/assessments according the same schedule as patinets without tumor 
progression, with more frequent radiologic assessment if clinically indicated (see below). 
 
Subjects may continue nivolumab beyond initial (suspected) progression only if they meet the 
following criteria: 
 Subject is in stable performance status (ECOG 0-1) and tolerating nivolumab 
 Treatment will not delay intervention to prevent imminent complications 
 Investigator-assessed overall clinical benefit 
 
Radiographic assessment should be repeated after suspected progression as clinically required in 
order to determine whether there has been a decrease in the tumor size or continued progression. 
Potential for clinical benefit should be balanced by clinical judgment as to whether the subject is 
clinically deteriorating and unlikely to receive benefit from continued treatment with nivolumab. 
Nivolumab treatment should be discontinued permanently upon confirmation of progression. 
 
5.3.2.5 Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology 
agent in this protocol. Early recognition and management of AEs associated with immune 
oncology agents may mitigate severe toxicity. Management Algorithms have been developed to 
assist investigators in assessing and managing the following groups of AEs: 
 
Gastrointestinal 
 
Renal 
 
Pulmonary 
 
Hepatic 
 
Endocrinopathy 
 
Skin 
 
Neurological 

 
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The above algorithms are found in the nivolumab Investigator Brochure. 
 
5.3.2.6 Treatment of Nivolumab-Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(Version 4.0) guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes 
before additional nivolumab administrations. 
 
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic 
medications indicated for ≤ 24 hours): 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor subject 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 subject closely. If symptoms recur, 
then no further nivolumab will 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 SoluCortef or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates). Grade 4: Life threatening; pressor or ventilatory support 
indicated): 
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 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 

 
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Page 18 of 62 
 
 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery of the 
symptoms. 
 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (eg, 
oral antihistamine or corticosteroids). 
 
5.4 
Concomitant Treatments 
  
It is expected that enrolled subjects will have systemic corticosteroids tapered as quickly as 
clinically appropriate during screening phase, and discontinued if possible prior to inclusion. 
 
Supportive care for all disease-related or treatment-related adverse events should be maximized 
for all subjects on this study. 
 
5.4.1 Prohibited and/or Restricted Treatments 
Immunosuppressive agents, including systemic corticosteroids, are prohibited during study 
treatment unless utilized to treat a drug-related adverse event. Subjects with a condition 
requiring systemic treatment with either corticosteroids (> 20 mg daily prednisone or > 3 mg 
dexamethasone per day (or equivalent) or other immunosuppressive medications (including 
within 14 days of inclusion) are excluded. Subjects continuing to require supra-physiologic 
steroids (prednisone > 20 mg daily or > 3 mg dexamethasone per day or equivalent) may not be 
included. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 20 mg daily 
prednisone or ≤ 3 mg dexamethasone per day or equivalent, are permitted in the absence of 
active autoimmune disease.  
 
5.4.2 Permitted Therapy 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
 
Steroid use should be minimized prior to inclusion. Systemic corticosteroid use or physiologic 
replacement doses of steroids are permitted, even if > 20 mg/day prednisone equivalents, for: a) 
treatment-related AEs or b) treatment of non-autoimmune conditions (eg, prophylaxis for 
contrast dye allergy, contact hypersensitivity). Details regarding corticosteroid use prior to and 
during the study will be collected (name of medication, doses utilized, start and stop dates, 
frequency of use, route of administration). Information regarding concomitant corticosteroid use 
may be analyzed with regard to study outcome measures. Subjects requiring chronic treatment 
with corticosteroids should be treated with histamine-2-receptor antagonists or proton pump 
inhibitors as prophylaxis for potential gastrointestinal adverse reactions (ulceration, perforation, 
hemorrhage) unless otherwise contraindicated. 
 

 
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Concomitant medications are recorded at baseline and throughout the treatment phase of the 
study in the appropriate section of the CRF. All medications (prescriptions or over the counter 
medications) continued at the start of the study or started during the study and different from the 
study drug must be documented in the concomitant therapy section of the CRF. 
 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs. 
5.5 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the Investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the Investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.3 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 AE as described above (section 5.3.2.3). 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, please 
see Section 5.3.2.4 
 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 subject 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 

 
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 Administrative reasons 
The End of Treatment visit procedures are listed in Section 6 (Protocol Flow Chart) and Section 
7.  After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring. Subjects who discontinue for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, starting a non-study cancer 
treatment, withdrawing consent or becoming lost to follow-up.  After documented disease 
progression, information on survival will be obtained until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
5.6 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of BMS decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
 
6.0 OUTCOME MEASURES 
6.1 
Primary Outcome Measures 
 Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0. 
 Changes in vital signs, physical findings, and clinical laboratory results 
6.2 
Secondary Outcome Measures 
 PFS, defined as the time from inclusion to the time of radiographic progression (as 
assessed by RECIST) or death from any cause during the study 
 Overall survival (OS), defined as the time from the date of inclusion to the date of death 
from any cause 
 Objective tumor response rate (ORR), defined as the proportion of patients with an 
objective tumor response (either partial response [PR] or complete response [CR] per 
investigator using RECIST) 
 Durable response rate (DRR), defined as the proportion of patients with an objective 
tumor response lasting at least 6 months 
 Duration of objective response (DOR) among patients with an objective response 
 PFS, ORR, DRR and DOR assessed by irRECIST v1.1 
 

 
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7.0 TRIAL FLOWCHART 
 
Trial Period: 
Screening Phase 
Treatment phasea 
Post-Treatment 
Treatment Cycle (C)/Title: 
(Each cycle is 2 weeks) 
Informed 
consent 
(Visit 1) 
Main 
Study 
Screenin
g  
(Visit 2) 
  
  
  
To be 
repeated 
until total 
treatment 
time of 12 
months 
Treatm
ent 
discont
inuatio
n 
Safet
y 
Follo
w-up 
Follow
-up 
Year 1 
after 
disc. 
Follo
w-up 
Year 
2-4 
after 
disc. 
Survi
val 
Follo
w-up 
C1 
D1 
C2 
D1 
C3
D1 
C4 
D1 
C5 
D1 
Scheduling Window (Days): 
  
-14 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
At time 
of disc. 
30 
days 
post 
disc. 
Every 3 
months 
post 
disc. 
Ever
y 6 
mont
hs  
  
Administrative Procedures 
Informed Consentb 
x 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
  
x 
  
  
  
  
  
  
  
  
  
  
Demographics and Medical 
History 
  
x 
  
  
  
  
  
  
  
  
  
  
Prior and Concomitant Medication 
Reviewc  
  
x 
  
  
  
  
  
  
  
  
  
  
Post-study anticancer therapy 
status 
  
  
  
  
  
  
  
  
  
x 
x 
  
Clinical Procedures/Assessments 
Review Adverse Eventsd,e 
  
x 
x 
x 
x 
x 
x 
X 
x 
x 
  
  
Full Physical Examination  
  
x 
  
  
  
x 
  
  
x 
  
  
  
Directed Physical Examination 
  
  
x 
x 
x 
  
x 
X 
  
x 
x 
  
Vital Signs and Weightf 
x  
x 
x 
x 
x 
x 
X 
x 
x 
x 
  
ECOG Performance Status 
  
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
  
Electrocardiogram (ECG) f 
 
x 
 
 
 
 
xf 
 
 
 
 
 
Survival Follow-up 
  
  
  
  
  
  
  
  
  
  
  
x 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
Pregnancy Testg 
  
x 
  
  
x  
  
  
  
PT/INR and aPTTh 
  
x 
  
  
  
  
  
  
  
  
  
  
CBC with Differentiali 
  
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
  
Comprehensive Serum Chemistry 
Paneli 
  
x 
x 
x 
x 
x 
x 
X 
x 
x 
x 
  
HIV, HBV and HCV test 
x  
  
  
  
  
  
  
  
  
  
  
Urine analysisi 
  
x 
  
  
  
x 
  
X 
x 
xl 
x 
  
 FT4 and TSH, anti TPOip 
  
x 
  
  
x 
  
x 
X 
x 
x 
x 
  
Treatment administration 
Nivolumab 
  
  
x 
x 
x 
x 
x 
  
  
  
  
  
Radiation therapy 
  
  
  
x 
x 
  
  
  
  
  
  
  
Efficacy Measurements 
18F-FDG PET/CTj 
  
x 
  
  
  
  
xk 
xm 
  
  
  
  
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival and Newly Obtained 
Tissue Collectionn 
  
x 
  
xr 
xr 
  
  
xr 
  
  
  
  
Plasma and Serum Collectiono  
  
x 
  
x 
x 
x  
x  
X 
  
xl 
x 
  

 
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Page 22 of 62 
 
 
Trial Period: 
Screening Phase 
Treatment phasea 
Post-Treatment 
Treatment Cycle (C)/Title: 
(Each cycle is 2 weeks) 
Informed 
consent 
(Visit 1) 
Main 
Study 
Screenin
g  
(Visit 2) 
  
  
  
To be 
repeated 
until total 
treatment 
time of 12 
months 
Treatm
ent 
discont
inuatio
n 
Safet
y 
Follo
w-up 
Follow
-up 
Year 1 
after 
disc. 
Follo
w-up 
Year 
2-4 
after 
disc. 
Survi
val 
Follo
w-up 
C1 
D1 
C2 
D1 
C3
D1 
C4 
D1 
C5 
D1 
Scheduling Window (Days): 
  
-14 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
At time 
of disc. 
30 
days 
post 
disc. 
Every 3 
months 
post 
disc. 
Ever
y 6 
mont
hs  
  
PBMC collectiono  
  
x 
  
x 
x 
  
x  
X 
  
xl 
  
a.              General, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless 
otherwise specified. Treatment cycles are 2 weeks; however the treatment cycle interval may be increased due to toxicity according to 
the dose modification guidelines. 
b.              Written consent must be obtained prior to performing any protocol specified procedure. Results of a test performed prior to the 
subject signing consent as part of routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame in the protocol. Subject number will be assigned when the study informed consent is signed. 
c.              Prior medications – Record all medications taken within 30 days of screening visit. Concomitant medications – Enter new 
medications started during the trial through the Safety Follow-up visit. Record all medications taken for AEs. 
d.              AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, whether gradable by CTCAE 
or not, will also be evaluated for seriousness. 
e.               After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a 
protocol-mandated intervention should be reported. After initiation of study drug, all adverse events will be reported until 90 days after 
the last dose of study treatment or until initiation of another anti-cancer therapy, whichever occurs first. After this period, investigators 
should report any serious adverse events that are believed to be related to prior treatment with study drug. For subjects included and 
never treated with study drug, SAEs should be collected for 30 days from the date of inclusion. All SAEs must be followed to 
resolution or stabilization. 
f.               Vital signs to include temperature, pulse, oxygen saturation, weight and blood pressure. Height will be measured at screening 
only. ECG is to be performed at screening , C5 day 1 and every 8th week thereafter, until disease progression or end of treatment with 
nivolumab. 
g.              For women of childbearing potential , a serum pregnancy test should be performed within 24 hours prior to first dose of trial 
treatment. Pregnancy tests (serum and/or urine tests) should be repeated every 5 cycles (10 weeks) ± 7 days. 
h.              Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject 
receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial. 
i.                Unresolved abnormal lab values that are drug related AEs should be followed until resolution. Lab tests do not need to be 
repeated after the end of treatment if lab tests are within normal range.  
j.              Tumor assessments by 18F-FDG PET/CT will be performed at screening, (Cycle 7), (Cycle 16) and at Month 12 (± 1 week). 
Tumor response will be evaluated using both and RECIST v1.1 (Appendix 15.3) and immune-modified RECIST criteria (Appendix 
15.4). In the absence of disease progression, tumor assessments should continue regardless of whether patients discontinue study 
treatment, unless they withdraw consent or the study is terminated by the Sponsor, whichever occurs first. 
k.              Cycle 7 and Cycle 16, Month 12 and yearly thereafter until 5 years after start of treatment 
l.              For patients not progressed during treatment, urine analysis, plasma and serum, and PBMC collection to be performed at first 
FU visit only (12 weeks after discontinuation). 
m.               In subjects who discontinue study therapy, a radiologic evaluation should be performed at the time of treatment 
discontinuation (i.e., date of discontinuation ± 4 weeks). If a previous scan was obtained within 4 weeks prior to the date of 
discontinuation, then a scan at treatment discontinuation is not mandatory. 
n.            Fresh frozen and FFPE tumor biopsies before start of treatment (Cycle 1), before start of radiotherapy (Cycle 2), at Cycle 3 and 
at disease relapse/progression. 
o.               PBMC; at screening (or day 1 Cycle 1), and at Day 1 at the following cycles; Cycle 2, Cycle 3, Cycle 5, Cycle 9, Cycle 16 
and at disease progression. 100 ml ACD blood at baseline. 50 ml ACD blood at later time points. To be taken before infusion of IMP. 
Plasma and serum will be collected at screening (or day 1 Cycle 1), Cycle 2 (Day 1 and 8), Cycle 3 (Day 1 and 8), Cycle 4 (Day 1), 
Cycle 5 (Day 1), Cycle 9 (Day 1), Cycle 16 (Day 1), Month 12 and at disease progression.  
p.             Thyroid function testing is to be done every 6 weeks during nivolumab treatment. 
r.          The sample collection is optional 
 

 
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8.0 TRIAL PROCEDURES 
8.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the Investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
8.1.1 Administrative Procedures 
8.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
8.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 

 
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8.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee to 
ensure that the subject qualifies for the trial.  
8.1.1.3 Medical History 
A medical history will be obtained by the Investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
8.1.1.4 Prior and Concomitant Medications Review 
8.1.1.4.1 Prior Medications 
The Investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this 
study will be recorded separately and not listed as a prior medication.  
8.1.1.4.2 Concomitant Medications 
The Investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  
8.1.1.5 Disease Details and Treatments 
8.1.1.5.1 Disease Details 
The Investigator or qualified designee will obtain prior and current details regarding disease 
status.  
8.1.1.5.2 Prior Treatment Details 
The Investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
8.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The Investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move 
into survival follow-up.  

 
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8.1.1.6 Assignment of Subject Number 
All consented subjects will be given a unique subject number that will be used to identify the 
subject for all procedures that occur during the screening period, and for all subjects eligible for 
treatment, during the treatment and follow-up period.  
Each subject will be assigned only one subject number. Subject numbers must not be re-used for 
different subjects. Any subject who is screened multiple times will retain the original subject 
number assigned at the initial screening visit. 
 
8.1.2 Clinical Procedures/Assessments 
8.1.2.1 Safety Assessments 
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Status, BP, HR, temperature and 
oxygen saturation by pulse oximetry at rest and should be performed within 28 days prior to first 
dose. Baseline signs and symptoms are those that are assessed within 14 days prior to first dose 
of study drug. Concomitant medications including steroid dose will be collected within 14 days 
prior to first dose of study drug through the study treatment period. 
Baseline local laboratory assessments should be done within 14 days prior to first dose and are 
to include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, albumin, Ca, Mg, Na, K, Cl, phosphate, LDH, glucose, 
amylase,lipase, TSH, free T4, and urine analysis. 
The following baseline local laboratory assessments should be done within 28 days prior to first 
treatment: Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA). 
Pregnancy testing must be performed within 72 hours prior to Day 1 and then every 5 cycles (10 
weeks) ± 7 days. 
While on-study the following local laboratory assessments are to be done within 3 days prior to 
each dose: CBC with differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN 
or serum urea level, creatinine, albumin (if clinically indicated), Ca, Mg, Na, K, Cl, phosphate, 
LDH, glucose, amylase, and lipase. Thyroid function testing is to be done every 6 weeks. 
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the safety follow-up phase toxicity 
assessments should be done in person. Once subjects reach the survival follow-up phase, either 
in person or documented telephone calls to assess the subject’s status are acceptable. 
 
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0. 
 
The start and stop time of the study therapy infusions should be documented. 
 
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected 
drug induced liver enzyme evaluations) will be monitored during the follow-up phase via on 
site/local labs until all study drug related toxicities resolve, return to baseline, or are deemed 
irreversible. 

 
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Some of the assessments referred to in this section may not be captured as data in the CRF. 
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. 
 
8.1.2.1.1 Full Physical Exam 
The Investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening and at Day 1, at Cycle 4 
and Cycle 8, and Day 1 at every fourth cycle onwards during study treatment as well as at the 30 
days safety follow-up visit. 
8.1.2.1.2 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the Investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
8.1.2.1.3 Vital Signs 
The Investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in the 
Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, oxygen saturation, 
weight and blood pressure. Height will be measured at screening only. 
8.1.2.1.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The Investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment, at discontinuation of trial treatment and during 
follow-up as specified in the Trial Flow Chart.   
8.1.2.2 Tumor Imaging and Assessment of Disease 
The imaging assessments will be performed by 18F-FDG PET/CT. The tumor response will be 
assessed according to RECIST v1.1 as primary method and and by Immune Modified Response 
Evaluation Criteria in Solid Tumors (imRECIST) as secondary method. After baseline tumor 
assessments, evaluation of tumor response will be performed at Cycle 7, Day 1 (± 7 days), 
Cycle 16, Day 1 (± 7 days), at 12 months (± 10 days) from the date of first dose, and every 12 
months thereafter (± 21 days) until 5 years after the first dose. Additional 18F-FDG PET/CT 
scans or other radiological evaluations will be performed if indicated.  
 
8.1.2.3 Tumor Tissue Collection and Correlative Studies Blood Sampling  
Fresh frozen and FFPE tumor biopsies will be obtained before start of treatment with nivolumab 
(Cycle 1), and thereafter optional before start of Cycle 2 (start of radiotherapy), at start of Cycle 
3, and at disease relapse/progression. 

 
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PBMCs will be collected before start of treatment with nivolumab, and at Day 1 at the following 
cycles; Cycle 2, Cycle 3, Cycle 5, Cycle 9, Cycle 16 and at disease progression. Plasma and 
serum will be collected at baseline, Cycle 2 (Day 1 and 8), Cycle 3 (Day 1 and 8), Cycle 4 (Day 
1), Cycle 5 (Day 1), Cycle 9 (Day 1), Cycle 16 (Day 1), Month 12 and at disease progression. 
For patients not progressing on study treatment, PBMCs and plasma and serum will also be 
collected 12 weeks after end of nivolumab therapy.  
 
8.1.2.4 Laboratory tests 
Laboratory tests for hematology, chemistry, urin analysis and other relevant tests are specified in 
Table 2. The lab results must be reviewed by the Investigator or qualified designee and found to 
be acceptable prior to each dose of trial treatment.  
Table 2 Laboratory Tests 
Hematology 
Chemistry 
Urine analysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
   
Platelet count 
Alanine 
aminotransferase (ALT) 
Protein 
INR 
WBC (total and 
differential) 
Aspartate 
aminotransferase (AST) 
 
aPTT 
Red Blood Cell 
Count 
Lactate dehydrogenase 
(LDH) 
Microscopic exam if 
abnormal results are 
noted 
 
Absolute Neutrophil 
Count 
Total protein 
 
Free tyroxine (T4) 
Absolute 
Lymphocyte Count 
CRP 
Urine pregnancy test † Thyroid stimulating hormone 
(TSH) 
 
Creatinine 
 
TPO 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Amylase 
 
Glucose 
 
 Lipase 
 
Phosphorus 
 
 HBV sAg and HCV Ab or 
HCV RNA 
 
Potassium   
 
 HIV-test 
 
Sodium 
 
  
 
Magnesium 
 
 PBMC 
 
Total Bilirubin 
 
 Plasma, serum 
 
Direct Bilirubin (If total 
bilirubin is elevated) 
 
 
† Perform on women of childbearing potential only.  

 
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8.1.2.5 Thyroid Function Testing 
At Screening, thyroid function testing is to include TSH and free T4. At subsequent time 
points, thyroid function testing consists of TSH only. However, if the TSH is abnormal 
testing of free T4 is to be performed. 
Management algorithms for suspected endocrinopathy adverse events (including abnormal 
thyroid function) can be found in the nivolumab investigator brochure. 
8.1.3 Other Procedures 
8.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 8. 
8.1.3.2 Screening Period 
Approximately 28 days prior to subject allocation, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Visit 
requirements are outlined in Section 6.0 – Trial Flow Chart. Results of a test performed prior 
to the subject signing consent as part of routine clinical management are acceptable in lieu of 
a screening test if performed within the specified time frame. Screening procedures are to be 
completed within 28 days prior to the first dose trial treatment except for the following: 
 
o Laboratory tests and ECOG PS are to be performed within 14 days prior to the first dose 
of trial treatment. 
 
o For women of childbearing potential, a serum pregnancy test will be performed within72 
hours prior to the first dose of trial treatment. A urine test may be considered if serum test 
is not appropriate. 
 
o The baseline tumor biopsy has to be obtained within 28 days prior to the first dose.  
 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 
 
8.1.3.3 Treatment Period 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures. 
 

 
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8.1.3.4 Post-Treatment Visits 
8.1.3.4.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or stabilization, until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded.   
8.1.3.4.2 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase. The remaining patients will move into the FollowUp Phase 
after end of nivolumab treatment. The patients should be assessed every 3 months the first 
year after discontinuation (± 7 days), the following three years (year 2-4 after discontinuation 
of study treatment) every six month, to monitor disease status.  Every effort should be made 
to collect information regarding disease status until the start of new anti-neoplastic therapy, 
disease progression, death and end of the study. Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated.    
8.1.3.4.3 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase. We will then monitor survival 
status by contacting the GP/local hospital or by phoning the patient every 3 month, until the 
end of the study. The survival status and, if applicable, the cause of death, will be recorded. 
 
 
8.2 
End of study 
The end of study is defined as 5 years after inclusion of the last patient.  
 
9.0 ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a preexisting medical condition in a clinical investigation subject administered study drug 
and that does not necessarily have a causal relationship with this treatment.  
 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of study drug, 
whether or not considered related to the study drug. 
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following: 

 
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 Related: There is a reasonable causal relationship between study drug administration 
and the AE. 
 Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject.  
 
9.1 
Management of adverse events 
For recommendations on the management of adverse events, please see the last updated 
version of the Investigator´s Brochure for nivolumab. 
9.2 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
results in death 
 
is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect 
 
is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in 
the definition above). Examples of such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalization.) Potential drug induced liver injury 
(DILI) is also considered an important medical event. (See Section 8.7 for the definition 
of potential DILI.) 
 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE. 
 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 
8 for reporting pregnancies). 
 

 
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Any component of a study endpoint that is considered related to study therapy (eg, death is 
an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be 
reported as SAE (see Section 8 for reporting details). 
 
NOTE: 
The following hospitalizations are not considered SAEs in this study: 
 
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 (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 
admission for administration of anticancer therapy in the absence of any other SAEs  
 
9.2.1 Serious Adverse Event Collection and Reporting 
The Investigator Brochure (IB) represents the Reference Safety Information to determine 
expectedness of serious adverse events for expedited reporting. Following the subject’s 
written consent to participate in the study, all SAEs, whether related or not related to study 
drug, must be collected, including those thought to be associated with protocol-specified 
procedures. All SAEs must be collected that occur during the screening period and within 90 
days of the last dose of nivolumab. If applicable, SAEs must be collected that relate to any 
later protocol-specified procedure (eg, a follow-up skin biopsy). For subjects included and 
never treated with study drug, SAEs should be collected for 30 days from the date of 
inclusion. 
 
The investigator must report any SAE that occurs after these time periods and that is believed 
to be related to study drug or protocol-specified procedure. 
 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of a 
study procedure), the relationship must be specified in the narrative section of the SAE 
Report Form. 
 
SAEs, whether related or not related to study drug, and pregnancies, must be reported to 
Sponsor (or designee) within 24 hours of awareness of the event. SAEs must be recorded on 
the SAE Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper 
forms).  
 

 
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If only limited information is initially available, follow-up reports are required.  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to 
Sponsor (or designee) using the same procedure used for transmitting the initial SAE report. 
 
All SAEs must be followed to resolution or stabilization. 
 
9.3 
Nonserious Adverse Events 
9.3.1 Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug until 90 
days from the last dose of study drug.  
 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as 
appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF. 
 
9.4 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE 
CRF page or SAE Report Form as appropriate:  
 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
 
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted 
 
Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy. 
 
It is expected that wherever possible, the clinical rather than laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value). 
 
9.5 
Pregnancy 
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half lives after product administration, the investigator must immediately notify the 
Sponsor of this event and complete and forward a Pregnancy Form to Sponsor within 24 
hours of awareness of the event and in accordance with SAE reporting procedures. 
 
In this case, the study drug will be permanently discontinued in an appropriate manner. 
 

 
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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 Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to Sponsor. Information on this pregnancy will be collected on the Pregnancy Form. 
 
9.6 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
 
9.7 
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. 
 
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. 
 
9.8 
Dose Limitied Toxicity (DLT) 
 
We foresee that DLT related to Grade 3 and/or 4 dermatitis and mucositt may be 
experienced.  
 
During dose escalation phase: If a patient experience a possibly nivolumab-related Grade 3 
adverse event at any dose level, an additional patient will be included at this dose level. If 
one more patient experience the same Grade 3 event on the same dose level (i.e. 2 of 4 
patients at one dose level experiences the same Grade 3 event), this will be defined as DLT 
reached, and the dose should be reduced by one level. If DLT is experienced at the lowest 
dose level (1,0 mg/kg), the dose will be reduced to 0.3 mg/kg. If two patients experience 
DLT at this dose level, the study will be terminated. If a patient experiences a Grade 4 event, 
the dose should immediately be reduced by one level. 
 
The Safety Monitoring Committee (SMC) will meet in the case of DLT, to discuss futher 
progress related to doses of nivolumab, and whether the protocol should be amended. In 

 
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addition, the SMC will meet after every time three patients have completed each dose level 
(i.e. completed the re-radiation), to discuss whether it will be safe to move to next dose level. 
No further patients will be included until the SMC has met. After the dose escalation phase 
has been completed, the SMC will meet if two patients experience AE grade 3 or one patient 
experiences AE Grade 4, considered related to nivolumab. No further patients will be 
included until the SMC has met. 
  
The SMC is a group of oncologists located at the Clinical Cancer Research Unit, with  
experience in immunotherapy treatment. The members will not be involved in the study 
design or the study treatment.  
 
9.9 
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. 
 
9.9.1 Evaluating Adverse Events 
An Investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
9.10 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to Competent Authorities and Investigators in 
accordance with applicable national laws and regulations.  
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported to the 
Competent Authority according to national regulation. The following timelines should be 
followed: 
The sponsor will ensure that all relevant information about SUSARs that are fatal or life-
threatening is recorded and reported as soon as possible to the Competent Authority 
concerned in any case no later than seven (7) days after knowledge by the sponsor of such a 
case, and that relevant follow-up information is subsequently communicated within an 
additional eight (8) days. 
All other SUSARs will be reported to the Competent Authority concerned as soon as possible 
but within a maximum of fifteen (15) days of first knowledge by the sponsor. 

 
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SUSARs will be reported using the CIOMS form since Oslo University Hospital (sponsor) is 
not connected to EudraVigilance.  
 

 
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10.0 COLLATERAL RESEARCH. 
An extensive research program will be conducted. The patient informed consent form will 
allow for performing biomarker analyses, immunological studies, gene profiling and studies 
of tumor evolution/heterogeneity during treatment, as well as comparison with data/material 
from other studies.  
10.1 Biobanking: 
Please see the study flow chart for information on the time points for collection of biopsies 
and peripheral blood. 
 Tumor biopsies collected pre, during and post therapy (time of progression). If 
sufficient tissue is avaliable, the tumor will be cut into two/three pieces: 
o Fresh tumor cells/ tumor infiltrating lymphocytes frozen as cell suspension for 
CYTOF/flow cytometry, analysis of T cell specificity with multimers and 
functional immune assays 
o Snap-frozen tumor biopsies 
o FFPE tissue  
 
 Peripheral blood samples collected pre-, during and post-therapy:  
o Peripheral blood mononuclear cells, processed with gradient centrifugation 
and frozen on liquid nitrogen  
o Plasma/serum, separated and frozen. 
 
10.2 Plans for translational research addressing exploratory endpoints 
The list below does not represent a mandatory list of assays that are to be performed, but 
provides an overview of the current plans. The prioritation of assays will be subject to 
review during the trial. Additional assays may be performed, reflecting ongoing 
developments in the field. Some of these assays will only be performed on selected 
patients, due to cost and work load.  
 
1. Gene profiling with selected panels 
2. Pathology/immunohistochemistry on all patients (incl. PD-L1, markers for immunogenic 
cell death and for lymphocyte and macrophage subpopulations) 
3. DNA exome seq. of tumor and normal PBMCs on selected patients (mutations, HLA 
types/loss, SNPs in immune pathways)    
4. RNA transcriptome sequencing of tumor on selected patients (gene expression profiles, 
neoantigens) 
5. Serum biomarkers/soluble biopsies, including 
a. circulating DNA 
b. circulating micro RNA  
c. Bioplex cytokine- and MMP panels  
6. Characterization of cell suspensions from tumor and peripheral blood: 

 
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a. CYTOF (investigating subpopulations/heterogeneity/evolution, both within tumor 
cells, immune cells and other stromal cells; relate CYTOF data to gene profiling 
and mRNA expression) 
b. Flow cytometry, including the use of panels for regulatory T cells and myeloid 
suppressor cells(4) 
7. Test of T cell reactivity against HPV-antigens, common tumor antigens and the 
individual spectrum of antigens in each patient´s tumor, identified through tumor 
sequencing/epitope prediction.  
a. Functional T cell assays, incl. ELISPOT, proliferation, Bioplex cytokine profiling, 
multimers (5, 6) 
8. Tumor gene profiling for investigating tumor evolution/hetergenousity during treatment. 
Possible validation with mass spectrometry, CyTOF and IHC.  
 
11.0  STATISTICAL ANALYSIS PLAN 
11.1 Statistical Analysis Plan Summary 
In this exploratory phase I study no formal hypothesis testing will be performed. Hence, the 
primary endpoint and secondary endpoints will be evaluated only by descriptive methods. 
Data will be described with proportions (percentage) for categorical data and with median, 
mean and range for continuous data. Kaplan-Meier curves will be produced for PFS and OS.  
Progression free survival (PFS), defined as the time from inclusion to the occurrence of 
disease progression, as determined by investigators from tumor assessments per RECIST, or 
death from any cause, whichever occurs first. Data for patients without disease progression 
or death will be censored at the last tumor assessment date.  
 
Overall survival (OS) will be calculated from the date of first dose of nivolumab until death. 
Patients alive at the time of data analysis will be treated as censored.  
Exploratory analyses will be carried out to evaluate the data of the immunological and 
molecular analyses (e.g. biomarker studies) carried out. The statistical analyses will be 
dependent on the biological factors investigated and the analysis methodology used, and will 
be defined separately for each molecular study. With regard to some of the 
secondary/exploratory objectives, comparative analyses between groups or between samples 
obtained at different time points will be performed. 
 
A number of 20 patients is considered suitable for addressing the primary endpoints, i.e. 
evaluating the safety and dose in the selected patient population. The biobank material 
obtained at consecutive time points from 20 patients should be sufficient for informative 
collateral studies.    
 
 
 

 
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12.0 EHICAL CONSIDERATIONS 
 
12.1 Compliance with Laws and Regulations 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations 
of the country in which the research is conducted, whichever affords the greater protection to 
the individual. The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting), in 
addition with the E.U. Clinical Trial Directive (2001/20/EC). 
 
12.2 Informed Consent 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research. The investigator or 
authorized designee will explain to each patient the objectives of the exploratory research. 
Patients will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period. A separate, specific 
signature will be required to document a patient's agreement to allow any remaining 
specimens to be used for exploratory research. Patients who decline to participate will not 
provide a separate signature. 
 
The Consent Forms must be signed and dated by the patient or the patient’s legally clinical 
records for each patient shall document the informed consent process and that written 
informed consent was obtained prior to participation in the study.  
 
The Consent Forms should be revised whenever there are changes to study procedures or 
when new information becomes available that may affect the willingness of the patient to 
participate. The final revised IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes. 
 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised Consent 
Forms, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated Consent Forms must remain in each patient’s 
study file or in the site file and must be available for verification by study monitors at any 
time. 
 
12.3 Ethics Committee  
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information will be submitted to the Ethics Committee, reviewed and 

 
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approved according national regulations before the study is initiated. This is also valid for 
any amendments and/or a new version of the study protocol (Amended Protocol).  
12.4 Confidentiality 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient names 
are not included in data sets. 
 
Patient medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the Informed Consent Form (or separate authorization for 
use and disclosure of personal health information) signed by the patient, unless permitted or 
required by law. 
 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
 
Data generated by this study must be available for inspection upon request by representatives 
of the Competent Authority, Sponsor and monitors. 
 
13.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
13.1 Study Documentation 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of EC and governmental 
approval.  
 
 
13.2 Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations.  
All significant protocol deviations will be recorded and reported in the Clinical Study Report 
(CSR). 
13.3 Monitoring 
The investigator/site will be visited on a regular basis by the Clinical Study Monitor, who 
will assess compliance with the trial protocol and general principles of Good Clinical 
Practice. The monitor will review the relevant CRFs for accuracy and completeness and will 
ask the site staff to adjust any discrepancies as required.  
 
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be 
allowed access to source data for source data verification in which case a review of those 
parts of the hospital records relevant to the study may be required.  

 
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13.4 Audit and Inspections 
 
Authorized representatives of a Competent Authority and Ethics Committee may visit the 
centre to perform inspections, including source data verification. Likewise the representatives 
from sponsor may visit the center to perform an audit. The purpose of an audit or inspection 
is to systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (ICH GCP), and any 
applicable regulatory requirements. The principal investigator will ensure that the inspectors 
and auditors will be provided with access to source data/documents. 
 
13.5 Data Management 
The Investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. Detailed information regarding Data Management procedures for this 
protocol will be provided separately. 
 
13.6 Publication Policy 
 
Upon study completion and finalization of the study report the results of this study will either 
be submitted for publication and/or posted in a publicly assessable database of clinical study 
results. The results of this study will also be submitted to the Competent Authority and the 
Ethics Committee according to EU and national regulations.  
All personnel who have contributed significantly with the planning and performance of the 
study (Vancouver convention 1988) may be included in the list of authors. 
 
 

 
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14.0  LIST OF REFERENCES 
1. 
Levy A, Chargari C, Marabelle A, Perfettini JL, Magne N, Deutsch E. Can 
immunostimulatory agents enhance the abscopal effect of radiotherapy? Eur J Cancer. 
2016;62:36-45. 
2. 
Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, et al. 
Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated 
head and neck squamous cell carcinoma. Cancer Res. 2013;73(6):1733-41. 
3. 
Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. 
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 
2016. 
4. 
Hansen GL, Gaudernack G, Brunsvig PF, Cvancarova M, Kyte JA. Immunological 
factors influencing clinical outcome in lung cancer patients after telomerase peptide 
vaccination. Cancer Immunol Immunother. 2015;64(12):1609-21. 
5. 
Kyte JA, Gaudernack G, Dueland S, Trachsel S, Julsrud L, Aamdal S. Telomerase 
Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma 
Patients. Clin Cancer Res. 2011;17(13):4568-80. 
6. 
Bentzen AK, Marquard AM, Lyngaa R, Saini SK, Ramskov S, Donia M, et al. Large-
scale detection of antigen-specific T cells using peptide-MHC-I multimers labeled with DNA 
barcodes. Nat Biotechnol. 2016. 
 
 

 
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15.0       ABBREVIATIONS 
Abbreviation/Term Definition 
Definition 
ACD 
Acid Citrate Dextrose 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
AST 
Aspartate Aminotransferase  
BP 
Blood Pressure 
BSA 
Body Surface Area 
BTLA 
B And T Lymphocyte Associated 
BUN 
Blood Urea Nitorgen 
CRF 
Case Report Form (electronic/paper) 
CTCAE 
Common Terminology Criteria for Adverse Event 
CTLA-4 
Cytotoxic T Lymphocyte Antigen 4 
CYTOF 
CYtometry Time Of Flight 
DILI 
Drug Induced Liver Injury 
DLT 
Dose Limited Toxicity 
DOR 
Duration Of response 
EC 
Ethics Committee, synonymous to Institutional Review 
Board (IRB) and Independent Ethics Committee (IEC) 
ECOG PS 
Eastern Cooperative Oncology Group Performance 
Status 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of 
Cancer 
ERC 
European Research Council 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed Paraphin Embedded  
HNSCC 
Head and Neck Squamous Cell Carcinoma  
HPV 
Human Papillomavirus 
HR 
Heart Rate 
IB 
Investgators Brochure 
ICH 
International Conference on Harmonization 
ICOS 
Inducible Costimulator Protein 
IFN 
Interferon 
IMP 
Investigational Medicinal Product  
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
mAb 
monoclonal Anti body 
MDSC 
Myeloid-derived Suppressor Cells 
MMP 
Matrix Metalloproteinase 

 
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NCI 
National Cancer Institute 
NSCLC 
Non Small Cell Lung Cancer 
ORR 
Objectiv Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell  
PD-1 
Programmed Death 1 
PD-L1 
Programmed Death Ligand-1  
PFS 
Progression-free Survival 
Q2W 
Once every 2 weeks 
RR 
Respiratory Rate 
RT 
Radiotherapy 
SAE 
Serious Adverse Event  
SMC 
Safety Monitoring Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WOCBP 
Women of childbearing potential  
 

 
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16.0 APPENDICES 
16.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
16.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
16.3 Response Evaluation Criteria in Solid Tumors 
 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), Version 
1.1 are presented below, with slight modifications and the addition of explanatory text as 
needed for clarity. 
 
16.3.1 Measurability of tumor at baseline 
 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
 
 
 

 
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Measurable Tumor Lesions 
Tumor Lesions. 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 computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
 10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the 
short axis will be measured and followed. See also notes below on “Baseline Documentation 
of Target and Nontarget Lesions” for information on lymph node measurement. 
 
Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, peritoneal spread, and abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques. 
 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
 
Bone lesions: 
 Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.  
 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 measurable lesions if the soft tissue component meets the 
definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
 

 
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Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
 
 
16.3.2 Target lesions: specifications by methods of measurements 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during study. Imaging-based evaluation should 
always be the preferred option. 
 
Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules). 
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested. 
 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
 
CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable. 
 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast due to allergy or renal insufficiency, the decision as to whether a 
noncontrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline 
and during the study should be guided by the tumor type under investigation and the 
anatomic location of the disease. For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether noncontrast CT or MRI (enhanced or 
nonenhanced) will be performed should also be based on the tumor type and the anatomic 
location of the disease and should be optimized to allow for comparison with the prior 
studies if possible. Each case should be discussed with the radiologist to determine if 
substitution of these other approaches is possible and, if not, the patient should be considered 
not evaluable from that point forward. Care must be taken in measurement of target lesions 

 
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on a different modality and interpretation of nontarget disease or new lesions since the same 
lesion may appear to have a different size using a new modality. 
 
Ultrasound. Ultrasound is not useful in the assessment of lesion size and should not be used 
as a method of measurement. 
 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The utilization of these 
techniques for objective tumor evaluation cannot generally be advised. 
 
16.3.3 Tumor response evaluation 
16.3.3.1 Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and to use this as a comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable lesion, as detailed 
above. 
 
16.3.3.2 Baseline documentation of target and nontarget 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 lesions (one site) and four lesions (two sites), respectively, will be 
recorded. Other lesions (albeit measurable) in those organs will be recorded as non-
measurable lesions (even if the size is > 10 mm by CT scan). 
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and be representative of all involved organs, but additionally, should 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 that can be measured reproducibly should be selected. 
 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes that 
are defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. 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 that is reported as being 20 
mm × 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 nontarget lesions. 

 
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Nodes that have a short axis < 10 mm are considered nonpathological and should not be 
recorded or followed. 
 
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 of 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 of diameters will be used as a 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 nontarget lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as “present,” “absent,” or in rare cases 
“unequivocal progression.” 
 
In addition, it is possible to record multiple nontarget lesions involving the same organ as a 
single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
 
16.3.3.3 Response criteria 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
 
 
Complete response (CR): disappearance of all target lesions  
Any pathological lymph nodes (whether target or nontarget) 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 of 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 (nadir), including baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  
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 on study 
 
Special Notes on the Assessment of Target Lesions 
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 < 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 CR criteria 
are met since a normal lymph node is defined as having a short axis < 10 mm. 
 
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 

 
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subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or 
lymph nodes that are recorded as target lesions at baseline become so faint on the 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 CRF as follows: 
 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 and below measurable limit (BML) should 
be ticked. (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 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 and BML should also be ticked.) 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and, in that case, BML should not be ticked. 
 
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. 
 
Evaluation of Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of nontarget lesions. While some nontarget lesions may actually be measurable, 
they need not be measured and, instead, should be assessed only qualitatively at the 
timepoints specified in the protocol. 
 
 
CR: disappearance of all nontarget lesions and (if applicable) normalization of tumor 
marker level) 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
 
Non-CR/Non-PD: persistence of one or more nontarget lesion(s) and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
 
PD: unequivocal progression of existing nontarget lesions 
The appearance of one or more new lesions is also considered progression. 
 
Special Notes on Assessment of Progression of Nontarget Disease 
 
When the Patient Also Has Measurable Disease. In this setting, to achieve unequivocal 
progression on the basis of the nontarget disease, there must be an overall level of substantial 
worsening in nontarget disease in a magnitude that, even in the 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 nontarget lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of overall 

 
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progression solely on the basis of change in nontarget disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
 
When the Patient Has Only Non-Measurable Disease. This circumstance arises in some 
Phase III 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 nontarget 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, that 
is, an increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion). Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic disease 
from localized to widespread or may be described in protocols as “sufficient to require a 
change in therapy.” If unequivocal progression is seen, the 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. 
 
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, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the 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. 
 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
 
16.3.3.4 Evaluation of response 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each timepoint for patients 
who have measurable disease at baseline. 

 
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When patients have non-measurable (therefore nontarget) disease only, Table 2 is to be used. 
 
Table 1 Timepoint Response: Patients with Target Lesions (with or without Nontarget 
Lesions) 
 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
 
SD 
Non-PD or not 
all evaluated 
No 
SD 
 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
CR= complete response; NE= not evaluable; PD = progressive disease; 
PR= partial response; SD = stable disease. 
 
Table 2 Timepoint Response: Patients with Nontarget Lesions Only 
 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
 
CR= complete response; NE= not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for nontarget disease since stable disease is increasingly 
used as an endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” when no lesions 
can be measured is not advised. 
 
Missing Assessments and Not-Evaluable Designation 
 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint. If only a subset of lesion measurements are made at an 

 
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assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response. This would be most likely to happen in 
the case of PD. For example, if a patient had a baseline sum of 50 mm with three measured 
lesions and, during the study, only two lesions were assessed, but those gave a sum of 80 
mm, the patient will have achieved PD status, regardless of the contribution of the missing 
lesion. 
 
If one or more target lesions were not assessed either because the scan was not done or the 
scan could not be assessed because of poor image quality or obstructed view, the response for 
target lesions should be “unable to assess” since the patient is not evaluable. Similarly, if one 
or more nontarget lesions are not assessed, the response for nontarget lesions should be 
“unable to assess” except where there is clear progression. Overall response would be 
“unable to assess” if either the target response or the nontarget response is “unable to assess,” 
except where this is clear evidence of progression as this equates with the case being not 
evaluable at that timepoint. 
 
Table 3 Best Overall Response When Confirmation Is Required 
 
Overall Response at 
First Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration for 
SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration for 
SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
NE 
NE 
NE 
 
CR= complete response; NE= not evaluable; PD = progressive disease; PR = partial response; 

 
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SD= stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even disease meeting PR 
criteria relative to baseline, qualifies as PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether the minimum duration for SD was met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, 
not CR, at the first timepoint. Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
 
Special Notes 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 CRF. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and nontarget disease as shown in 
Table 1, Table 2, and Table 3. 
 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
In studies for which patients with advanced disease are eligible (i.e., primary disease still or 
partially present), the primary tumor should also be captured as a target or nontarget lesion, 
as appropriate. This is to avoid an incorrect assessment of complete response if the primary 
tumor is still present but not evaluated as a target or nontarget lesion. 
 
16.4 Immune-modified Response Evaluation Criteria in Solid Tumors 
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents like atezolizumab, which can produce delayed responses that may 
be preceded by initial apparent radiological progression, including the appearance of new 
lesions. Therefore, immune-modified response criteria have been developed that account for 
the possible appearance of new lesions. 
 
Immune-modified Response Evaluation Criteria in Solid Tumors (irRECIST) is derived from 
RECIST, Version 1.1 (v1.1) conventions1,2,3 and immune-related response criteria3,4,5 (irRC). 
When not otherwise specified, RECIST v1.1 conventions will apply.  
 
Immune-Modified RECIST and RECIST v1.1: Summary of Changes 

 
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RECIST v1.1 
Immune-Modified RECIST 
 
New lesions after baseline 
Define progression 
New measurable lesions are 
added into the total tumor 
burden and followed. 
 
Non-target lesions 
May contribute to the 
designation of overall 
progression 
Contribute only in the 
assessment of a complete 
response 
 
Radiographic progression 
First instance of ≥20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease 
 
Determined only on the basis 
of measurable disease 
 
RECIST= Response Evaluation Criteria in Solid Tumors. 
 
_________________________ 
 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1) Eur J Cancer 2009;45:228−47. 
2 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti−PD-L1 antibody in 
cancer. N Engl J Med 2012;366:2443−54. 
3 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immunetherapy activity in solid 
tumors: immune-related response criteria Clin Can Res 2009;15:7412−20. 
4 Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response assessment: does reducing 
the number of lesions impact response assessment in melanoma patients treated with ipilimumab. J Immunother 
Can 2014;2:17. 
5 Nishino M, Giobbie-Hurder A, Gargano M et al. Developing a common language for tumor response to 
immunotherapy: immune-reated response criteria using unidimensional measurements. Clin Can Res 
2013;19:3936−43. 
 
16.4.1 Definitions of measurable/non-measurable lesions 
All measurable and non-measurable lesions should be assessed at Screening and at the 
protocol-specified tumor assessment timepoints. Additional assessments may be performed, 
as clinically indicated for suspicion of progression. 
 
 
 
16.4.1.1 Measurable lesions 
Tumor Lesions. 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 as 
follows: 
 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 

 
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 10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and follow-up, only the 
short axis will be measured and followed. 
 
16.4.1.2 Non-measurable lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 but < 15 mm), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, peritoneal spread, and abdominal mass/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques. 
 
16.4.1.3 SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
 
Bone Lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring 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. 
 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area or in an area subjected to other loco-
regional therapy are usually not considered measurable unless there has been demonstrated 

 
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progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
 
16.4.2 Tumor response evaluation 
16.4.2.1  Definitions of target/non-target lesions 
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 that, for instances in which patients have only one or two organ sites involved, a 
maximum of two lesions (one site) and four lesions (two sites), respectively, will be 
recorded. Other lesions (albeit measurable) in those organs will be recorded as non-
measurable lesions (even if the size is >10 mm by CT scan). 
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and be representative of all involved organs, but in addition, should 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 that can be measured reproducibly should be selected. 
 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes that 
are defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. 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, 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 that is reported as being 20 mm 
× 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 of < 10 mm are considered non-pathological and should not be 
recorded or followed. 
 
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions. 
Non-Target Lesions 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required. 
 

 
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It is possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
 
After baseline, changes in non-target lesions will contribute only in the assessment of 
complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including non-target lesions) and will not be used to 
assess progressive disease. 
 
New Lesions 
During the study, all new lesions identified and recorded after baseline must be assessed at 
all tumor assessment timepoints. New lesions will also be evaluated for measurability with 
use of the same criteria applied to prospective target lesions at baseline per RECIST, (e.g., 
non−lymph node lesions must be ≥ 10mm; see note for new lymph node lesions below). Up 
to a maximum of five new lesions total (and a maximum of two lesions per organ), all with 
measurements at all timepoints, can be included in the tumor response evaluation. New 
lesion types that would not qualify as target lesions per RECIST cannot be included in the 
tumor response evaluation. 
 
New lesions that are not measurable at first appearance but meet measurability criteria at a 
subsequent timepoint will be measured from that point on and contribute to the sum of 
longest diameters (SLD), if the maximum number of 5 measurable new lesions being 
followed has not been reached. 
 
16.4.2.2  Calculation of sum of the diameters 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden. 
 
The sum of the diameters is calculated at baseline and at each tumor assessment for the 
purpose of classification of tumor responses. 
 
Sum of the Diameters at Baseline: The sum of the diameters for all target lesions identified 
at baseline prior to treatment on Day 1. 
 
Sum of the Diameters at Tumor Assessment: For every on-study tumor assessment 
collected per protocol or as clinically indicated the sum of the diameters at tumor assessment 
will be calculated using tumor imaging scans. All target lesions selected at baseline and up to 
five new measurable lesions (with a maximum of two new lesions per organ) that have 
emerged after baseline will contribute to the sum of the diameters at tumor assessment. 
Hence, each net percentage change in tumor burden per assessment with use of immune-
modified RECIST accounts for the size and growth kinetics of both old and new lesions as 
they appear. 
 
Note: In the case of new lymph nodes, RECIST v1.1 criteria for measurability (equivalent to 
baseline target lesion selection) will be followed. That is, if at first appearance the short axis 

 
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of a new lymph node lesion ≥ 15 mm, it will be considered a measureable new lesion and 
will be tracked and included in the SLD. Thereafter, the lymph node lesion will be measured 
at subsequent timepoints and measurements will be included in the SLD, even if the short 
axis diameter decreases to < 15 mm (or even < 10 mm). However, if it subsequently 
decreases to < 10 mm, and all other lesions are no longer detectable (or have also decreased 
to a short axis diameter of < 10 mm if lymph nodes), then a response assessment of CR may 
be assigned. 
 
If at first appearance the short axis of a new lymph node is ≥ 10 mm and < 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion. It will not 
be included in the SLD unless it subsequently becomes measurable (short axis diameter ≥ 15 
mm). 
 
The appearance of new lymph nodes with diameter < 10 mm should not be considered 
pathological and not considered a new lesion. 
 
16.4.2.3 Response criteria 
Timepoint Response 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each timepoint for patients 
who have measurable disease at baseline.  
 
Complete Response (CR): Disappearance of all target and non-target lesions. Lymph nodes 
that shrink to < 10 mm short axis are considered normal. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of all target and 
all new measurable lesions, taking as reference the baseline sum of diameters, in the absence 
of CR. 
 
Note: The appearance of new measurable lesions is factored into the overall tumor burden, 
but does not automatically qualify as progressive disease until the sum of the diameters 
increases by ≥ 20% when compared with the sum of the diameters at nadir. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of the diameters while on study. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of all target and 
selected new measurable lesions, taking as reference the smallest sum on study (nadir SLD; 
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. 
 
Impact of New Lesions on Immune-Modified RECIST 
New lesions alone do not qualify as progressive disease. However, their contribution to total 
tumor burden is included in the sum of the diameters, which is used to determine the overall 
immune-modified RECIST tumor response. 

 
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Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is 
considered not evaluable (NE) at that timepoint. If only a subset of lesion measurements are 
made at an assessment, usually the case is also considered NE at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response. This would only happen in the case of 
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed but those gave a sum of 80 mm, the patient will 
be assigned PD status, regardless of the contribution of the missing lesion. 
 
Table 1 Immune-Modified RECIST Timepoint Response Definitions 
 
% Change in Sum of the 
Diameters a 
Non-Target Lesion Response 
Assessment 
Overall Immune-Modified 
RECIST Timepoint 
Response 
− 100% from baseline b 
CR 
CR 
 
− 100% from baseline b 
Non-CR or not all evaluated 
PR 
≤ − 30% from baseline 
Any 
PR 
> − 30% to < +20% 
Any 
SD 
Not all evaluated 
Any 
NE 
≥ + 20%from nadir SLD 
Any 
PD 
 
CR= complete response; NE= not evaluable; PD = progressive disease; PR = partial response; 
RECIST=Response Evaluation Criteria in Solid Tumors; SD = stable disease; SLD = sum of the longest 
diameter. 
a Percent change in sum of the diameters (including measurable new lesions when present). 
b When lymph nodes are included as target lesions, the % change in the sum of the diameters may not be 100% 
even if complete response criteria are met, since a normal lymph node is defined as having a short axis of < 10 
mm. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm 
in order to meet the definition of CR. 
 
 

 
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16.5 Methods of contraception 
 
 

 
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17.0    SIGNATURES 
 
17.1 Sponsor's Representative 
TYPED NAME 
Stein Kaasa, MD PhD  
TITLE 
Head of Department  
SIGNATURE 
 
DATE SIGNED 
 
 
 
17.2 Investigator 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol). I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice. I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 8.2 – Serious Adverse Events. I also agree to handle all clinical supplies 
provided by the Sponsor and collect and handle all clinical specimens in accordance with the 
protocol. I understand that information that identifies me will be used and disclosed as 
described in the protocol, and that such information may be transferred to countries that do 
not have laws protecting such information. Since the information in this protocol and the 
referenced Investigator’s Brochure is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision, or conduct of the trial is 
prohibited. I will ensure that the necessary precautions are taken to protect such information 
from loss, inadvertent disclosure or access by third parties. 
 
TYPED NAME 
Jon Amund Kyte, MD PhD 
TITLE 
Principal investigator 
SIGNATURE 
 
DATE SIGNED 
 
 
TYPED NAME 
Åse Bratland, MD PhD 
TITLE 
Principal investigator 
SIGNATURE 
 
DATE SIGNED