Conditions: Non-Small Cell Lung Cancer
Keywords: Lung Cancer NSCLC Nivolumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
Patients with Stage III unresectable non-small cell lung cancer will receive thoracic radiation, cisplatin and etoposide followed by nivolumab or placebo given every 2 weeks for a year.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the Overall Survival (OS) for patients with Stage III unresectable non-small cell lung cancer treated with or without nivolumab following concurrent chemoradiation.

II. To compare Progression-Free Survival (PFS) according to RECIST 1.1 criteria for patients with Stage III unresectable non-small cell lung cancer treated with or without nivolumab following concurrent chemoradiation.

Arms:
arm 1: 60 Gy of radiation therapy given concurrently with cisplatin-etoposide chemotherapy followed by nivolumab arm 2: 60 Gy of radiation therapy given concurrently with cisplatin-etoposide chemotherapy followed by placebo

Interventions: intervention 1: Radiation Therapy (RT) intervention 2: Cisplatin intervention 3: Etoposide intervention 4: Nivolumab intervention 5: Placebo
Intervention descriptions: intervention 1: 2 Gy fractions once a day, 5 days per week, for a total of 60 Gy in 30 fractions. intervention 2: Concurrently with radiation therapy, 50 mg/m2, IV, on days 1, 8, 29, and 36, to begin with day 1 of radiation therapy. intervention 3: Concurrently with radiation, 40 mg/m2, IV, on days 1-5 and 29-33, to begin with day 1 of radiation therapy. intervention 4: Beginning 4-12 weeks after chemoradiation, 240 mg, IV, every 2 weeks for 16 weeks, then 480 mg, IV, for 36 weeks. intervention 5: Beginning 4-12 weeks after chemoradiation, 240 mg, IV, every 2 weeks for 16 weeks, then 480 mg, IV, for 36 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
RTOG Foundation Collaboration with Bristol-Myers Squibb 
 
RTOG 3505 
 
A Limited Participation Study 
 
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND 
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY 
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG 
CANCER 
 
Sponsor: RTOG Foundation  
 
 
Principal Investigator/Medical Oncology  
David E. Gerber, MD 
 
 
 
 
Study Co-Chairs 
 
Medical Oncology 
Corey Langer, MD 
Radiation Oncology 
James J. Urbanic, MD 
Medical Physics 
Robert Jeraj, PhD 
Quality of Life 
Ben Movsas, MD 
Translational Science  
Bo Lu, MD 
Pathology 
Kirk Jones, MD 
 
 
Senior Statistician 
Chen Hu, PhD 
 
 
 
Closure Date: 
November 11, 2017 
Termination Date: January 23, 2019 
 
Protocol Acceptance 
On behalf of the RTOG Foundation, Inc. 
 
 
Walter J. Curran, Jr., MD 
 
 
 
Date:  January 29, 2019 
RTOG Foundation Chairman  


RTOG Foundation 3505 
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Version Date:  January 30, 2017 
 
 
 
RTOG Foundation Collaboration with Bristol-Myers Squibb 
 
RTOG 3505 
 
A Limited Participation Study 
 
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND 
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY 
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG 
CANCER 
 
 
Sponsor: RTOG Foundation  
 
 
Principal Investigator/Medical Oncology  
David E. Gerber, MD 
 
 
 
 
Study Co-Chairs 
 
Medical Oncology 
Corey Langer, MD 
Radiation Oncology 
James J. Urbanic, MD 
Medical Physics 
Robert Jeraj, PhD 
Quality of Life 
Ben Movsas, MD 
Translational Science  
Bo Lu, MD 
Pathology 
Kirk Jones, MD 
 
 
Senior Statistician 
Chen Hu, PhD 
 
 
 
Protocol Acceptance 
On behalf of the RTOG Foundation, Inc. 
 
 
 
 
Walter J. Curran, Jr., MD 
 
 
 
Date:  January 30, 2017 
RTOG Foundation Chairman  
 
 


RTOG Foundation 3505 
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Version Date:  January 30, 2017 
 
 
 
RTOG 3505 
(ClinicalTrials.gov NCT # NCT02768558)(5/10/16) 
 
 
A Limited Participation Study 
 
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND 
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY 
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG 
CANCER 
 
 
Principal Investigator/Medical Oncology 
David E. Gerber, MD 
Harold C. Simmons Cancer Center 
UT Southwestern Medical Center 
5323 Harry Hines Blvd, Mail Code 8852 
Dallas, TX 75390-8852 
214-648-4180/FAX 214-648-1955 
David.Gerber@UTSouthwestern.edu 
Translational Science Co-Chair 
Bo Lu, MD 
Thomas Jefferson University 
111 South 11th Street 
Philadelphia, PA 19107 
215-955-6705/FAX 215-955-0310 
bo.lu@jefferson.edu 
 
 
Radiation Oncology Co-Chair 
James J. Urbanic, MD 
University of California, San Diego 
1200 Garden View Road, Suite 210 
Encinitas, CA  92024 
858-246-0500/FAX 858-246-0501 
jurbanic@ucsd.edu 
Medical Physics Co-Chair 
Robert Jeraj, PhD 
University of Wisconsin Carbone Cancer 
Center 
7033 WIMR, 1111 Highland Ave 
Madison, WI 53705 
608-263-8619/FAX 608-262-2413 
rjeraj@wisc.edu 
 
 
Medical Oncology Co-Chair 
Corey Langer, MD 
6 PCAM 
3400 Civic Center Blvd 
University of Pennsylvania 
Philadelphia, PA 19104 
215-615-5888/FAX 215-615-5122 
corey.langer@uphs.upenn.edu 
Pathology Co-Chair 
Kirk Jones, MD 
Department of Pathology 
Box 0102 
505 Parnassus Ave, Moffitt Room M565 
UCSF San Francisco, CA 94115 
415-476-7864/FAX 415-476-5271 
kirk.jones@ucsf.edu 
Study Team continued on next page 
 
 


RTOG Foundation 3505 
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Version Date:  January 30, 2017 
 
RTOG FOUNDATION  
RTOG 3505 
 
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND 
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY 
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG 
CANCER 
 
 
Study Team (continued) 
 
 
Quality of Life/PRO Co-Chair 
Ben Movsas, MD 
2799 West Grand Blvd 
Henry Ford Hospital 
Detroit MI 48202 
313-916-5188 /FAX 313-916-3264 
Bmovsas1@hfhs.org 
Senior Statistician 
Chen Hu, PhD 
Johns Hopkins Sidney Kimmel 
Comprehensive Cancer Center/RTOG 
Foundation 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-928-0153 
chu@acr.org 
 
RTOG Foundation Headquarters Contact Information  
 
Data Managers:   
For questions concerning eligibility or data submission 
Jeff Serianni, jserianni@acr.org 
Amy Krystkiewicz, 
akrystkiewicz@acr.org 
ACR Core Laboratory/RTQA:  
For questions concerning RT planning or RT data 
requirements 
Jennifer Presley, jpresley@acr.org 
ACR Core Laboratory/RTQA:   
For questions concerning data submission to TRIAD 
Triad-Support@acr.org 
ACR Diagnostic Imaging 
For questions concerning central imaging review 
Emilie Connors, 215-574-3201, 
econnors@acr.org 
Serious Adverse Event Coordinator 
For questions concerning serious adverse event 
reporting procedures, timelines, and queries 
Sara McCartney, 267-940-9404, 
smccartney@acr.org 
Project Manager: For questions concerning regulatory 
documentation, investigational drug supply and/or 
shipment issues. 
Erin Cunningham, 215-717-0831, 
ecunningham@acr.org 
Membership:  
For questions concerning contracts and reimbursement 
RTOG-Membership@acr.org 
For Code Breaks, 8:30 a.m. to 5 p.m. ET 
215-574-3150, ask for the 
Supporting Statistician 
For Code Breaks after business hours or on weekends 
or holidays 
215-459-3576 
 


RTOG Foundation 3505 
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Version Date:  January 30, 2017 
 
RTOG FOUNDATION 
RTOG 3505 
 
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND 
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY 
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG 
CANCER 
 
Participating Sites: A list of participating sites can be accessed on the RTOG website. 
 
 
 
Protocol Agents 
Agent 
Supply 
IND # 
IND Sponsor 
Cisplatin 
Commercial 
Exempt 
N/A 
Etoposide 
Commercial 
Exempt 
N/A 
Nivolumab/Placebo 
Bristol-Myers 
Squibb 
130197 
RTOG Foundation, Inc. 
 
 
 
 
 
Document History  
 
 
Version Date 
Release Date 
Amendment 2 
January 30, 2017 
February 22, 2017 
Amendment 1 
May 27, 2016 
June 6, 2016 
Approved Only 
April 25, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by RTOG Foundation, Inc. It is 
intended to be used only in conjunction with institution-specific IRB 
approval for study entry.  No other use or reproduction is authorized by 
RTOG nor does RTOG assume any responsibility for unauthorized use of 
this protocol. 


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TABLE OF CONTENTS 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objective ....................................................................................................8 
1.2 
Secondary Objectives...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
There is a strong rationale to combine immunotherapy and radiation 
therapy (RT). ............................................................................................................9 
2.2 
The PD-1/PD-L1 immune regulatory checkpoint represents a new and 
effective target for cancer treatment ......................................................................10 
2.3 
Nivolumab (BMS-936558, previously MDX-1106 and ONO-4538), an 
anti-PD-1 monoclonal antibody, has emerged as one of the most 
promising immunotherapies for lung cancer. ........................................................11 
2.4 
Rationale for the Study Design ..............................................................................17 
2.5 
Biomarker Studies ..................................................................................................22 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ................23 
3.1 
Patient Selection Guidelines ..................................................................................24 
3.2 
Eligibility Criteria ..................................................................................................24 
3.3 
Ineligibility Criteria ...............................................................................................27 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........29 
5. TREATMENT PLAN/Regimen description ..............................................................................36 
5.1 
Chemotherapy/Other Agent-Based Therapy ..........................................................37 
5.2 
Radiation Therapy ..................................................................................................38 
5.3       General Concomitant Medication and Supportive Care Guidelines ......................46 
5.4 
Emergency Unblinding Procedure .........................................................................47 
5.5 
Duration of Therapy ...............................................................................................47 
6. TREATMENT MODIFICATIONS/managEment.....................................................................47 
6.1 Chemoradiotherapy Dose Modifications .....................................................................47 
6.2  Cisplatin and Etoposide Dose Modifications ..............................................................48 
6.3   Nivolumab/Placebo Dose Modifications ...................................................................49 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................55 
7.1 Protocol Agents ............................................................................................................55 
7.2 
Adverse Events (AEs) ............................................................................................56 
7.3 
Serious Adverse Events (SAEs).............................................................................57 
7.4 
Serious Adverse Event (SAE) Reporting Requirements .......................................58 
8. 
REGISTRATION AND STUDY ENTRY  PROCEDURES ............................................62 
8.1 
Regulatory Requirements.......................................................................................62 
8.2 
RT  Registration Requirements ..............................................................................62 
8.3 
Patient Enrollment .................................................................................................62 


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9.0 
DRUG INFORMATION ...................................................................................................62 
9.1 
Investigational Study Agent ...................................................................................62 
9.2 
Commercial Agent .................................................................................................63 
10. Pathology/BIOSPECIMENS ...................................................................................................64 
10.1 Tissue/Specimen Submission.....................................................................................64 
10.2     Mandatory Studies .................................................................................................65 
10.3 Optional Specimen Collection for RTOG 3505 Research and Banking ....................66 
11. 
SPECIAL studies (Non-Tissue) .........................................................................................69 
11.1  Toxicity, Patient-Reported Outcomes (PROs), and Health-Related Quality 
of Life (QOL) .........................................................................................................69 
12. 
Modality Reviews ..............................................................................................................73 
12.1 Radiation Therapy Quality Assurance Reviews ........................................................73 
12.2  Drug Quality Assurance Reviews .............................................................................73 
13. 
DATA AND RECORDS ...................................................................................................73 
13.1    Summary of Dosimetry Digital RT Data Submission (Submit to ACR Core   
Laboratory/RTQA see the study-specific guide on the RTOG Foundation 
3505 protocol page of the RTOG website, www.rtog.org, for details of 
TRIAD.) .................................................................................................................73 
13.2 Summary of Diagnostic Imaging Digital Data Submission (Submit to ACR 
Imaging Corelab; see the study-specific guide on the RTOG Foundation 
3505 protocol page of the RTOG website, www.rtog.org, for details of 
TRIAD.)) ................................................................................................................74 
14. 
STATISTICAL CONSIDERATIONS...............................................................................75 
14.1 
Study Design ..........................................................................................................75 
14.2 
Study Endpoints .....................................................................................................75 
14.3 
Primary Objectives Study Design ..........................................................................76 
14.4 
Study Monitoring ...................................................................................................79 
14.5 
Accrual/Study Duration Considerations ................................................................82 
14.6 
Dose Level Guidelines ...........................................................................................83 
14.7 
Secondary Endpoints .............................................................................................83 
14.8 
Exploratory Hypothesis and Endpoints .................................................................85 
REFERENCES ..............................................................................................................................87 
APPENDIX I .................................................................................................................................92 
APPENDIX II ................................................................................................................................99 
Appendix III .................................................................................................................................105 
APPENDIX IV.............................................................................................................................110 
 


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 Step 1 REGISTRATION 
Tissue submission for PD-L1 assessment* 
Thoracic RT 60 Gy 
Cisplatin 50mg/m² Days 1, 8, 29, 36 
Etoposide 50mg/m² Days 1-5, 29-33 
Step 2 Registration**  
STRATIFICATION 
Zubrod 0 vs. 1; squamous vs. non-squamous; PD-L1 status (≥1%, <1%, not 
evaluable/undetermined) 
Nivolumab or Placebo 240mg 
infused over 30 min q2 weeks x 
16 weeks then 480 mg q4 weeks 
x 36 weeks 
Randomization 
RTOG 3505 
 
Randomized, Double Blinded Phase III Trial of Cisplatin and Etoposide plus Thoracic 
Radiation Therapy Followed by Nivolumab/Placebo for Unresectable Locally Advanced 
Non-Small Cell Lung Cancer 
 
                                                               SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Verification that archived tissue block is available for submission as the completed 
submission will be required at least 5 weeks prior to Step 2 Registration 
**Assessment for progression after chemoRT; if evidence of distant metastases or 
local disease progression, will not be randomized  
 
 
 
Stage III unresectable non-small cell lung 
cancer  


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1. OBJECTIVES 
1.1 
Primary Objective 
 To compare the overall survival (OS) for patients with Stage III unresectable non-
small lung cancer treated with or without nivolumab following concurrent 
chemoradiation. 
o Overall survival is defined as the time from randomization to death due to any 
cause. 
 To compare progression-free survival (PFS) based on an assessment by an 
Independent Radiology Review Committee (IRRC) according to RECIST 1.1 criteria 
for patients with Stage III unresectable non-small lung cancer treated with or without 
nivolumab following concurrent chemoradiation. 
o PFS is defined as the time from randomization to documented progressive 
disease or death due to any cause, whichever occurs first; 
o PFS will be determined by IRRC per guidelines of Section 4.3. 
1.2 
Secondary Objectives 
 To compare toxicities in the control and experimental arms; 
 To compare Functional Assessment of Cancer Therapy - Trial Outcome Index for 
lung cancer (FACT-TOI) at 15 months; 
 To evaluate OS and PFS in patients with (1) PD-L1-positive, (2) PD-L1-negative and 
PD-L1 not evaluable/undetermined tumors; 
1.3      Exploratory Objectives 
 To evaluate biomarkers and biomarker correlatives; 
 To determine the proportion of patients alive at 12 and 24 months; 
 To determine the proportion of patients progression free at 12 and 24 months 
according to RECIST 1.1; 
 To evaluate PROMIS fatigue at 3 months, EQ-5D utilities and EQ-VAS before and 
after progression; 
 To evaluate PFS based on investigator assessment  
2. BACKGROUND 
We have reached a plateau in outcomes for locally advanced non-small cell lung cancer (LA-
NSCLC). Despite aggressive therapy with concurrent chemoradiation, fewer than 20-25% of 
patients with stage III NSCLC achieve 5-year survival and are presumably cured.  To date, 
modifications of chemotherapy have not improved these outcomes.  The addition of 3 cycles 
of consolidation docetaxel after concurrent cisplatin-etoposide with thoracic radiation had no 
impact on overall survival compared to chemoradiation alone (Hanna 2008).  A similar, 
much larger trial performed in Southeast Asia showed no survival advantage whatsoever for 
consolidative docetaxel/cisplatin after definitive chemoradiation compared to chemoradiation 
alone (Ahn JS 2015). Finally, a study of maintenance gefitinib after completion of cisplatin-
based concurrent chemoradiation in unselected patients with LA-NSCLC demonstrated a 
decrease in survival (Kelly 2008).  The addition of the anti-EGFR monoclonal antibody 
cetuximab to chemoradiation did not extend survival (Bradley 2015). 
 
Furthermore, in 2015, there is no evidence that achievable radiotherapy (RT) doses above 60 
Gy using standard 3D technology are better than 60 Gy, suggesting that opportunities exist 


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for outcome improvement lie in modification of medical components of chemoradiation 
regimens.  In an interim analysis of the Radiation Therapy Oncology Group (RTOG) 0617 
clinical trial, patients receiving a radiation dose of 74 Gy had a median progression-free 
survival of 9.8 months, compared to 11.8 months for patients receiving 60 Gy.  The high-
dose RT arms were closed after overall survival results crossed the futility boundary (Bradley 
2015). 
 
2.1 There is a strong rationale to combine immunotherapy and radiation therapy (RT).  
While NSCLC is typically considered relatively non-immunogenic, RT is thought to augment 
tumor immunogenicity (Iyengar 2013).  The abscopal effect refers to the observation that RT 
to a local area results in an antitumor effect distant to the radiation site.  One proposed 
mechanism for this phenomenon is inducing the release of circulating tumor antigen or 
inflammatory factors that could then mediate an augmented immune response against distant 
malignant lesions expressing similar tumor antigens.  Supporting this hypothesis, local RT 
has been shown to increase the activity of natural killer cells (Uchida 1989). 
 
Conversely, the therapeutic effects of ablative RT on local tumors are dependent on anti-
tumor immune responses (Iyengar 2013).  Of note, Formenti and colleagues demonstrated 
that the abscopal effect of radiotherapy is in part immune mediated and that T cells are 
required to mediate distant tumor effects of radiotherapy (Demaria 2004).  In a preclinical 
model, ablative RT dramatically increased T-cell priming in draining lymphoid tissues, 
leading to reduction of the primary tumor or distant metastases in a CD8+ T-cell-dependent 
fashion.  In the same model, these RT-initiated immune responses were greatly amplified by 
local immunotherapy (Lee 2009). Particularly relevant to the current proposal, RT has been 
shown to increase tumor expression of PD-L1, and combined RT plus PD-1-pathway 
targeting results in synergistic suppression of tumor-infiltrating myeloid-derived suppressor 
cells (MDSCs), thereby promoting anti-tumor immunity (Deng 2014). 
 
To date, the most extensive experience combining immune modulating therapies with 
radiation therapy for lung cancer has been with L-BLP25 (Tecemotide), a mucin-1 (MUC1) 
antigen specific cancer vaccine.  In a phase 3 trial, 1513 patients with stage III NSCLC 
previously treated with chemotherapy and radiation (either concurrent or sequential) were 
randomized to L-BLP25 (Tecemotide) or placebo.  Approximately 65% of patients received 
concurrent chemoradiation, and 35% received sequential chemoradiation.  274 patients were 
excluded from the primary analysis population as a result of a clinical hold, resulting in 
analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified 
intention-to-treat population. Although the study failed to meet its primary endpoint of 
improved OS in the overall study population, a pre-planned subgroup analysis demonstrated 
an improvement in median OS from 20.6 months to 30.8 months (HR 0.78; 95% CI, 0.64-
0.95; P=0.016) in those patients who had received concurrent chemoradiation prior to 
randomization (Butts 2014, Mitchell 2015).  Although no firm conclusions can be drawn 
from this experience, these results suggest that concurrent chemoradiation may provide the 
optimal platform on which to add immunotherapies. 
 
With the availability of immunotherapies such as the anti-Cytotoxic T-Lymphocyte Antigen 
4 (CTLA-4) monoclonal antibody ipilimumab (FDA approved for melanoma) and agents 


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targeting the programmed death-1 (PD-1) pathway, the potential benefit of combining these 
agents with RT has become evident clinically.  For instance, a recent case report described a 
patient with metastatic melanoma had evidence of slow progression of a paraspinous mass, 
hilar lymph nodes, and a liver lesion while receiving ipilimumab.  The patient received 
palliative RT to the paraspinous mass.  There was no radiographic improvement noted 6 
weeks later.  However, after re-initiation of ipilimumab, the paraspinous mass resolved 
completely.  Furthermore, the hilar lymph nodes and liver metastasis (both of which had 
previously progressed during ipilimumab treatment but had not been irradiated) also 
responded (Postow 2012). 
 
Among cancer types, lung cancer may be a particularly attractive setting to incorporate 
immunotherapy into treatment paradigms.  A number of studies have suggested that tumor 
mutational burden is associated with benefit from immunotherapy (Rizvi 2015, Le 2015).  
Presumably, increased mutational burden results in increased tumor antigenicity, thereby 
priming the tumor for immune attack.  As shown in Figure 1 below, lung cancer carries one 
of the highest mutational burdens of any malignancy.  In this figure, each dot represents a 
sample, the red horizontal lines represent median numbers of mutations, and the vertical axis 
(log scale) shows the number of mutations per megabase. 
 
Figure 1. Mutational burden by malignancy   
 
 
 
 
2.2 The PD-1/PD-L1 immune regulatory checkpoint represents a new and effective target 
for cancer treatment 
In contrast to CTLA-4 (which exerts its regulatory effects in the priming phase of the 
immune response in regional lymph nodes), the negative regulatory effects of the PD-1 
pathway occur in the effector phase of the immune response in peripheral tissues.  Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2, resulting in 
dephosphorylation of multiple effector molecules involved in the CD3 T-cell signaling 
cascade (Talmadge 2007). PD-1 is expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regulatory cells (Tregs), and natural killer (NK) cells 
(Hodi 2010).  Although healthy organs express little (if any) PD-L1, numerous cancers are 


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known to express abundant levels of PD-L1.  PD-1 has been suggested to regulate tumor-
specific T-cell expansion in patients with melanoma, suggesting that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and therefore represents an attractive 
target for therapeutic intervention.  Indeed, no fewer than six monoclonal antibodies targeting 
this pathway have entered clinical development for the treatment of various malignancies 
(BMS-936558/MDX1106/nivolumab [Opdivo; Bristol-Myers Squibb]; CT-011 [CureTech]; 
MK-3475/pembrolizumab [Keytruda; Merck]; BMS-936559/MDX-1105 [Bristol-Myers 
Squibb]; Medi-4736/durvalumab [MedImmune]; MPDL-3280A/atezolizumab [Genentech]), 
of which nivolumab and pembrolizumab have been approved for melanoma and NSCLC.   
 
2.3 Nivolumab (BMS-936558, previously MDX-1106 and ONO-4538), an anti-PD-1 
monoclonal antibody, has emerged as one of the most promising immunotherapies for 
lung cancer. 
Nivolumab is a fully human, IgG4 (kappa) monoclonal antibody that binds PD-1 on activated 
immune cells to disrupt engagement of receptor with ligands PD-L1 (B7-H1/CD274) and 
PD-L2 (B7-DC/CD273).  This action results in counteracting inhibitory signals and 
augmenting host antitumor responses.  In early clinical trials, nivolumab monotherapy 
demonstrated clinical activity in multiple tumor types, including melanoma, renal cell 
carcinoma, and NSCLC (Brahmer 2010). In a multicenter phase I trial enrolling NSCLC, 
melanoma, renal cell carcinoma, castration-resistant prostate cancer, and colorectal cancer, 
radiographic response rate in advanced, previously treated NSCLC was 18% (14 of 76 
patients) (Topalian 2012). In some cases, these responses were prolonged.  For 8 of the 14 
responding cases, responses lasted ≥ 24 weeks; in 2 cases, responses lasted more than one 
year.  In 7% of cases, stable disease lasted ≥ 24 weeks.  
 
Response rates varied according to treatment dose, histology, and biomarkers.  In the 1.0 
mg/kg cohort, response rate was 6%.  In the 3.0 mg/kg arm, response rate was 27%.  In the 
10.0 mg/kg arm, response rate was 20%.  For squamous cases, response rate was 17% (9/54) 
[22% at the 3.0 mg/kg level], compared to 18% (13/74) [26% at the 3.0 mg/kg level] in non-
squamous cases.  For tumors negative for PD-L1 by immunohistochemistry, there were no 
radiographic responses (0/17).  For PD-L1-positive tumors, response rate was 36% (9/25; 
P=0.006) (Brahmer 2013). 
 
While treatment in this study was overall well tolerated, there were instances of immune-
related adverse events.  The most common treatment-related adverse events included fatigue, 
rash, diarrhea, pruritus, decreased appetite, and nausea.  Apparent immune-related adverse 
events included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis.  In total, 
grade 3 or 4 treatment-related adverse events occurred in 14% of patients.  Pneumonitis 
occurred in 3% of patients (1% grade 3-4). There were 3 deaths attributed to pneumonitis (2 
NSCLC, 1 colorectal cancer).  In many cases, early pneumonitis was reversible with stopping 
treatment, initiating glucocorticoids, or both. 
 
Nivolumab has also been given in combination with platinum doublet chemotherapy for 
advanced NSCLC.  In a phase I trial dose de-escalation trial, 43 patients were treated with 
nivolumab plus either gemcitabine-cisplatin, pemetrexed-cisplatin, or carboplatin-paclitaxel 
(Rizvi 2013). No DLTs were observed with any combination when nivolumab was 


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administered 10 mg/kg every 3 weeks.  Grade 3 pneumonitis developed in 3 patients (7%).  
Other apparent immune-related grade 3-4 toxicities included rash, nephritis, and colitis. 
 
More recently, two phase 3 clinical trials (Checkmate 057 and Checkmate 017) comparing 
nivolumab to single-agent docetaxel chemotherapy in previously treated advanced NSCLC 
have been conducted (see Table 1).  Both trials have demonstrated improved overall survival 
with nivolumab compared to docetaxel.   
 
Table 1. Checkmate 057 and Checkmate 017 Summary of Results 
 
 
The Checkmate 057 trial enrolled patients with non-squamous NSCLC; the trial met its 
primary endpoint of improving OS. In the unselected population, for patients receiving 
nivolumab (N=287), median overall survival (OS) was 12.2 months compared with 9.4 
months for docetaxel (N=268) (HR 0.73, HR 0.59-0.89, p=0.0015) (Figure 2). Fewer grade 3 
to 5 adverse events were reported for nivolumab (10%) when compared with docetaxel 
(54%) in the Checkmate 057 trial. Clinical benefit was particularly evident for patients whose 
tumors had PD L1 staining of 1% or more, with OS of 17.2 to 19.4 months compared with 8-
9 months for docetaxel (HR 0.59) (Borghaei H 2015). Conversely, there did not appear to be 
a benefit for nivolumab over docetaxel in the PDL1-negative population (HR 0.9). 
 
In the Checkmate 057 trial, treatment-related select adverse events observed included 
infusion-related reactions (3%; no grade 3-4), rash (9%; <1% grade 3-4), pneumonitis (3%; 
1% grade 3-4), ALT/AST increased (3%; <1% grade 3-4), diarrhea (8%; 1% grade 3-4), and 
hypothyroidism (7%; no grade 3-4) (Borghaei H 2015). 
 
Currently, the National Comprehensive Cancer Network (NCCN) guidelines (version 


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7.2015) recommend nivolumab as subsequent therapy for PS 0-2 patients with metastatic 
nonsquamous NSCLC who have progressed on or after platinum-based chemotherapy 
(category 2A).  The NCCN panel does not recommend testing for PD L1, because many 
patients with metastatic NSCLC benefit from nivolumab including PD L1 negative 
population.   
 
Checkmate 017 enrolled patients with squamous NSCLC and also met its primary endpoint 
of improving OS (Brahmer 2015).  Patients were randomized to nivolumab (3 mg/kg IV over 
60 minutes every 2 weeks) (n=135) versus standard of care docetaxel (75 mg/m2 IV every 3 
weeks) (n=137).  In a prespecified interim analysis, compared to docetaxel, nivolumab 
resulted in a 41% reduction in the risk of death (HR 0.59; 95% CI, 0.44-0.79; P=0.00025).  
Median OS was 9.2 months in the nivolumab arm (95% CI, 7.3-13.3 months) and 6 months 
in the docetaxel arm (95% CI, 5.1-7.3 months).  As shown in Figure 2, there is early and 
persistent separation of survival curves, with suggestion of a “tail” that may represent longer-
term survival in approximately 20% of patients.  Notably, the trial included patients 
regardless of tumor PD-L1 status. 
 
In the nivolumab arm, the most common adverse reactions (reported in ≥20% of patients) 
were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), 
cough (32%), nausea (29%), and constipation (24%).  Serious adverse events occurred in 
59% of patients receiving nivolumab.  The most frequent serious adverse events reported in 
≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease 
exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. 
Pneumonitis occurred in 7 patients (6%).  There were five grade 3 cases, and two grade 2 
cases.  All patients discontinued nivolumab and experienced complete resolution following 
high-dose corticosteroids.  Median time to onset of pneumonitis was 3.3 months (range 1.4-
13.5 months).  Overall, nivolumab was discontinued due to adverse events in 27% of 
patients, and 29% of patients receiving nivolumab had a drug delay for an adverse event. 
 
With at least 10 months of minimum follow up for all patients, the confirmed objective 
response rate (ORR), the study’s primary endpoint, was 15% (95% CI, 9-22%), of which all 
were partial responses.  Median time to onset of response was 3.3 months (range 1.7-8.8 
months) after treatment initiation.  Among responders, 67% had ongoing responses with 
durability of response ranging from 1.9+ to 11.5+ months. Among this cohort, 59% had 
durable responses of ≥6 months.   
 
Currently, the NCCN guidelines (version 7.2015) recommend nivolumab as subsequent 
therapy for PS 0-2 patients with metastatic squamous NSCLC who have progressed on or 
after platinum-based chemotherapy (category 1).  
 
More recently, nivolumab was compared to chemotherapy in the first-line setting.  The 
CheckMate 026 trial randomized patients with previously untreated advanced NSCLC with 
≥1% PD-L1 positive cells to nivolumab or histology-dependent platinum-doublet therapy.  
There was no significant difference in the primary endpoint of PFS in the PD-L1 ≥5% 
population.  Median PFS was 4.2 months with nivolumab and 5.9 months with chemotherapy 
(HR 1.15; 95% CI, 0.91-1.45; P=0.25) (Socinski 2016).  Importantly, these results are not 


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directly relevant to the present trial because of differences in (1) the clinical setting and (2) 
the control arm.   
 
 
 
Figure 2.  Overall survival in the Checkmate 057 (top) and 017 (bottom) trials. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety Summary of CheckMate 017 presented at ASCO 2015 
   
Nivolumab  
n = 131  
Docetaxel 
n = 129  
Any 
Grade  
Grade 
3–5a  
Any 
Grade  
Grade 
3–5  
Treatment-related AEs, 
%  
58  
7  
86  
57  
Treatment-related AEs 
leading to 
discontinuation, %  
3b 
2  
10c  
7  
Treatment-related 
deaths, % 
0  
2d 
No grade 5 events were reported with nivolumab. b1% pts had increased ALT/AST, 
increased lipase, myasthenic syndrome, or rash, and 2% pts had pneumonitis. cPeripheral 
neuropathy (3%) and fatigue (2%). dInterstitial lung disease, pulmonary hemorrhage, and 
sepsis (1 pt each). 
 
 
Treatment-related AEs (≥10% of patients) in CheckMate 017 presented at ASCO 2015 
 
Nivolumab  
 n = 131  
Docetaxel  
n = 129  
Any 
Grade  
Grade 3–
4  
Any 
Grade  
Grade 3–
4  
Total patients with an 
event, %  
58  
7  
86  
55  
Fatigue  
16  
1  
33  
8  
Decreased appetite  
11  
1  
19  
1  
Asthenia  
10  
0  
14  
4  
Nausea  
9  
0  
23  
2  
Diarrhea  
8  
0  
20  
2  
Vomiting  
3  
0  
11  
1  
Myalgia  
2  
0  
10  
0  


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Anemia  
2  
0  
22  
3  
Peripheral neuropathy  
1  
0  
12  
2  
Neutropenia  
1  
0  
33  
30  
Febrile neutropenia  
0  
0  
11  
10  
Alopecia  
0  
0  
22  
1  
 
 
Treatment-related Select AEs of CheckMate 017 presented at ASCO 2015 
Nivolumab 
n = 131  
Docetaxel 
n = 129  
Any 
Grade  
Grade 
3–4  
Any 
Grade  
Grade 3–4  
Endocrine, % 
Hypothyroidism  
4 
4 
0 
0  
0 
0  
0 
0  
Gastrointestinal, %  
Diarrhea 
Colitis 
8 
8 
1 
1 
0 
1 
20 
20 
0 
2 
2 
0 
Hepatic,a %  
ALT increased 
AST increased 
2 
2 
2 
0 
0 
0 
2 
1 
1 
1 
1 
1 
Pulmonary, %  
Pneumonitis 
Lung infiltration 
Interstitial lung disease  
5 
5 
1 
0 
1 
1 
0 
0 
1b 
0 
0 
1b 
0 
0 
0 
0 
Renal,c %  
Blood creatinine 
increased 
Tubulointerstitial 
nephritis 
3 
3 
1 
1 
0 
1 
2 
2 
0 
0 
0 
0 
Skin,d %  
9 
0 
9 
2 
Hypersensitivity/Infusion 
reaction, %  
Hypersensitivity 
Infusion-related 
reaction  
1 
0 
1  
0 
0 
0 
2 
2 
1 
1 
1 
0 
 
 
The overall safety experience with nivolumab, as a monotherapy or in combination with 
other therapeutics, is based on experience in approximately 4,000 subjects treated to date. For 


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monotherapy, the safety profile is similar across tumor types. The only exception is 
pulmonary inflammation adverse events (AEs), which may be numerically greater in subjects 
with NSCLC. This may be because in some cases, it can be difficult to distinguish between 
nivolumab-related and unrelated causes of pulmonary symptoms and radiographic changes. 
There is no pattern in the incidence, severity, or causality of AEs related to nivolumab dose 
level (Investigator Brochure, version 14). 
 
To date, across the clinical trial experience in 691 patients with solid tumors, fatal immune-
mediated pneumonitis has occurred in 0.7% (5/691) of patients receiving nivolumab.  All 
five fatal cases occurred in a dose-finding study with nivolumab doses of 1 mg/kg (2 
patients), 3 mg/kg (2 patients), and 10 mg/kg (1 patient).  Perhaps reflecting cumulative 
experience with and knowledge of this potential toxicity, there were no fatal cases of 
pneumonitis in the phase 3 Checkmate 017 and Checkmate 057 trials.  In the Checkmate 017 
trial in previously treated advanced squamous NSCLC, pneumonitis occurred in 5% of 
patients receiving nivolumab, of which there was only one Grade 3 case and no Grade 4 
cases.  The median time to onset of treatment-related pulmonary events was 15.1 weeks 
(range, 2.6 to 85.1).  All but one patient with pulmonary events received corticosteroids.  All 
cases resolved, with median time to resolution of 5.0 weeks (range 0.6 to 12.1).  Among 
these resolved cases, one patient experienced subsequent recurrence of pneumonitis, which 
responded to corticosteroid treatment.  A total of 4/131 (3%) patients discontinued 
nivolumab due to pneumonitis. In the Checkmate 057 trial, any grade pneumonitis was 3% 
and grade 3 and above pneumonitis was 1%. The low rate of pneumonitis and the good 
response to supportive therapy seen in the most recent nivolumab trials suggests that, with 
appropriate monitoring and precautions, this agent could be studied in combination with 
thoracic radiation therapy. 
 
Although nivolumab has not yet been studied in combination with RT, data are available for 
nivolumab-treated patients who previously received RT. While the precise timing and nature 
of treatments were not captured, of the 129 patients with NSCLC treated on the phase 1, 
dose-escalation, cohort expansion trial (CA209-003), 75 (58%) had previously received RT.  
In the overall patient population of 129 NSCLC cases, there were 9 cases of pneumonitis 
(7.0%) and three cases of grade 3-4 pneumonitis (2.3%), suggesting that the overwhelming 
majority of NSCLC patients treated with nivolumab after prior RT do not develop 
pneumonitis.  There also is limited experience for patients receiving RT during or after 
nivolumab therapy. Among approximately 3,000 patients across tumor types (NSCLC, renal 
cell carcinoma, melanoma) treated with nivolumab to date, approximately 50 were treated 
with palliative RT during or immediately following nivolumab therapy. Sites of palliative RT 
included brain (whole brain RT as well as stereotactic radiation), bone, and thorax (for 
obstructive lesions).  No serious adverse events were associated with these cases of palliative 
RT administration.  
     
2.4 Rationale for the Study Design 
      Study population:  Enrollment is not restricted to patients with PD-L1-positive tumors for 
numerous reasons.  Despite early reports suggesting that PD-L1-positive patients appear to 
derive particular benefit from PD-1- and PD-L1-targeted therapies, the definition of PD-L1-
positivity remains unclear.  Furthermore, in preclinical models, RT has been shown to 


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increase tumor expression of PD-L1 (Deng 2014), which would limit the correlation of 
outcomes with pre-RT tissue biomarkers.  The observation that tumor PD-L1 expression may 
be prognostic in general lung cancer populations—but not among cases treated with radiation 
or chemotherapy (Sun 2014)—further suggests that baseline assessment of this biomarker 
may not adequately define the target population most likely to benefit.  Finally, in the 
CheckMate 017 and 057 trials, nivolumab was associated with improved OS in an unselected 
population.  Notably, in the CheckMate 057 trial (non-squamous NSCLC), there was no 
benefit for nivolumab over docetaxel in the PDL1-negative population (HR 0.90; 95% CI, 
0.66-1.24).  Nevertheless, these results cannot be extrapolated to this clinical trial due to 
important clinical and biologic differences between populations and treatment paradigms. 
For these reasons, this trial does not restrict enrollment to PD-L1-positive NSCLC. To 
investigate the association between this biomarker and clinical outcomes, we will correlate 
baseline tumor PD-L1 expression with clinical outcomes in this trial. 
 
Chemotherapy regimen: Concurrent cisplatin-etoposide (EP) plus thoracic RT to 60 Gy is an 
established and proven therapy for stage III NSCLC, with clinical outcomes superior to 
sequential regimens or to RT alone.  This regimen has been successfully combined with 
“consolidation” chemotherapy, such as docetaxel 75 mg/m2 q21d with acceptable toxicity 
profiles (Hanna 2008).  In a randomized phase 2 trial, the regimen had improved outcomes 
compared to a carboplatin-paclitaxel-based regimen (3-year OS 33% vs 13%) (Wang 2012), 
although survival differences between the regimens have not been noted in population-based 
observational studies (Ezer 2014, Santana-Davila 2015).  This regimen (EP-RT) is ideally 
suited to combination with consolidation nivolumab because, in contrast to carboplatin-
paclitaxel chemoradiation regimens, (a) the entire chemotherapy course is administered 
during the 6 to 7 weeks of thoracic radiation and (b) the steroid requirement (which could 
hypothetically reduce the efficacy of nivolumab) is lower.  Finally, rates of radiation 
pneumonitis—a toxicity that could hypothetically be exacerbated by immunotherapy—may 
be lower with concurrent cisplatin-etoposide than with concurrent carboplatin-paclitaxel 
(approximately 5% versus 15%) (Hanna 2008, Belani 2005).  
 
Immunotherapeutic agent: Compared to anti-CTLA-4 antibodies (eg, ipilimumab, 
tremelimumab), anti-PD-1 antibodies such as nivolumab appear to have greater anti-tumor 
effect in NSCLC, as evidenced by the unprecedented overall survival results in previously 
treated advanced NSCLC seen in the Checkmate 017 and Checkmate 057  studies.   They 
also appear to result in substantially lower rates of certain autoimmune toxicities, including 
colitis and hypophysitis. As of October 2015, nivolumab has been U.S. FDA approved for 
the treatment of both squamous and non-squamous previously treated advanced NSCLC. 
 
Timing, duration, dose, and schedule of nivolumab: There is preclinical evidence supporting 
the administration of immunotherapy before, during, and after RT.  However, administration 
of immunotherapy before chemoradiation could delay potentially curative treatment for this 
aggressive disease.  Furthermore, several clinical and laboratory observations support the 
evaluation of a sequential (consolidation) approach.  Administration of the 
immunotherapeutic L-BLP25 vaccine after completion of concurrent chemoradiation was 
found to be well tolerated and have efficacy in stage III NSCLC (Butts 2014).  In a 3-arm 
phase II study in advanced NSCLC, the anti-CLTA-4 antibody ipilimumab yielded the 


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greatest benefit in a phased approach (ie, starting with chemotherapy Cycle #3 rather than 
Cycle #1), suggesting that tumor debulking prior to immunotherapy may enhance efficacy 
(Lynch 2012). Furthermore, as no chemotherapy will be given with nivolumab, no steroid 
premedication will be administered, thereby theoretically optimizing immune stimulation.  
Patients with severe toxicities from concurrent chemoradiation will be identified prior to 
administration of nivolumab and will have additional time to recuperate from their toxicities.  
Finally, clinical observations of anti-CTLA-4 antibodies suggest that immunotherapy 
administration following RT may provide synergistic effects (Postow 2012). 
 
The initiation of nivolumab 4-12 weeks after completion of chemoradiation reflects previous 
experience with combined modality regimens for locally advanced disease, prior experience 
with nivolumab and palliative radiation therapy, and optimization of potential synergistic 
effects.  In concurrent chemoradiation regimens that continue chemotherapy after completion 
of thoracic radiation, the first post-radiation chemotherapy cycle is commonly given 3-4 
weeks after thoracic radiation has ended (Hanna 2008, Belani 2005).  In the START phase 3 
trial of tecemotide (MUC1 vaccine) after chemoradiotherapy, vaccine was initiated 4-12 
weeks after chemoradiotherapy completion and was well tolerated (Butts 2014).  As 
described above, administration of palliative RT with at least a 14-day window between RT 
and nivolumab dosing in multiple disease settings has not been associated with increased 
toxicity.  Finally, relatively early initiation of immunotherapy may also capitalize on residual 
and ongoing radiation-induced tumor antigenic stimulation (Iyengar 2013, Uchida 1989).     
 
The administration of nivolumab for up to 1 year is based on theoretical rationale, selected 
cases of apparent clinical benefit, experience in advanced NSCLC, and tolerability. This 
duration covers the time period when patients are at greatest risk of recurrence or 
progression.  Furthermore, preclinical studies have demonstrated that continued stimulation 
of the immune system contributes to the anticancer effects of CTLA-4 blockade.  The 
potential value of repeated dosing also has been seen in human studies of the anti-CTLA-4 
antibody ipilimumab.  In one dramatic and illustrative case, a heavily pretreated patient with 
ovarian cancer and increasing CA-125 (GVAX vaccine refractory) was enrolled onto a 
monotherapy ipilimumab (MDX-010) study (Hodi 2008). After the first dose of ipilimumab 
(MDX-010), her CA-125 decreased dramatically. Re-dosing at the time of CA-125 increase 
resulted in an even more rapid decline in her CA-125. Repeated dosing following CA-125 
increases occurred 4 times to date and with clear and dramatic reductions in CA-125.    
 
There are also data on the tolerability of prolonged anti-PD-1 therapy from phase 1 trials in 
advanced NSCLC.  A number of patients who continued nivolumab beyond 6 months (and a 
smaller number beyond 12 months) due to prolonged radiographic response or stable disease 
were able to do so without apparent cumulative toxicity (Topalian 2012). 
 
Finally, disease-related considerations suggest that a one-year duration of nivolumab is 
optimal.  Among patients with stage 3 NSCLC who achieve disease control after 
chemoradiation, approximately 75% of cases that eventually progress will do so within the 
first 12 months after completion of chemoradiation, suggesting that this is the highest risk 
period (Butts 2013).  Post-treatment fluorodeoxyglucose (FDG) uptake not representing 
disease recurrence or progression has been reported up to 15 months after completion of 


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chemoradiation (Larici 2011).  If such radiographic findings correspond to physiologic 
effects related to tumor antigenic stimulation, then this period of time might represent the 
optimal period to capitalize on the abscopal effect.   
 
Nivolumab dose, infusion time, and schedule:  In this trial, patients assigned to the 
nivolumab arm will receive a fixed dose of 240 mg IV infused over 30 minutes every two 
weeks for 16 weeks, followed by nivolumab 480 mg IV infused over 30 minutes every 4 
weeks for 36 weeks (52 weeks total).  
 
Nivolumab monotherapy has been extensively studied in NSCLC populations in studies 
CA209003, CA209063, CA209017, and CA209057 with body weight normalized dosing 
(mg/kg). Nivolumab pharmacokinetics (PK) and exposures of subjects in these studies have 
been characterized by population  pharmacokinetic (PPK) analysis of data collected in these 
studies, together with PK data from several Phase 1, 2, and 3 clinical studies of nivolumab 
monotherapy in solid tumors. Nivolumab PK was determined to be linear, with dose 
proportional exposures over a dose range of 0.1 to 10 mg/kg. Nivolumab clearance and 
volume of distribution were found to increase with increasing body weight, but the increase 
was less than proportional, indicating that a mg/kg dose represents an over-adjustment for the 
effect of body weight on nivolumab PK. Conversely, given the relationship between 
nivolumab PK and body weight, a flat-dose is expected to lead to lower exposures in heavier 
subjects, relative to the exposures in lighter subjects. Table 2 presents summary statistics of 
the estimated nivolumab steady-state trough, peak and time-averaged concentration (Cminss, 
Cmaxss, and Cavgss, respectively; document on file) in NSCLC subjects receiving 3 mg/kg, 
together with corresponding statistics of exposures predicted for a flat nivolumab dose of 240 
mg. It should be noted that a dose of 240 mg nivolumab is identical to a dose of 3 mg/kg for 
subjects weighing 80 kg, which is the approximate median body weight of NSCLC subjects 
in the three Phase 2 and 3 clinical studies of nivolumab monotherapy in NSCLC subjects 
(CA209017, CA209057, and CA209063). As evident from the data presented below, the 
geometric mean values of Cminss, Cmaxss, and Cavgss with flat dosing are slightly (< 15%) 
higher than that produced by a 3 mg/kg dose, and the coefficient of variation (cv%) in these 
measures of exposure are only slightly (< 10%) greater than that of 3 mg/kg dosing. 
Nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and 
the relationship between nivolumab exposure produced by 3mg/kg and efficacy has been 
found to be relatively flat. 
 
The summary statistics of nivolumab steady state exposure are listed in below Table 2. 
 
Table 2.  Nivolumab steady state exposure 
 
 
 
Rationale for 480mg Q4W Dosing 


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Nivolumab 480 mg every 4-week schedule (Q4W) will be more convenient for subjects. 
Based on pharmacokinetic modeling, the 480 mg Q4W (after steady state is reached with 240 
mg every 2 weeks) will provide steady-state average concentrations similar to 3 mg/kg or 
240 mg Q2W, which has been shown to provide longer survival in NSCLC patients. 
However, 480 mg Q4W is expected to result in higher (approximately 20%) steady-state 
maximum concentration (peaks), and lower (approximately 10%) steady-state trough 
concentrations compared to steady state of 3 mg/kg Q2W. Nivolumab was adequately 
tolerated up to 10 mg/kg, the highest dose level tested, and no maximum tolerated dose was 
identified. In addition, the exposure-response relationship for safety is flat. Thus, a slight 
increase in the steady-state maximum concentration is not expected to increase the safety risk 
of nivolumab. Furthermore, a marginal decrease in steady-state trough concentration is not 
expected to reduce the efficacy as high trough concentrations and > 90% intra-tumoral 
receptor occupancy are still maintained at 480 mg Q4W dose. Nivolumab 480 mg Q4W is 
expected to have similar efficacy and safety profile to 240mg Q2W. 
 
Rationale for Shorter Infusion Times for Nivolumab  
Prolonged infusion times place a burden on patients and treatment centers. Establishing that 
nivolumab can be safely administered using shorter infusion times of 30 minutes duration for 
nivolumab in subjects will diminish the burden provided no change in safety profile. 
 
Previous clinical studies of nivolumab monotherapy have used a 60-minute infusion duration 
for nivolumab. However, nivolumab has been administered at up to 10 mg/kg with the same 
infusion duration: nivolumab has been administered safely over 60 minutes at doses ranging 
up to 10 mg/kg safely over long treatment duration. In Study CA209010, (a Phase 2, 
randomized, double blinded, dose-ranging study of nivolumab in subjects with 
advanced/metastatic clear cell RCC) a dose association was observed for infusion site 
reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 
10 mg/kg). All the events were grade 1-2 and were manageable. An infusion duration of 30 
minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to 
present any safety concerns compared to the prior experience at 10 mg/kg nivolumab dose 
infused over a 60-minute duration. Overall, infusion reactions including high-grade 
hypersensitivity reactions have been uncommon across nivolumab clinical studies. Overall, a 
change in safety profile is not anticipated with 30-minute infusion of nivolumab.  
 
Radiotherapy credentialing and review. Across studies and disease types, there has been no 
pattern to suggest that prior RT predisposes patients to recall reactions or other toxicities in 
the prior radiation field, nor does pneumonitis appear to be associated with the presence of 
intra-thoracic malignancy.   
However these data-sets are quite limited and largely related to patients treated in the 
metastatic setting with the thoracic radiotherapy having occurred at some time prior to the 
nivolumab using a variety of radiotherapy doses and techniques but often in the palliative 
range.  Definitive chemoradiotherapy carries a real risk for lung injury.  Therefore, this trial 
testing adjuvant nivolumab will require substantial radiotherapy treatment 
credentialing/benchmarking and periodic case review of the radiotherapy dosimetry.  
Through an active quality assurance program, we hope to minimize the chance for increased 
toxicity related to sub-optimal radiotherapy techniques.  


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Additionally, central review of follow-up imaging will occur.  This is being required for three 
main reasons: 1) Co-primary end-point of PFS; 2) Correlation with any potential increase in 
lung toxicity; 3) Scientific understanding of potential differences in imaging changes that 
could occur in immunotherapy cohort compared to placebo cohort. 
 
2.5 Biomarker Studies 
2.5.1 Tumor PD-L1 Expression 
The effect of tumor PD-L1 expression on treatment response to anti-PD-1 targeted 
immunotherapy is a key focus of ongoing investigation. Identification of predictive 
biomarkers of response to therapy protects patients from exposure to risks of ineffective 
therapies and improves cost-effectiveness. Submission of formalin-fixed and paraffin 
embedded tumor samples (blocks) from core or excisional biopsy is required for all patients 
at the time of study enrollment. Preferably, an archived tumor block sample should be 
shipped for this study. If an archived tumor block sample is not available, then two 2mm 
punches from the core needle biopsy blocks may be provided for analysis. If punches are 
not available, at a minimum, one H&E and 5 positively charged unstained slides may be 
sent (see details in Section 3.2.15). NOTE: core or excisional biopsy is required.  Fine 
needle aspirates (FNA) and cytology specimens are not adequate for PD-L1 analysis.  
  
Analysis of PD-L1 expression will be performed by use of the 28-8 antibody to PD-L1 
(BMS) using the Dako IHC platform (Taube 2012). PD-L1 membrane staining will be 
assessed by light microscopy. Either complete circumferential or partial linear plasma 
membrane staining will constitute positive PD-L1 staining. While cytoplasmic staining 
may be observed, it will not be used in the evaluation of tissue sample status.  Alternative 
biomarkers may be evaluated as determined by additional data associated with disease 
progression or response to nivolumab. 
2.5.2 Optional tumor tissue collection and studies 
An optional image-guided core needle (at least 18 gauge) tumor biopsy upon evidence of 
progressive disease (PD) after step 2 registration, may be performed according to 
institutional practice, provided it is not associated with unacceptable clinical risk.  If a 
standard-of-care diagnostic biopsy to confirm recurrence is obtained, at least two core 
biopsies, minimum, should be obtained as part of this recurrence biopsy. Paraffin 
embedded tissue from this biopsy will be used for confirmation of recurrence and for 
additional research by the RTOG.  Patients consenting to have their tissue submitted at 
recurrence will have a tube of whole blood collected. 
These samples will be shipped and stored at the Biospecimen Bank at UCSF.  
Optional Tumor samples (immune-related or response-related markers) 
The remaining tumor samples after the PD-L1 staining will be shipped back and stored at 
UCSF. They will be used for the following studies:  The expression and spatial distribution 
of immune-related or response-related markers by Multiplex immunohistochemistry may 
also include, but may not be limited to, PD-L1, CTLA-4, CD3, CD4, CD8, CD45RO, 
forkhead box P3, granzyme B, OX40, PD1, cleaved caspase 3 and Ki67. Archived material 
(or biopsies if available) may also be analyzed for the presence of key mutations which 


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may include but are not limited to: EGFR, K-ras, N-ras, B-raf, anaplastic lymphoma kinase 
and the met proto oncogene to evaluate their potential relevance and correlations with 
response to nivolumab. 
 
2.5.3 Optional blood collection for Blood borne biomarkers 
Blood samples will be analyzed to evaluate protein, nucleic acid, and cellular biomarkers 
that relate to nivolumab. PBMC will also be isolated from whole blood and will be 
preserved, and may be used for subsequent flow cytometry or assessment of the diversity of 
the immune cell repertoire based on VDJ coding region analysis, the relationship to clinical 
responses, and changes in response to treatment with nivolumab. Blood collected for 
analysis of immune cell gene expression profiles within the peripheral compartments will 
be evaluated for any relationship with efficacy endpoints. Serum samples will also be 
collected for analysis of circulating soluble factors in relation to immune status at baseline 
and in response to treatment. Factors to be analyzed may include but are not limited to: the 
presence of IFN-γ tumour necrosis factor-α, interleukin (IL)-2, IL-6, IL-10, IL-8, IL-12, 
and levels of soluble PD-L1 using Luminex platform. 
Autoantibody profiles 
Recent studies have found that more than 25% of healthy individuals have strong IgG 
humoral immune responses to a variety of self-antigens, indicating that a “benign” form 
autoimmunity is much more common than autoimmune disease (Wandstrat 2006, Li 2011, 
Tan 1997). This autoimmunity is directed against a variety of self-antigens. These findings 
indicate that many healthy individuals exhibit significant autoimmunity that is regulated in 
the peripheral immune system by pathways such as those triggered by CTLA-4 and PD1. 
Consistent with this, CTLA-4 and PD1 are both known to potentiate autoimmune disease, 
suggesting that the inhibition of these regulatory pathways aggravates pre-existing 
autoimmunity.  Based on this, we hypothesize that checkpoint therapy immune-related 
adverse events often result from the activation of pre-existing autoimmunity.  
 
We will test this hypothesis by utilizing a variety of novel technologies developed in the 
Department of Immunology at UT Southwestern to quantify autoimmune responses.  
Specifically, the UT Southwestern core facility has the ability to measure IgG autoantibody 
reactivity against more than 120 antigens simultaneously with as little as 5 l of serum or 
plasma.  We will screen the autoantibodies in sera from individuals before, during, and 
after nivolumab therapy using this system. 
 
The protein array system that we have developed for autoantibody screening can also be 
used to assess antibodies against any antigen. Consequently, a panel of tumor-type-specific 
antigens will also be incorporated into these arrays so that we can follow the level and 
specificity of anti-tumor humoral immunity elicited by checkpoint therapy in individual 
patients and correlate this with disease progression. 
 
3. 
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
 
Note: Exceptions to inclusion and exclusion criteria are not permitted.  For questions 
concerning eligibility, please contact the Biostatistical/Data Management Center (via the 
contact list on the RTOG website). For radiation therapy-related eligibility questions, 
please contact ACR Core Laboratory/RTQA (via the contact list on the RTOG website). 


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This does not include diagnostic imaging questions as described in Section 2. 
3.1 Patient Selection Guidelines 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also should 
consider all other relevant factors (medical and non-medical), as well as the risks and 
benefits of the study therapy, when deciding if a patient is an appropriate candidate for this 
trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential (WOCBP) and men who are sexually active should be 
willing and able to use medically acceptable forms of (hormonal or barrier method of birth 
control; abstinence) contraception prior to study entry and for the duration of study 
participation. 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/placebo. Men who are sexually active with WOCBP should use any 
contraceptive method with a failure rate of less than 1% per year. Men receiving 
nivolumab/placebo and who are sexually active with WOCBP will be instructed to adhere 
to contraception for a period of 31 weeks after the last dose of investigational product 
Women who are not of childbearing potential (i.e., who are postmenopausal or surgically 
sterile) as well as azoospermic men do not require contraception 
3.1.3 Submission of tumor tissue for PD-L1 expression analysis is required for all patients. 
Investigators should check with their site Pathology department regarding release of 
biospecimens before approaching patients about participation in the trial. (See details of 
tumor tissue submission in Section10.) 
 
3.2 Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
Step 1 Registration Prior to Chemoradiation 
3.2.1 Pathologically (histologically or cytologically) proven diagnosis of NSCLC with 
unresectable, medically inoperable disease, or patients who refuse resection stage IIIA or 
stage IIIB disease (AJCC 7th edition) 
 Unresectable stage IIIA disease is defined by multiple and/or bulky N2 mediastinal 
lymph nodes on computed tomography (CT) scan such that, in the opinion of the 
treating investigator, the patient was not a candidate for surgical resection.  
 N2 disease must have been documented by biopsy, or at a minimum by 
fluorodeoxyglucose positron emission tomography (PET) or CT if nodes were more 
than 2 cm. 
 T4 disease is often considered resectable at the discretion of a thoracic surgeon.   
Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a 
thoracic surgeon and felt to be unresectable or if they are either medically inoperable 
or refuse surgery. 
 
Stage IIIB patients have N3 or T4N2 status. N3 status must have been documented by 
the presence of a contralateral (to the primary tumor) mediastinal lymph node or 


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supraclavicular or scalene lymph node proven by biopsy, or at a minimum by 
fluorodeoxyglucose PET or more than 2 cm on CT scan. Patients with disease 
extending into the cervical region (defined as disease extending above cricoid 
cartilage) are not eligible. 
 Patients with either N2 or N3 adenopathy and Tx disease will be eligible and 
categorized as Stage IIIA or IIIB based on their nodal status. 
3.2.2 Appropriate stage for study entry based on the following diagnostic workup: 
 History/physical examination, including documentation of height, weight, BSA, and 
vital signs, within 30 days prior to registration; 
 CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is 
medically contraindicated) of the lung and upper abdomen through the adrenal 
glands within 60 days prior to registration (recommended within 30 days prior to 
registration); 
 MRI of the brain with contrast (or CT with contrast if MRI is medically 
contraindicated) within 60 days prior to registration; note: the use of intravenous 
contrast is required for the MRI or CT (unless medically contra-indicated). 
 Whole-body FDG-PET/CT within 60 days prior to registration; note: patients do 
not need to have a separate CT of chest and upper abdomen with contrast if PET/CT 
imaging includes a high quality CT chest with contrast. 
3.2.3 Age ≥ 18 years;  
3.2.4 The trial is open to both genders; 
 
3.2.5 Zubrod Performance Status of 0-1 within 30 days prior to registration; 
3.2.6 Adequate hematologic function within 14 days prior to registration defined as follows: 
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; 
 Platelets ≥ 100,000 cells/mm3; 
 Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥9.0 g/dl is acceptable.);  
3.2.7 Adequate renal function within 14 days prior to registration defined as follows: 
 Serum creatinine within normal institutional limits or creatinine clearance ≥60 ml/min  
3.2.8 Adequate hepatic function within 14 days prior to registration defined as follows: 
 Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution (except 
subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL); 
 ALT, AST ≤ 3.0 x ULN for the institution; 
3.2.9  Adequate respiratory function within 180 days prior to registration defined as follows: 
 FEV1 > 1.2 liters; DLCO ≥ 50% predicted; 
3.2.10  Patients with post-obstructive pneumonia are eligible provided they no longer require                          
intravenous antibiotics at registration; 
3.2.11  Patients must be at least 3 weeks from prior thoracotomy (if performed); if prior 
thoracotomy then measurable disease on imaging must be present   
3.2.12  A pleural effusion, which is a transudate, cytologically negative and non-bloody, are 
eligible if the radiation oncologist feels the tumor can be encompassed within a 
reasonable field of radiotherapy; if pleural fluid is too small a volume to effectively 
sample by thoracentesis and does not show increased metabolic activity on CT/PET 
imaging, the patient will be remain eligible. 
3.2.13 Negative serum pregnancy test within three days prior to registration for women of 
childbearing potential  


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3.2.14 The patient must provide study-specific informed consent prior to study entry. Patients 
who lack the psychological or intellectual capacity to consent for themselves are 
excluded. 
3.2.15  Sites must verify that archived tissue will be available prior to Step 1 registration to the 
trial although the actual submission can be immediately after Registration Step 1 but at 
least 5 weeks prior to Registration Step 2.  
 
Recognizing the difficulties obtaining adequate tissue for analysis from locally advanced 
lung cancer patients, there are three options available.  We would encourage investigators 
to provide the preferred amount of samples to assist in the greatest scientific yield. 
NOTE: core or excisional biopsy is required for this study.  Fine needle aspirates (FNA) 
and cytology specimens are not adequate for PD-L1 analysis.   
 
Preferred:  H&E slide and archived tissue tumor block. If sites wish the block to be 
returned they may submit the block and the Biospecimen Bank will cut the unstained for 
the required study and then punch and return the block 
 
Alternative:  If an archived tumor block sample cannot be shipped for this study, then two 
3mm punches from the core needle biopsy blocks may alternatively be provided for 
analysis in addition to the H&E slide.  
 
Minimum:  One (1) H&E stained slide (required) and five positively charged unstained 
slides cut at 3-4 microns from the same block as the H&E. Unstained slides must be 
stored at 4⁰C same day as being cut and shipped with a cold pack at 4⁰C within 5 
business days after being cut. Do NOT store or ship unstained slides at room temperature. 
 
Step 2 Registration (after completion of chemoradiation, before randomization) 
3.2.16 Zubrod performance Status of 0 or 1.  
3.2.17 Must be randomized less than 12 weeks following completion of chemoradiotherapy to 
ensure nivolumab/placebo begins no later than 12 weeks following completion of 
chemoradiotherapy.  
3.2.18 Laboratory values must meet the following criteria and must be obtained within 21 days 
prior to randomization 
 WBC  
 
≥ 2000/μL 
 Neutrophils  
≥ 1000/μL 
 Platelets 
 
≥ 50 x103/μL 
 Hemoglobin  
> 9.0 g/dL (Note: The use of transfusion or other 
intervention to achieve Hgb ≥9.0 g/dl is acceptable.) 
 Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min 
(if using the Cockcroft-Gault formula below): 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                           72 x serum creatinine in mg/dL 
 
Male CrCl = (140 - age in years) x weight in kg x 1.00 
72 x serum creatinine in mg/dL 
 


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 AST/ALT  ≤ 3 x ULN  
 Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who 
can have total bilirubin < 3.0 mg/dL)  
3.2.19  All toxicities attributed to prior chemoRT therapy other than alopecia, fatigue, or 
peripheral neuropathy must have resolved to ≤Grade 2 (NCI CTCAE version 4) 
 
before administration of nivolumab or placebo. 
3.2.20 Negative serum pregnancy test for women of childbearing potential within 7 days of 
randomization 
3.2.21 Agreement of women of childbearing potential to use highly effective contraception 
during receipt of study drug and up to 161 days (23 weeks) from the last dose of 
nivolumab/placebo and men receiving nivolumab/placebo who are sexually active with 
women of childbearing potential to use highly effective contraception during receipt of 
study drug for 31 weeks from the last dose of nivolumab/placebo. 
3.2.22  Mandatory submission per 3.2.15 is required for PD-L1 and other biomarker analysis.  
 
3.3 
Ineligibility Criteria 
Patients with one or more of the following conditions are NOT eligible for this study. 
Step 1 Registration (prior to chemoradiation): 
3.3.1 Definitive clinical or radiologic evidence of metastatic disease; 
3.3.2    Prior or current invasive malignancy (except non-melanomatous skin cancer, localized 
bladder and prostate cancer) unless disease free for a minimum of 2 years (for example, 
carcinoma in situ of the breast, oral cavity, or cervix are all permissible);  
3.3.3 Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields. For example, patients with prior breast radiotherapy treatments 
would likely be excluded;  
3.3.4   Prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell costimulation or 
immune checkpoint pathways; 
3.3.5 A condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days of study 
drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg 
daily prednisone equivalents are permitted in the absence of active autoimmune disease;   
3.3.6 Severe, active co-morbidity defined as follows: 
 An active, known or suspected autoimmune disease. Subjects are permitted to enroll 
if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to 
autoimmune condition only requiring hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger; 
 Known immunosuppressive disease, for example HIV infection or history of bone 
marrow transplant or CLL; 
 Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory 
illness requiring hospitalization or precluding study therapy at the time of 
registration. COPD  requiring chronic oral steroid therapy; 


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 Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months;  
 Transmural myocardial infarction within the last 6 months; 
 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
 History of symptomatic or previously established interstitial lung disease; 
 Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid (HCV antibody) indicating acute or chronic infection; 
 History of severe hypersensitivity reaction to any monoclonal antibody or allergy to 
study drug components; 
 As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition 
to hepatotoxicity should be used with caution in patients treated with nivolumab-
containing regimen; 
3.3.7 Pregnancy, nursing females, or women of childbearing potential and men who are 
sexually active and not willing/able to use medically acceptable forms of contraception; 
this exclusion is necessary because the treatment involved in this study may be 
significantly teratogenic. 
 
Step 2 Registration (after completion of chemoradiation, before randomization): 
3.3.8  Failure to complete minimum required amounts of chemoradiation (defined as at least 50% 
of intended days of chemotherapy administration and at least 54 Gy total dose of radiation) 
3.3.9 Bilateral lung V20 >37% on radiation therapy treatment plan used for concurrent 
chemoradiotherapy 
3.3.10  Grade 3 and above pulmonary toxicity of dyspnea, hypoxia, or pneumonitis experienced 
during chemoradiation 
3.3.11 Evidence of disease progression after chemoradiation or evidence of metastastic disease   
 
 


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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 Assessment tables at registration, treatment, and follow-up time points: 
 
 
Concurrent ChemoRT PRE-TREATMENT ASSESSMENTS REGISTRATION STEP 
1 
Assessments 
Prior to Registration Step 1 
(calendar days) 
Prior to Treatment 
(calendar days) 
Mandatory tissue submission 
for PD-L1 analysis (see note) 
Verify available 
 
History and physical exam 
30 
 
Zubrod performance status 
30 
 
Tumor measurements 
30 
 
Rad Onc exam 
30 
 
Med Onc exam 
30 
 
CBC/differential; ANC, 
platelets; hemoglobin 
14 
 
Na, K, CO2, Cl,  
14 
 
Mg, Ca, LDH 
14 
 
Serum creatinine  
14 
 
Total bilirubin, AST, ALT, 
Alk Phos  
14 
 
Serum pregnancy test 
3 
 
Cytology/Pathology Report 
confirming NSCLC 
90 
 
Whole body FDG-PET/CT 
(base of skull to mid thigh) 
60 
 
CT chest with contrast and 
include adrenals* 
60 
 
MRI of brain (CT if MRI 
contraindicated) 
60 
 
Pulmonary function testing 
(PFTs/DLCO) 
90 
 
Informed consent 
Within 30 days including Day 
of registration 
 
FACT-L, PROMIS, EQ-5D-
5L 
 
X1  
Specimen collection for 
banking 
 
If patient consents:  14. See 
Section 10. 
 
* Patients do not need to have a separate CT of chest and upper abdomen with contrast if 
FDG-PET/CT imaging includes a high quality CT chest with contrast 
1After consent, prior to initiation of chemoRT 
 
Notes for Pre-Treatment Assessment 
Mandatory submission:  Preferred:  H&E slide and archived tissue tumor block. If sites 


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wish the block to be returned they may submit the block and the Biospecimen Bank will 
cut the unstained for the required study and then punch and return the block 
 
Alternative:  If an archived tumor block sample cannot be shipped for this study, then two 
3mm punches from the core needle biopsy blocks may alternatively be provided for 
analysis in addition to the H&E slide.  
 
Minimum:  One (1) H&E stained slide (required) and five positively charged unstained 
slides cut at 3-4 microns from the same block as the H&E. Unstained slides must be 
stored at 4⁰C same day as being cut and shipped with a cold pack at 4⁰C within 5 
business days after being cut. Do NOT store or ship unstained slides at room temperature. 
 
Sites must verify that tissue is available prior to Step 1 registration to the trial although 
the actual submission can be immediately after Registration Step 1 but at least 5 weeks 
prior to Registration Step 2.  
 
NOTE: core or excisional biopsy is required for this study.  Fine needle aspirates (FNA) 
and cytology specimens are not adequate for PD-L1 analysis.   
 
 
Concurrent Chemo RT ASSESSMENTS DURING TREATMENT 
 
Assessments 
Weekly during Concurrent 
Treatment 
At week 1 and 5 only during 
concurrent chemoRT 
Performance status 
X 
 
Rad Onc Evaluation 
X 
 
Med Onc evaluation 
 
X1 
CBC/differential; platelets 
X1 
 
Na,K,CO2, Cl,  
X1 
 
Mg, Ca, LDH 
X1 
 
Total bilirubin, ALT, AST 
 
X1 
Serum creatinine or 
creatinine clearance 
X1 
 
Adverse event evaluation 
X 
 
Specimen collection for 
banking 
 
X2 
1 C1D1 testing does not need to be repeated if performed within 7 days of starting protocol 
therapy. 
2Day 1 and Day 42  
 
 


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Nivolumab/Placebo PRE-TREATMENT ASSESSMENTS REGISTRATION STEP 2 
 
Assessments 
Prior to Registration 
Step 2 
(calendar days) 
Prior to 
Treatment with 
nivolumab/placebo 
-14 days 
Medical history and 
height 
21 
 
Physical examination 
including vital signs 
(blood pressure, 
weight) 
21 
 
Zubrod performance 
status 
21 
 
Na, K, CL, Mg, Phos, 
Ca, LDH 
21 
 
Total bilirubin, AST, 
ALT, Alk Phos, 
amylase, lipase, 
glucose, albumin 
21 
 
BUN; Serum creatinine  
21 
 
CBC/differential; 
platelets 
21 
 
Thyroid function (TSH, 
free T3 and free T4), 
fasting am cortisol 
21 
 
Serum pregnancy test 
X1 
 
AE evaluation  
 
X 
CT of chest with 
contrast and include 
adrenals 
30 (and at least 14) 
after chemoRT 
completed 
 
Mandatory Tissue 
Submission for PD-L1 
Analysis 
35 and ideally 
immediately after 
Registration Step 1 
 
FACT-L, PROMIS, 
EQ-5D-5L 
 
X2 
 
1Within one week of study randomization 
 
2After Step 2 registration, prior to initiation of nivolumab/placebo 
 
 
 


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ASSESSMENTS DURING NIVOLUMAB/PLACEBO TREATMENT (1 YEAR) 
Assessments 
On Day 1 of each Cycle 
Every 3 months 
Physical examination 
including vital signs (blood 
pressure, weight) 
X 
 
Zubrod performance status 
X 
 
Na, K, CL, Mg, Phos, Ca, 
LDH 
X 
 
Total bilirubin, AST, ALT, 
Alk Phos, amylase, lipase, 
glucose, albumin  
X 
 
CBC/differential; platelets  
X 
 
BUN, creatinine 
X 
 
TSH  
X1 
 
AM cortisol 
 
As needed if symptomatic 
Serum or urine Pregnancy 
test 
X2 
 
AE evaluation 
X 
 
CT of chest with  contrast 
and include adrenals 
 
X3 
Specimen collection for 
banking 
 
X 
FACT-L, PROMIS, EQ-5D-
5L 
 
X4 
1 Every 6 weeks during q2 week dosing, then every 8 weeks during q4 week dosing; assess free 
T3 and free T4 if clinically indicated (e.g. abnormal TSH or symptomatic) 
 2Every 4 weeks3After completion of chemoradiotherapy, radiographic assessment with CT chest 
with contrast including adrenals will occur prior to starting nivolumab/placebo as a component 
of Step 2 Registration.  Further radiographic assessment will occur every 3 months for 2 years 
(including the year of nivolumab/placebo).  The first day of nivolumab/placebo will be used for 
calculation of the 3 month intervals. After 2 years, radiographic disease assessment should be 
performed every 6 months during year 3-5 then annually thereafter. FDG-PET/CT should be 
done to confirm clinically uncertain progression or treatment related effects at the discretion of 
the treating investigator. This imaging may be done locally. 
4At 3, 6, 9 and 12 months; should be collected regardless of disease status of the patient 
  
 
 


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ASSESSMENTS IN FOLLOW UP POST NIVOLUMAB/PLACEBO 
Assessments 
Every 3 mos  until 2 
years post chemoRT then 
every 6mos until 5 years 
post chemoRT, then 
yearly 
History and physical exam 
X 
Zubrod performance status 
X 
Tumor status 
X 
Med Onc exam 
X 
AE Evaluation 
X 
CBC with diff, Plts 
X1 
Na, K, CL, Mg, Phos, Ca, LDH, 
glucose 
X1 
Total bilirubin, ALT, AST, Alk 
Phos, albumin 
X1 
Serum creatinine, BUN 
X1 
TSH* 
 
X1 
Serum or Urine Pregnancy test 
X1 
 CT Chest with contrastand 
include adrenals 
X2 
FACT-L, PROMIS, EQ-5D-5L 
X3 
* Assess free T3 and free T4 if clinically indicated (e.g. abnormal TSH or 
symptomatic) 
1 At 35 days from the last dose (± 7 days) or coinciding with the date of 
discontinuation of study drug (± 7 days) if the date of discontinuation is greater 
than 42 days from the last dose. Repeat in 80 days (from first follow-up 
assessment) only if study drug related toxicity persists. Pregnancy test must be 
performed at both time points. Assess free T3 and free T4 if clinically indicated. 
2After completion of chemoradiotherapy, radiographic assessment with CT 
chest with contrast including adrenals will occur prior to starting 
nivolumab/placebo as a component of Registration Step 2.  Further radiographic 
assessment will occur every 3 months for 2 years (including the year of 
nivolumab/placebo).  The first day of nivolumab/placebo will be used for 
calculation of the 3 month intervals. After 2 years, radiographic disease 
assessment should be performed every 6 months during year 3-5 then annually 
thereafter. FDG-PET CT should be done to confirm clinically uncertain 
progression or anatomic changes in the thorax likely due to the effects of 
chemoradiotherapy, at the discretion of the treating investigator. This imaging 
may be done locally. 
3FACT-L, PROMIS, and EQ-5D-5L are collected at 15 and 18 months from 
start of nivolumab/placebo; should be collected regardless of disease status of 
the patient. EQ-5D-5L is collected at 2, 3, 4, and 5 years from start of 
nivolumab/placebo. 


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Follow-up of Patients Discontinuing Therapy Early 
After completion of study treatment, subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up. After documented disease progression each subject will be followed for overall 
survival until death, withdrawal of consent, or the end of the study (whichever occurs first).  
 
 
4.2  Definition of Disease Assessments 
 
Tumor assessments will be made using modified RECIST 1.1 criteria. The same measurable 
and non-measurable lesions will be followed from baseline across on-study time points using 
RECIST 1.1 guidelines.  A RECIST 1.1 tumor assessment will be derived for each on-study 
time point for each enrolled subject, from which the primary objective of the trial will be 
determined. In subjects whose in-field disease status is ambiguous, but who have not 
developed systemic progression, treatment may continue. Follow-up scans will be reviewed 
by ACR Diagnostic Imaging Core Lab in consultation with the study PIs, if necessary to 
determine status based on the below guidelines. Patients with uncertain progression may 
require repeat imaging at 6 weeks rather than 3 months if disease status remains uncertain. 
 
Refer to Appendix II for detailed definitions of RECIST v1.1 response assessment 
 
4.3 Central Image Collection and Review 
4.3.1 Imaging Schedule 
Imaging exams will be collected at the following time points. Images must be submitted in 
digital format to the ACR DI Core Lab for archiving: 
 
 
Baseline (prior to study treatment) 
 
Post-chemoRT  
 
All mandated follow-up imaging: every 3 months for 2 years; every 6 months for years 3-
5; then yearly  
 
At disease progression 
 
And at request when treatment occurs beyond progression and subsequent tumor   
evaluations 
 
Imaging studies (defined in Section 4.1) as well as the Image Transmittal Worksheet will be 
submitted to the ACR DI Core Lab within 2 weeks of image acquisition for all image data 
sets, excluding imaging visits where disease progression is suspected. Where disease 
progression is suspected, all imaging studies performed from baseline to date of  progression 
must be submitted to ACR DI Core Lab within 3 business days of the date progression is 
determined.   
 
 
 


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4.3.2 Independent Review of Progression 
At the time of investigator-assessed progression, sites must request an Independent Review of 
Progression from the ACR DI Core Lab. This Independent Review of Progression at the time 
of investigator-assessed progression is a separate process from the IRRC review to assess the 
primary endpoint. All subjects who are assessed to have RECIST 1.1 progression by the 
treating investigator must have all available tumor assessments submitted for an Independent 
Review of Progression. The Independent Review of Progression will be conducted by a 
blinded, third party, independent radiologist contracted by ACR DI who will assess the scans 
for RECIST 1.1 progression. When the review is complete, results from the central radiology 
review and local interpretation will be compared.  If the central reviewer agrees with the local 
assessment of progression, subsequent therapy may be initiated per investigators’ clinical 
decision, and protocol therapy may be discontinued or continued based on the guidelines in 
section 6.3.5 (Treatment Beyond Disease Progression). 
 
If there is discordance between the local and central reviews (central review does not confirm 
progression), a central adjudicator from the imaging committee organized by the ACR DI 
Core Lab will review both the local and central results and determine which interpretation 
(local or central) with which they agree.  The adjudicator’s decision is then the final decision 
of the ACR DI committee on the progression review.  
 
If the adjudicator agrees with the local assessment of progression, subsequent therapy may be 
initiated per investigators’ clinical decision, and protocol therapy may be discontinued or 
continued based on the guidelines in section 6.3.5 (Treatment Beyond Disease Progression). 
 
If the adjudicator agrees with the central reviewer and does not confirm progression, these 
cases will be discussed with the individual sites and a consensus decision will be made as to 
the participation of the patient on the trial therapy.  The adjudicator’s decision will become 
the interpretation which must be used by the local site’s treating physician if the patient is to 
remain on protocol therapy.  It is the local site treating physician’s responsibility to determine 
whether to base clinical decisions on the local read or the central read if there is discordance; 
however, if the patient is to remain on protocol therapy, interpretation from the centralized 
review must be used.   
 
In those cases when the site investigators disagree with final adjudicated central review 
interpretation, subsequent therapy may be initiated per investigators’ clinical decision, and 
protocol therapy may be discontinued. The local site investigators also have the option of 
continuing therapy beyond their local interpretation of progression based on section 6.3.5. If 
treating the patient beyond progression with nivolumab the unusual situation is created in 
which the local site has reported progression, the central review with adjudication disagrees 
and the patient is continuing on nivolumab.  In this specific situation the patient remains on 
study and continues tumor assessments outlined by protocol until central review determines 
RECIST 1.1 progression. 
 
For any patient being treated beyond progression based on the criteria outlined in Section 
6.3.5, central imaging review must occur again at the time further progression is documented 
by the local site.  This further progression is defined as an additional 10% increase in tumor 


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burden volume from time of initial PD. This includes an increase in the sum of all target 
lesions and/ or the development of new measurable lesions. If this further progression is 
confirmed by central review treatment should be discontinued permanently.  
 
If clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression 
has been assessed by the central reviewers.  The independent review of progression will occur 
within 5-7 working days of receipt of all needed imaging at ACR. Subjects who start 
subsequent therapy without prior assessment of RECIST 1.1 progression by the central review 
process must continue tumor assessments (if clinically feasible) according to the protocol-
specified schedule and submit them for central review. When RECIST 1.1 progression is 
assessed by the investigator (whether assessed before or after the start of palliative local 
therapy or subsequent therapy), the central review center must be notified. Tumor assessments 
may be discontinued when the independent central radiologist assesses the subject to have met 
RECIST 1.1 criteria for progression. 
 
4.3.3 Independent Radiology Review Committee (IRRC) 
For all randomized subjects with Baseline imaging and at least one on-study time-point, a 
timepoint-by-timepoint imaging evaluation will be performed by an Independent Radiology 
Review Committee (IRRC), consisting of two (2) trained radiologist reviewers and an 
adjudicator, if warranted. The two primary reviewers will determine time point and cross time 
point response assessments. Neither primary reviewer will have access to the other primary 
reviewer’s annotations or tumor response data. Upon completion of both reviewers’ read, 
comparison of key adjudication variables for each of the independent reviewers is performed 
and if warranted, adjudication is conducted.   
 
The IRRC review is not subject to input from clinical sites or imaging facilities.  All tumor 
assessments will be provided by ACR DI Core Lab for statistical analysis as described in the 
protocol. Dosimetry information from the radiation therapy treatment plan may be requested 
and used to better understand the imaging changes seen.  This is particularly critical due to the 
possibility of evolving radiation lung fibrosis during the time period of nivolumab/placebo 
treatment. 
 
At the time of the final analysis for PFS, the IRRC will review tumor assessments in all 
randomized subjects to determine RECIST 1.1 response for the analyses of PFS. This IRRC 
review for the final PFS analysis will be a separate process from the blinded independent 
radiology review at the time of investigator-assessed progression.  
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
This will be a randomized, double-blind, placebo-controlled phase 3 clinical trial.  Patients 
will be treated with standard concurrent chemoradiation (thoracic radiation to 60 Gy plus 
cisplatin-etoposide), followed by randomization to nivolumab or placebo, which will be 
started 4-12 weeks after completion of concurrent chemoradiation administered every 2 weeks 
as an intravenous infusion over 30 minutes for up to a total of 1 year. 
 
Concurrent chemoradiation: Chemotherapy and radiotherapy are to begin within 48 hours 
of each other.  Day 1 of radiotherapy must be Monday, Tuesday, or Wednesday, but no later 
in the week.  Treatment must begin within 14 days after registration.   


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5.1 Chemotherapy/Other Agent-Based Therapy  
5.1.1 Concurrent Chemotherapy 
Concurrent chemoradiation must begin within 14 days after step 1 registration. 
Consists of one treatment course 
 
Cisplatin Dose Administration 
Cisplatin 50mg/m2 is given intravenously on days 1 and 8, and days 29 and 36 of 
concurrent therapy. 
After administering appropriate antiemetics, cisplatin will be infused over 1-2 hours along 
with vigorous hydration. 
 
Cisplatin Supportive Care Guidelines 
Patients must receive intravenous hydration and and polyantiemetics on day 1, day 8, day 
29, and day 36 cisplatin therapy.  These should be administered according to institutional 
practice and the patient’s baseline electrolyte levels.   As an example, one commonly 
employed regimen is as follows:    prior to cisplatin, begin intravenous hydration with 
1,000 ml NS + 20 meq KCL + 4 gms MgSO4 at 250 cc/hr over two hours.  The cisplatin 
may be preceded and followed by 12.5 grams of mannitol, IV push. After cisplatin 
infusion, complete the remaining 500 cc of hydration fluid over two hours.  The patient 
should be encouraged to drink as much liquid as possible overnight if an outpatient; 
otherwise, an additional two liters of fluid should be given IV over the next 12 hours if the 
patient is an inpatient.   
 
Appropriate polyantiemetic regimens must be used prior to and following the 
administration of cisplatin (e.g., phenothiazine, antihistamine, benzodiazepine plus 
dexamethasone - OR - ondansetron or 5HT3 antagonist with or without dexamethasone 
and PRN benzodiazepines, as well as neurokinin/substance P inhibitors).   
Etoposide Dose Administration 
Etoposide 50mg/m2 is given intravenously on days 1-5, and days 29-33 of concurrent 
therapy.  
Infuse etoposide over at least 45-60 minutes. Infusions of 30 minutes or less greatly 
increase the risk of hypotension. 
 
5.1.2 Nivolumab/placebo 
Nivolumab is approved in US and Europe to treat metastatic melanoma. On March 5, 2015, 
nivolumab was US FDA approved for the treatment of patients with metastatic squamous 
NSCLC with progression on or after platinum-based chemotherapy. Subsequently, 
nivolumab was also approved in Europe for this indication in NSCLC. On October 9, 2015, 
nivolumab was US FDA approved for the treatment of patients with metastatic non-
squamous NSCLC with progression on or after platinum-based chemotherapy. 
 
 
Nivolumab/placebo must begin within 4-12 weeks after completion of chemoradiation 
If subjects meet all eligibility criteria and have recovered sufficiently from treatment with 
chemoradiation, initial consolidation therapy with nivolumab/placebo will be started a 


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minimum of 4 weeks and a maximum of 12 weeks after chemoradiation is complete. 
Treatment with a dose of nivolumab/placebo 240 mg IV will occur on day 1 of each 2 week 
cycle for 16 weeks followed by 480 mg on day 1 of each 4 week cycle until progressive 
disease or unacceptable toxicity develop or until the subject has completed 52 weeks of 
therapy with nivolumab/placebo. Nivolumab should be dosed no sooner than 12 days 
during the every 2 week administration and no sooner than 26 days during the every 4 
week administration. 
 
Nivolumab/Placebo Dose Administration          
Nivolumab/placebo 240 mg is given intravenously every 2 weeks for 16 weeks then dosed 
480 mg every 4 weeks for 36 weeks for a total of  52 weeks (1 year).  
For both the 240 mg and the 480 mg doses, nivolumab/placebo is to be administered as a 30-
minute IV infusion and diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution.  
Patients may be dosed no less than 12 days from the previous dose of drug; and dosed up to 
3 days after the scheduled date if necessary. 
There will be no dose modifications for nivolumab/placebo 
 
See Section 6.0 for nivolumab/placebo dose delay and management  
 
5.2 Radiation Therapy 
Protocol treatment must begin within 14 days after Step 1 registration. 
 
Note:  All participating institutions will be credentialed for lung photons 3DCRT or 
IMRT prior to registering patients to the study.   
 
For detailed information on the specific technology requirement required for this 
study, please refer to the study specific guide on the RTOG Foundation 3505 
protocol page of the RTOG website, www.rtog.org 
 
Protocol treatment will be scored according to the Compliance Criteria table in 
Section 5.2.8. 
 
It is recommended that radiation therapy be delivered after chemotherapy per Section 5. 
Day 1 of radiotherapy must be Monday, Tuesday, or Wednesday, but no later in the week.   
 
5.2.1Treatment Technology 
This protocol requires the use of photons delivered either using 3D-CRT or IMRT 
techniques. Tomotherapy is allowed if appropriately credentialed for its use. Use of 
CyberKnife is not permitted for this trial. 
The use of IGRT is highly encouraged but not required. No margin reduction will be 
allowed whether IGRT is used or not, and separate IGRT credentialing will not be required.  
 
Institutions must complete the pre-registration credentialing requirements before 
registering patients on this study.  
 


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5.2.2 Immobilization and Simulation 
Immobilization 
Proper immobilization is critical for this protocol. Patient setup reproducibility must be 
achieved using appropriate clinical devices. 
Simulation Imaging 
Contiguous CT slices of maximum 3 mm slice thickness should be obtained starting from 
the level of the cricoid cartilage and extending inferiorly through the entire liver volume. 
I.V. contrast-enhanced CT- simulation is recommended but not required in this study.  
CTs and PET/CTs should be used to guide tumor and normal organ volume definition. In 
the event that contrast-enhanced datasets are used for treatment planning, the density of 
the contrast should be overridden to a representative background electron density. 
Motion Management Technique 
Motion management is highly recommended for this protocol. In instances in which 
motion management is not possible, larger expansion volumes will be used to adequately 
cover the motion-related uncertainties. The types of motion management allowed on this 
study are 4DCT with ITV, active breath-hold, gated treatment, and abdominal 
compression. IMRT will be restricted to patients with less than 1cm of tumor motion on 
4D imaging or utilizing of gating, ABC, or breath hold methods.  Abdominal 
compression as a method of minimizing respiratory motion is allowed.   
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow up 
A whole-body FDG-PET/CT and an IV contrast enhanced CT scan or MRI exam (if CT 
scan with contrast is medically contraindicated, when MR of the chest is submitted, a non-
contrast chest CT should also be submitted) of the lung and upper abdomen through the 
adrenal glands are required within 60 days prior to registration. These exams will be used 
for disease staging and to assist in volume delineation in all eligible patients (see Section 
4.0). 
The ACR Imaging Core Lab group will collect the pre-chemoradiation treatment FDG-
PET/CT and dedicated contrast enhanced chest CT. ACR Imaging Core Lab will also 
collect all mandated follow-up CT (and/or MRI) scans of the chest and upper abdomen 
post-treatment, at the time of progression, and at the time point immediately prior to 
progression. See Section 8.2.1 for digital data imaging submission details. If FDG-PET/CT 
is obtained at any of the above time points including at time of progression, this should be 
should be submitted as well. 
ACR Imaging Core Lab also will be involved in the analysis of submitted imaging data as 
part of the confirmation of local progression review and central review of radiographic 
response/recurrence. 
 
5.2.4 Accounting for Tumor Motion Approaches and Internal and Setup Margins 
Internal margin (IM): The IM used will be dictated by the motion management decision 
made at time of simulation. It is required for all cases, with the exception of instances in 
which simulation is done with 4DCT to develop a MIP of tumor volume (see number 4 
below). 
1. 
If the simulation is done with a free-breathing CT only, the IM will be 1 cm in 
the superior- inferior direction and 0.5 cm in the axial direction. 


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2. 
If simulation is done with abdominal compression, the IM will be 0.7 cm in the 
superior-inferior direction and 0.5 cm in the axial direction. 
3. 
If simulation is done using an active breath-hold or gated breathing technique, 
the IM will be 0.5 cm in all directions. 
4. 
If simulation is done using a 4DCT to develop a maximum intensity projection 
of the tumor volume based on the entire tumor motion, no IM is needed.  (This is the 
encouraged and preferred method) 
Setup Margin (SM): The SM will be 0.5 cm in all directions. No margin reduction will be 
allowed, even when using IGRT. The final PTV is constructed by expanding the just ITV 
or sum of the CTV + IM by the SM based on the definitions from Table A or B in section 
5.2.5.  
 
5.2.5  Definition of Target Volumes and Margins 
All structures must be labeled for digital RT data submission as listed in the table below. 
Capital letters, spacing and use of underscores must be applied exactly as indicated. 
Resubmission of data may be required if labeling of structures does not conform to the 
DICOM standard name listed. 
The structures marked as “Required” in the table must be contoured and submitted with 
the treatment plan.  
There are two tables below.  The first table applies to patients being treated using method 1, 2, 
or 3 from section 5.2.4.   The second table applies only to patients being treated with method 
4 of section 5.2.4 (4DCT with maximum intensity projection of the tumor volume based on 
the entire tumor motion) 
Contouring of the ITV_6000 is necessary only when the ITV approach is used. 
 
TABLE A: FREE BREATHING / ABDOMINAL COMPRESSION / ACTIVE 
BREATH HOLD / GATING MOTION MANAGEMENT TECHNIQUES 
DICOM Standard 
Name 
Description 
Detailed Specification 
GTV_6000 
GTV to receive 60 Gy 
Required for free 
breathing, active breath 
hold or gating motion 
management 
techniques 
The primary tumor and clinically positive lymph 
nodes seen on the planning CT 
(> 1cm short axis diameter) and pre-treatment 
PET scan (SUV > 3) will constitute the GTV. This 
volume(s) may be disjointed. In the event of a 
collapsed lobe or lung segment, the use of PET to 
distinguish tumor from fluid/atelectasis is 
encouraged. An ITV is defined at this point as the 
enveloping GTV motion over the course of a 
respiratory cycle. 


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CTV_6000 
CTV to receive 60 Gy 
Required 
The CTV is defined to be the GTV plus a 0.5 cm 
margin to account for microscopic tumor 
extension. If an ITV is used then a 0.5 cm margin 
is added to the ITV to form a CTV.  The CTV 
should be adjusted to not expand into other 
organs such as esophagus, major blood vessels, 
or bone. 
PTV_6000 
PTV to receive 60 Gy 
Required 
The PTV will be equal to the CTV+IM+SM.  IM 
and SM are defined in Section 5.2.4 above. In 
cases in which the PTV expansion extends 
outside of the skin, towards the spinal cord or into 
the spinal canal, it can be assumed that tumor 
motion will not occur in this direction, and the PTV 
margin in this direction can be limited. PTV 
margin can be limited up to 0.5 cm towards this 
particular dimension (skin or spinal cord). 
 
TABLE B: 4D CT WITH MAXIMAL INTENSITY TUMOR VOLUME 
TECHNIQUE (PREFERRED METHOD) 
DICOM Standard 
Name 
Description 
Detailed Specification 
iGTV_6000 
Defined as the 
enveloping GTV motion 
over the course of the 
entire respiratory cycle 
 
 
Required when a 4DCT 
is used to encapsulate 
entire breathing cycle 
volume   
The primary tumor and clinically positive lymph 
nodes seen on the planning CT (> 1 cm short axis 
diameter) and pre-treatment PET scan (SUV > 3) 
over the course of a respiratory cycle. This 
volume(s) may be disjointed. In the event of a 
collapsed lobe or lung segment, the use of PET to 
distinguish tumor from fluid/atelectasis is 
encouraged. 
ITV_6000 
ITV to receive 60 Gy 
 
Required when iGTV is 
drawn 
The ITV will be equal to the iGTV plus a 0.5 cm 
clinical margin as appropriate to account for 
microscopic tumor extension.  


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PTV_6000 
PTV to receive 60 Gy 
Required 
The PTV will be equal to the ITV+SM.  SM is 
defined in Section 5.2.4 above. In cases in which 
the PTV expansion extends outside of the skin, 
towards the spinal cord or into the spinal canal, it 
can be assumed that tumor motion will not occur 
in this direction, and the PTV margin in this 
direction can be limited. PTV margin can be 
limited up to 0.5 cm towards this particular 
dimension (skin or spinal cord). 
 
5.2.6 Definition of Critical Structures and Margins 
Note: All required structures must be labeled for digital RT data submission exactly 
as listed in the first column of the table below. Capital letters and spacing must be 
used exactly as indicated. Resubmission of data may be required if labeling of 
structures does not conform to the DICOM Standard Name listed. 
DICOM Standard 
Name 
Description 
Detailed Specification 
SpineCanal 
Spinal Canal 
Required 
Boundaries: The bony limits of the spinal canal 
Cranial 
Top of C1 (or first CT slice) 
Caudal 
Bottom of L2 (or last slice of CT) 
Lungs 
Both Lungs minus 
GTV_6000 (or 
iGTV_6000) 
 
Required 
Boundaries: Use Lung OAR Atlas* 
Other notes: Both lungs merged into 1 structure 
and excluding the overlap with 
GTV_6000/iGTV_6000 
Esophagus 
Required 
Boundaries: The esophagus contour should include 
the mucosa, submucosa, and all muscular layers 
out to the fatty adventitia. 
Cranial:  Bottom of cricoid cartilage 
Caudal: GE junction 
BrachialPlexus 
Required for upper 
lobe tumors 
The ipsilateral brachial plexus should be contoured 
for upper lobe tumors 
Heart 
Required 
Cranial: Ascending Aorta 
Caudal: Apex 
External 
Required 
External contour of patient encompassing all 
internal organs on each slice 
NonPTV 
Required 
External (as described above) minus PTV 
*Investigators can access the Lung OAR Atlas at 
http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx 
 
5.2.7 Dose Prescription 
Note: The information provided in this section can be used for adjusting the dose 
constraints for treatment planning purposes. This table together with the planning 
priorities in Section 5.2.9 should be used during dose optimization. It is important to 


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remember that ideal plans might not be achievable in all cases.  Thus, the 
Compliance Criteria table could be different than the information given here. Cases 
will be scored using the Compliance Criteria table. 
 
Target Standard 
Name 
Dose (Gy) 
Fraction 
Size (Gy) 
# of 
fractions 
Dose 
specification 
technique 
PTV_6000 
60 
2.0 
30 
Covering 
exactly 95% of 
PTV 
 
5.2.8 Compliance Criteria 
The compliance criteria listed below will be used to score each case. Given the 
limitations inherent in the treatment planning process, the numbers given in this 
section can be different than the prescription table. The Per Protocol and Variation 
Acceptable categories are both considered to be acceptable. The Per Protocol 
cases can be viewed as ideal plans, and the Variation Acceptable category can 
include more challenging plans that do not fall at or near the ideal results. A final 
category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable. Plans falling in this 
category are considered to be suboptimal and additional treatment planning 
optimization is recommended. 
Target Volume Constraints and Compliance Criteria 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
PTV_6000 
D95%(Gy) 
60 
58.8 to 61.2Gy 
(excluding 60 Gy) 
*Dmin(Gy) 
≥ 57 
≥54 Gy 
*Dmax(Gy) 
≤ 72 
≤75 Gy 
* Dmin and Dmax values are for a volume of 0.03 cc. 
Normal Structure Constraints and Compliance Criteria 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable
SpineCanal 
D0.03cc(Gy) (max) 
≤ 50 
none 
Lungs 
V5Gy(%) 
≤ 65 
≤ 70 
V20Gy(%) 
≤ 35 
≤ 37 
Dmean(Gy) 
≤ 20 
≤ 22 
Esophagus 
V35Gy(%) 
≤ 50 
≤ 55 
V70Gy(%) 
≤ 20 
≤ 25 
Dmean(Gy) 
≤ 34 
≤ 37 
BrachialPlexus 
Dmax(Gy) 
≤63 
≤ 66 
Heart 
V30Gy(%) 
≤ 50 
≤ 55 
V45Gy(%) 
≤ 35 
≤ 40 
D0.03cc(Gy) (max) 
≤ 70 Gy 
≤ 75 Gy ** 
*The Variation Acceptable category extends the Per Protocol category numbers to allow 


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for more challenging treatment planning problems.  The Variation Acceptable range does 
not include the Per Protocol values.  Plans will be scored as Deviation Unacceptable when 
Per Protocol and Variation Acceptable constraints are not met. 
** When this value cannot be achieved, treatment plans must be modified to move dose 
distribution hotspots away from the heart to avoid having the case scored as a Deviation 
Unacceptable. 
Delivery Compliance Criteria 
Per Protocol 
Variation 
Acceptable 
Start date (days after 
step 1 registration) 
14 days 
15-30 days 
RT Elapsed Days 
< 45 days 
46-51 days 
Interruptions (other than 
holidays or weekends) 
0-2 days 
3-7 days 
Note: Cases will be scored as Deviation Unacceptable when the time limits given 
above are not met. 
5.2.9 Treatment Planning Priorities and Instructions 
 
Critical Structure and Target priorities are listed in order of decreasing importance: 
 
SpineCanal 
 PTV  
 
 
Lungs 
 
 
Esophagus 
 
 
Heart 
 
 
BrachialPlexus 
 
If lung dose constraints are exceeded, several solutions can be entertained: 
 
For 3D-CRT: Increase the weighting of AP/PA treatments by 1, and reduce 
the obliques. This can be done as long as the cord dose, which takes precedence, is 
not exceeded. 
 
For 3D-CRT or IMRT: Reduce the CTV to the minimum range suggested 
above and/or reduce the PTV by choosing another motion management option 
with smaller internal margins. 
It is recommended that the esophagus not be circumferentially irradiated with > 60 
Gy (i.e. the 60 Gy isodose line should not encompass the entire axial cross-section 
of the esophagus at any level). 
5.2.10   Dose Calculations 
 Required algorithms 
Acceptable choices of algorithm are listed at 
http://irochouston.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TP
S%20-%20algorithm%20list%20updated.pdf. Any algorithm used for this study must 
be credentialed by MD Anderson Dosimetry Lab. 
Primary dataset for dose calculation 
The primary dataset for dose calculation must be a free-breathing CT that was 


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acquired along with 4DCT, an average intensity pixel CT (AveIP) generated from the 
4DCT, the breath- hold/gated CT, or the free-breathing CT acquired with no other 
motion management. Maximum Intensity Pixel (MIP) generated images from 4DCTs 
may not be used as the primary dose calculation dataset. 
Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions. 
5.2.11    Patient-Specific QA 
Any patient-specific QA that needs to be acquired should follow institutional 
guidelines. 
5.2.12    Daily Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate 
accuracy and precision throughout its entire process from target and normal tissue 
delineation, to radiation delivery, to adaptation of therapy to anatomic and biological 
changes over time in individual patients. In this section we use the terminology IGRT 
to focus on image-guidance at the time of radiation delivery to ensure its adherence to 
the planned treatment. 
A reliable method of daily image guidance will be utilized.  This can include but is not 
limited to daily conebeam imaging, fiducial marker tracking systems, kV – kV 
matching.  Daily conebeam imaging aligned to the tumor and soft-tissue anatomy is 
considered the preferred approach. 
5.2.13   R.T. Quality Assurance Reviews 
The Radiation Oncology Principal Investigator, James Urbanic, MD, and appointed 
delegates will perform an RT Quality Assurance Review after complete data for the 
first 20 cases enrolled has been received at ACR Core Laboratory/ RTQA. Dr Urbanic 
and delegates will perform additional reviews after complete data for the next 20 
cases enrolled has been received at ACR Core Laboratory/ RTQA. This pattern will 
occur throughout the study accrual period.  These final cases will be reviewed within 
3 months after this study has reached the target accrual or as soon as complete data 
for all cases enrolled has been received at ACR Core Laboratory/ RTQA, 
whichever occurs first. 
5.2.14 Radiation Therapy Adverse Events 
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and 
esophagitis are expected side effects of radiation therapy.  
Cardiac Toxicity 
Radiation-induced myocarditis rarely occurs at doses lower than 50 Gy.  
Neurologic Toxicity 
Radiation-induced transverse myelitis rarely occurs at doses lower than 50 Gy. 
Esophagitis 
Esophageal complaints are common with combined modality therapy. Esophagitis 
does not constitute a reason to interrupt or delay radiotherapy or chemotherapy 
provided oral intake is sufficient to maintain hydration. Patients should be advised to 
avoid alcoholic, acidic, or spicy foods or beverages. Viscous Xylocaine, Carafate, or 
other medications should be used for symptomatic relief. Occasionally, narcotics may 
be required. 
It is not necessary to biopsy acute esophagitis in the first 2 weeks of combined therapy 
since it is rarely due to underlying viral or fungal disease. Acute esophagitis may 


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persist for 4-6 weeks. If Grade 4 (CTCAE, v. 4) esophagitis occurs, and a treatment 
interruption is being considered, every effort should be made to limit it to ≤ 3 
treatment days. Patients requiring hospitalization because of esophagitis may have 
their treatment interrupted.  
Pulmonary Toxicity 
Pneumonitis is possible in the later weeks of chemoradiotherapy and during the weeks 
that follow.  In general, pneumonitis is a diagnosis of exclusion and is treated with a 
combination of corticosteroids and supportive care at the discretion of the treating 
physician.  Radiographic evidence of radiation change and subsequent fibrosis of the 
lung will occur within lung volume receiving ≥ 20 Gy, usually within the first 6 months 
after initiation of treatment. It is essential to spare as much normal lung as possible in 
order to avoid symptomatic lung injury. 
5.3       General Concomitant Medication and Supportive Care Guidelines 
5.3.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
Subjects are permitted the use of 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 (e.g., contrast dye allergy) or for treatment of non-
autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact 
allergen) is permitted. Steroids are also permitted for the prevention/treatment of 
nausea/vomiting during chemoradiation and are permitted, as indicated, for treatment of 
toxicities such as radiation pneumonitis.  
 
Other permitted supportive/ancillary medications include but are not limited to the 
following:  
 Anticonvulsants 
 Antiemetics 
 Anticoagulants 
 Antidiarrheals 
 Analgesics 
 Hematopoietic Growth Factors 
 Nutritional supplementation 
 Highly active antiretroviral therapy (HAART) 
5.3.2 Prohibited Therapies 
The following medications are prohibited during the study (unless utilized to treat a drug 
related adverse event): 
 Immunosuppressive agents 
 Immunosuppressive doses of systemic corticosteroids (except as stated in above 
Permitted Therapy for Nivolumab) 
 Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents for treatment of NSCLC 
 Myeloid growth factors 
5.3.3 Participation in Other Trials 


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Patients may not participate in other clinical trials that are intended to treat the diagnosed 
lung cancer or intended to reduce toxicity of therapy. 
5.4 Emergency Unblinding Procedure  
The decision to break the unblinding code must be based on an extraordinary clinical 
circumstance for which knowledge of drug assignment will affect clinical judgment.  
 
Sites can call RTOG Foundation Headquarters during business hours (8:30 AM to 5 PM ET), 
at 215-574-3150 and ask to speak to the Supporting Study Statistician. For after hours, 
weekends, and holidays, call 215-459-3576.  
5.5 Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections for up to one year or until one of the 
following criteria applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
Sponsor discontinuation of study 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT        
There are no dose modifications for nivolumab/placebo. Instead, the dose will be delayed or 
discontinued as specified below 
 
6.1 Chemoradiotherapy Dose Modifications 
Key to the successful and safe administration of nivolumab/placebo will be close monitoring 
of toxicities arising from the antecedent concurrent chemoradiation.  Treatment 
modifications for in-field toxicities will be as follows: 
 
Toxicity 
 
CTCAE grade 
XRT 
Cisplatin 
Etoposide 
Esophagus/pharynx 
4 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Esophagus/pharynx 
3 
No change or hold 
≤ 5 days 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Esophagus/pharynx 
2 
No change 
No change 
No change 
Pulmonary 
4 
Discontinue 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Pulmonary 
3 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Skin 
4 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Hold treatment 
until ≤ Grade 2 
Skin 
3 
No change 
No change 
No change 
 
Radiation therapy is held for neutropenia (ANC < 500/mcl); radiation therapy may be 
restarted when the ANC ≥ 500/mcl. 


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If treatment is interrupted ≥ 3 weeks for pneumonitis discontinue all protocol therapy 
 
6.2  Cisplatin and Etoposide Dose Modifications 
 
Concurrent chemoradiotherapy consists of a single, 8 week treatment course. 
The grades of adverse events below refer to CTCAE, v. 4. 
 
Cisplatin (50 mg/m2) is administered intravenously on days 1 and 8, and days 29 and 36 
of concurrent chemoradiation.  Etoposide (50 mg/m2) is administered intravenously on 
days 1-5 and days 29-33 of concurrent chemoradiation. 
 
If cisplatin and/or etoposide are held for greater than 2 consecutive weeks, the drugs will be 
held permanently for the duration of concurrent therapy.  
 
The following dose levels are used for dose modifications during both the concurrent 
chemoradiation phase. There will be no dose reduction below level -1. 
 
Dose Level 
Cisplatin 
Etoposide 
0 
50 mg/m2 
50 mg/m2 
-1 
40 mg/m2 
40 mg/m2 
 
Hematologic Toxicity 
Dose modification on Day 1 and Day 29 during concurrent chemoradiation  
 
ANC 
 
Platelet 
Cisplatin and Etoposide Dose 
≥ 1,500/mcl 
and 
≥ 100,000/mcl 
Continue w/ previous dose 
< 1,500/mcl 
or 
< 100,000/mcl 
Hold* 
*Check weekly and resume therapy at previous dose (no dose reduction) when 
counts recover to ANC ≥ 1,500 and platelets ≥ 100,000/mcl.  
 
Febrile neutropenia occurring during chemoradiation will result in a decrease of the cisplatin 
and etoposide dose level by –1. Febrile neutropenia occurring despite dose reduction during 
chemoradiation will result in discontinuation of chemotherapy. Radiation therapy is held for 
neutropenia (ANC < 500/mcl); radiation therapy may be restarted when the ANC ≥ 500/mcl. 
 
The use of myeloid growth factors will be prohibited during the entire treatment due to 
potential interaction with concurrent or previous RT. 
 
Renal Toxicity 
Dose modification on Day 1 and Day 29 of cisplatin and etoposide: 
 
CrCl < 50 ml/min 
Hold therapy. Administer fluids and repeat 
creatinine in one week. 


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If after one week CrCl ≥ 50 ml/min 
Administer both cisplatin and etoposide at 
full dose, but increase pre- and post-
cisplatin hydration. 
If after one week CrCl < 50 ml/min 
Discontinue chemotherapy. 
 
Day 8 and Day 36 cisplatin modifications 
 
Omit cisplatin if grade 4 neutropenia on day 8 or day 36; no modification 
for grades 1-3 myelotoxicity 
 
Omit cisplatin if patient develops ≥ Grade 2 renal toxicity, Grade 4 
esophagitis, or febrile neutropenia 
 
If cisplatin omitted on day 8, it should not be given again until day 29; if 
cisplatin omitted on day 36, it should not be given again 
 
Hepatic Toxicity 
Give the following doses for etoposide only: 
 
Bilirubin 
Etoposide 
< 1.5 mg/dl 
Same dose level 
1.5 -3.0 mg/dl 
 1 dose level 
≥  3.0 mg/dl 
Hold* 
 
*Hold until <3.0 mg/dl then resume with one level dose reduction 
 
Gastrointestinal Toxicity 
Nausea/Vomiting: For ≥ grade 3 nausea or vomiting despite maximum antiemetics, decrease 
cisplatin by one dose level for the next dose. If nausea and vomiting improve, cisplatin dose 
should be re-escalated to the previous dose, if possible. 
Neurotoxicity (Peripheral) 
Cisplatin doses should be modified for neurologic toxicity (see below). Serum magnesium 
and calcium levels should be checked; vitamin B12 levels may need to be evaluated 
especially in older patients.  
Grade 1: Give cisplatin at full dose. 
Grade ≥ 2: Hold cisplatin until neurotoxicity resolves to  ≤  grade 1, then resume with one 
dose level reduction. Continue treatment with etoposide. If cisplatin is held for ≥  21 days, 
discontinue cisplatin. 
Ototoxicity: Discontinue cisplatin for ≥ grade 3 ototoxicity. 
Hypomagnesemia and Hypokalemia: is not an indication for stopping therapy. Oral and 
parenteral supplementation is indication for serum levels < LLN. 
 
All Other Treatment-Related Toxicities that Exceed grade 2: (except alopecia, nausea, 
vomiting, fatigue and anorexia, and grade 3 myelosuppression on days 8 and 36), hold 
cisplatin and etoposide until the toxicities have resolved to grade 2 or less and resume 
cisplatin and etoposide with one dose level reduction. 
6.3   Nivolumab/Placebo Dose Modifications 
There are no nivolumab/placebo dose modifications.  Depending on toxicities, 
nivolumab/placebo is either given at full dose, withheld, or discontinued. 


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6.3.1 Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with adverse events that can differ in 
severity and duration than adverse events caused by other therapeutic classes. Nivolumab is 
considered an immuno-oncology agent in this protocol. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of 
adverse events: Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and 
Neurological. See the nivolumab Investigator Brochure for the treatment algorithms.  
Early recognition and intervention are recommended according to the management 
algorithms found in  the Investigator Brochure. In addition, the Investigator Brochure (IB) 
includes ophthalmologic evaluations for any visual symptoms in order to evaluate for 
nivolumab related uveitis. Investigators should follow the algorithms for immune-related 
events. 
 
Note: The algorithms are essential guides for AE management, but the guidance provided 
in these algorithms should not replace the investigator’s medical judgment but should 
complement it.  
 
For patients expected who require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider the following 
recommendations: 
 
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent 
opportunistic infections such as Pneumocystis jiroveci and fungal infections. 
 
Early consultation with an infectious disease specialist should be considered. 
Depending on the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate. 
 
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the differential 
diagnosis. 
 
Additional details on the safety of nivolumab, including results from clinical studies, are 
available in the IB. 
6.3.2 Dose Delay Criteria 
Because of the potential for clinically meaningful nivolumab-related AEs requiring 
early recognition and prompt intervention, management algorithms have been 
developed for suspected AEs of selected categories. [see the nivolumab Investigator 
Brochure] 
Nivolumab/placebo administration should be delayed for CTCAE, v. 4 toxicities as 
indicated in the management algorithms that in the opinion of the treating physician are 
related to the study drug. Nivolumab/placebo administration should be delayed for the 
following: 
 
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 
 
Any Grade 3 skin, drug-related adverse event 


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 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, AST, ALT, or total bilirubin: 
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay. It is 
recommended to consult with the principal investigator for Grade 3 amylase or 
lipase abnormalities. 
o If a patient has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥  2 toxicity 
o If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥  3 toxicity 
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, warrants delaying the dose of study medication. 
 
6.3.3 Criteria to Resume Treatment 
Patients may resume treatment with nivolumab/placebo when the drug-related AE(s) 
resolve to Grade ≤1 or baseline value, with the following exceptions: 
 
Patients may resume treatment in the presence of Grade 2 fatigue  
 
Patients who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
 
Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment 
in the presence of Grade 2 AST/ALT OR total bilirubin 
 
Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 
 
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed 
 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
If the criteria to resume treatment are met, the patient should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol, the next scheduled time point will be delayed until 
dosing resumes. Cycle number is to be counted continuously (without skipping numbers) in 
case the nivolumab/placebo dose is delayed or interrupted. 
If treatment is delayed > 6 weeks the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation section. 
For patients treated with corticosteroids: 
Grade 2 events must resolve to < Grade 1 before considering retreatment.  
 
All patients treated with steroids for grade ≥2 drug related immune mediated adverse 
events should have nivolumab/placebo held until resolution to < Grade 1 for at least 2 
weeks following complete removal from steroid treatment except for maintenance 
replacement doses for adrenal insufficiency (preferably no greater than 10mg prednisone 


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equivalent daily).   
 
All patients treated with steroids for grade ≥3 events should have nivolumab/placebo 
discontinued.  Patients with grade 3 thyroiditis and skin rash may continue therapy as for 
grade 2 events with resolution and stable replacement treatment. 
 
Patients with hepatitis, pancreatitis, pneumonitis, and colitis are at risk for exacerbation 
with retreatment if there is residual inflammation and should resolve to Grade 0 or baseline 
before retreatment.  Baseline can mean the initial grade i.e. grade <2 where permitted on 
study. 
 
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with 
replacement hormones including thyroid hormone and physiologic doses only of 
corticosteroids.  
 
Please note that grading for hypophysitis with symptoms of headache, visual or neurologic 
changes or radiologic evidence of pituitary enlargement and other CNS events such as 
aseptic meningitis or encephalitis should be considered grade 3 events.  
 
New immune-related events or exacerbation of existing events during steroid treatment or 
taper suggest the presence of ongoing immune activation and should require permanent 
discontinuation of nivolumab.  
 
A patient who is treated with steroids, evaluated, and found to not have an autoimmune or 
inflammatory event requiring steroid treatment, may be restarted if asymptomatic off 
steroids for 2 weeks and other restarting criteria are met.  
6.3.4 Discontinuation Criteria 
Treatment should be permanently discontinued for the following: 
 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment  
 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, 
diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, and infusion 
reactions 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic adverse event, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 


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 
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation:  
o AST or ALT > 8 x ULN 
 
o Total bilirubin > 5 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
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 
 
Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage drug-related 
adverse events are allowed. Prior to re-initiating treatment in a patient with a dosing 
interruption lasting > 6 weeks, the Principal Investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted 
o Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a patient 
with a dosing interruption lasting > 6 weeks, the Principal Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted 
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the patient with continued 
nivolumab/placebo dosing 
6.3.5 Treatment Beyond Disease Progression   
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. Patients will be permitted to continue 
treatment beyond initial RECIST 1.1 defined progressive disease (PD) as long as the 
following criteria are met: 
1. 
Investigator-assessed clinical benefit and do not have rapid disease progression 
2. 
Tolerance of study drug 
3. 
Stable performance status 
4. 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression 
5. 
Patient provides written informed consent prior to receiving additional 
nivolumab/placebo treatment, using the ICF addendum describing any reasonably 
foreseeable risks or discomforts, or other alternative treatment options. 
 
The decision to continue treatment beyond initial progression should be discussed with the 
Principal Investigator and documented in the study records. A radiographic assessment/ 
scan should be performed within 4-6 weeks of original PD to determine whether there has 
been a decrease in the tumor size, or continued PD. If PD is not confirmed on the 4-6 week 


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imaging after initial progression, the patient should then revert to imaging on the 12 week 
cycle with the timing to start from the scan of initial disease progression. The assessment of 
clinical benefit should be balanced by clinical judgment as to whether the patient is 
clinically deteriorating and unlikely to receive any benefit from continued treatment with 
nivolumab. If the investigator feels that the patient continues to achieve clinical benefit by 
continuing treatment, the subject should remain on the trial and continue to receive 
monitoring according to the assessment schedule. 
 
Further progression is defined as an additional 10% increase in tumor burden volume from 
time of initial PD. This includes an increase in the sum of all target lesions and/ or the 
development of new measurable lesions. Treatment should be discontinued permanently 
upon documentation of further disease progression.  
 
Patients with global deterioration of health status who require discontinuation of treatment 
without objective evidence of disease progression at the time of treatment discontinuation 
should be reported as ‘symptomatic deterioration’. Every effort should be made to 
document objective progression (i.e. radiographic confirmation) even after discontinuation 
of treatment. 
 
6.3.6Treatment of Nivolumab/Placebo-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, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE v. 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 the patient until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 
mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes 
before additional nivolumab/placebo administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
Stop the nivolumab/placebo infusion, begin an IV infusion of normal saline, and treat the 
patient with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 
(acetaminophen) 325 to 1000 mg; remain at bedside and monitor patient until resolution of 
symptoms. Corticosteroid or bronchodilator therapy may also be administered as 
appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, 


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the rate may be increased to 100% of the original infusion rate. Monitor the patient closely. 
If symptoms recur then no further nivolumab/placebo will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the patient until 
resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes 
before additional nivolumab/placebo administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for other 
clinical sequelae [e.g., renal impairment, pulmonary infiltrates]. Grade 4: life threatening; 
vasopressor or ventilatory support indicated).  
Immediately discontinue infusion of nivolumab/placebo. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. The patient should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab/placebo 
will be permanently discontinued. Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. Remain at bedside and monitor the patient until recovery 
from symptoms. In the case of late-occurring hypersensitivity symptoms (e.g., appearance 
of a localized or generalized pruritis within 1 week after treatment), symptomatic treatment 
may be given (e.g., oral antihistamine, or corticosteroids). 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 Protocol Agents  
Investigational Agents 
The investigational agent administered in RTOG 3505 is being made available under an IND 
sponsored by RTOG Foundation and distributed by a third party drug distributor. The 
placebo will be prepared by an unblinded pharmacist on site. For nivolumab/placebo, 
determination of whether an adverse event meets expedited reporting criteria, see the 
reporting table in Section 7.4 of the protocol. 
Commercial Agents 
The commercial agents in RTOG 3505 are cisplatin and etoposide. 
 
7.1.1   Adverse Events for Investigational Study Agents  
Investigators must obtain the current version of the BMS-936558 (nivolumab) 
Investigator Brochure (IB) for comprehensive pharmacologic and safety information. The 
IB can be accessed on the RTOG Foundation 3505 protocol page of the RTOG website, 
www.rtog.org. Sites must use their username and password to access the protocol page 
and the IB.  
7.1.2   Adverse Events for Commercial Study Agents  


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Refer to the package insert for detailed pharmacologic and safety information 
 
7.2 Adverse Events (AEs)  
This study will use the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for adverse event reporting.  All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0. 
7.2.1  Definition of an Adverse Event (AE)  
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not considered related to 
the medicinal (investigational) product (attribution of unrelated, unlikely, possible, 
probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
AEs, as defined above, experienced by patients accrued to this protocol should be reported 
on the AE section of the appropriate case report form (see Section 13).  
 
All nonserious adverse events (not only those deemed treatment-related) are to be collected 
continuously during the treatment period and for a minimum of 100 days following the last 
dose of study treatment. 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. 
 
The following laboratory test result abnormalities should be captured on the nonserious AE 
CRF page and SAE Report Form if they meet seriousness criteria: 
 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 (e.g., anemia versus low hemoglobin value). 
 
Definition of Immune-Mediated Adverse Events (IMAES)  
IMAEs include events, regardless of causality, occurring within 100 days of the last dose. 
IMAEs are specific events (that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal 
dysfunction, 
rash, 
and 
endocrine 
[adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis]) for 
which patients received immunosuppressive medication for treatment of the event, with 
the exception of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, 


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hypophysitis, diabetes mellitus, adrenal insufficiency), which are included regardless of 
treatment since these events are often managed without immunosuppression. The table 
below provides a summary of the IMAEs category and their respective preferred terms. 
 
Preferred Terms Included in Analysis of IMAEs 
 to Support Warnings and Precautions 
IMAE Category 
PTs included under IMAE Category 
Pneumonitis 
Pneumonitis, Interstitial lung disease 
Diarrhea/Colitis 
Diarrhea, Colitis, Enterocolitis 
Hepatitis 
Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune 
hepatitis, AST increased, ALT increased, Bilirubin 
increased, ALP increased 
Adrenal insufficiency 
Adrenal insufficiency 
Hypothyroidism/Thyroiditis 
Hypothyroidism, Thyroiditis 
Thyroiditis acute (collapsed with thyroiditis for 
frequency), Autoimmune thyroiditis (collapsed with 
thyroiditis for frequency) 
Hyperthyroidism 
Hyperthyroidism 
Hypophysitis 
Hypophysitis 
Diabetes mellitus 
Diabetes mellitus, Diabetic ketoacidosis 
Nephritis and renal 
dysfunction 
Nephritis, Nephritis allergic, Tubulointerstitial nephritis, 
Acute renal failure, Renal failure, Increased creatinine 
Rash 
Rash, Rash maculopapular 
 
NOTE: If the event is a Serious Adverse Event (SAE) (see next section), further reporting 
will be required. Reporting AEs only fulfills Data Management reporting requirements.  
 
7.3 Serious Adverse Events (SAEs)  
Serious Adverse Events that meet expedited reporting criteria defined in the table below 
will be reported via the SAE report form in RAVE.  SAEs that require 24h notification 
are defined in the expedited reporting table. 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that 
results in any of the following outcomes: 
 Death; 
 A life-threatening adverse drug experience; 
 Inpatient hospitalization or prolongation of existing hospitalization for ≥24 hours; 
 A persistent or significant disability/incapacity; 
 A congenital anomaly/birth defect; 
 Other serious/important medical events; 


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 Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE, when, based upon medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported in an expedited manner. 
 
  
7.4 Serious Adverse Event (SAE) Reporting Requirements 
It is the responsibility of the investigator to document all adverse events which occur 
during the study. All serious adverse events that meet expedited reporting criteria defined 
in the reporting table below will be reported via the RTOG SAE Report Form in RAVE. 
RTOG will report SAEs to Bristol-Myers Squibb within 24 hours of awareness. RTOG will 
report unexpected and related SAEs to the FDA and Bristol-Myers Squibb via the 
MedWatch Form per the requirements set forth in the Code of Federal Regulations, Section 
312.32.  
7.4.1 Reporting SAEs  
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 reported per the 
reporting table below that occur from time of consent and within 100 days of the last 
dose of study drug. Subjects who are randomized and never receive treatment must have 
SAEs collected for 30 days from the date of randomization. If applicable, SAEs must be 
collected that relate to any later protocol-specified procedure (e.g., a follow-up skin 
biopsy). 
 
The investigator should 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 should 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 should be specified in the narrative 
section of the SAE Report Form.  
 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
SAE in question. The SAE summary also must include the investigator’s assessment of 
relatedness to all components of protocol treatment. Amend the SAE report with follow-up 
information, when it becomes available. In the rare event when Internet connectivity is 
disrupted, a 24-hour notification must be made to RTOG Operations Office by phone, 215-
574-3191.  An electronic report must be submitted immediately upon re-establish of the 
Internet connection.  
 
SAEs that occur during the follow-up period beginning 100 days after end of treatment and 
are considered by the investigator to be related to protocol treatment must be reported 
expeditiously via the SAE Report Form.  


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All SAEs must be reported in RAVE within the designated timeframe outlined in the 
reporting table below. RTOG will complete a preliminary review of the SAE details 
and will contact the site with queries, as applicable. RTOG will report the SAE to 
Bristol-Myers Squibb within 24 hours of notification of the event. RTOG will report 
to the FDA per 21 CFR 312.  
 
Pregnancy  
Patients who become pregnant during the study should discontinue the study immediately.  
Investigators should report a pregnancy, including a male participant’s impregnation of his 
partner, expeditiously as a grade 3 SAE coded in the CTCAE v.4 as “pregnancy, 
puerperium and perinatal conditions, other—pregnancy” on the SAE report form (in 
RAVE) and submit  the Pregnancy Report Form in Rave within 14 days of notification. 
RTOG will report the pregnancy to Bristol-Myers Squibb within 24 hours of notification of 
the event. Patients should be instructed to notify the investigator if it is determined after 
completion of the study that they become pregnant, including a male participant’s 
impregnation of his partner, either during the treatment phase of the study or within 100 
calendar days after the end of treatment. The pregnancy outcome for patients on study 
should be reported to RTOG. RTOG will report the status to Bristol-Myers Squibb. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Any Phase Study Utilizing a Commercial Agent1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to RTOG 
via the SAE Report Form within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via the SAE Report 
Form within 24 hours of learning of the AE, followed by a complete expedited 
report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted 
within 10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of protocol treatment and 
are related to protocol treatment require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
Unexpected Grade 4 and all Grade 5 AEs 
 
 
 
 


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Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur within 100 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to RTOG 
via the SAE Report Form within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting 
in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via the SAE Report Form 
within 24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 100 days after the last administration of investigational 
agent/intervention and are considered related to protocol treatment require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  


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 
Grade 3 adverse events 
Specific Protocol Inclusions and Exceptions to Expedited Reporting: 
Hemophagocytic lymphohistiocytosis is an inclusion to expedited reporting. Hemophagocytic 
lymphohistiocytosis is a rare but potentially fatal disease of normal but overactive histiocytes 
and lymphocytes. It is a manifestation of cytokine release syndrome. Occurring at any grade, 
hemophagocytic lymphohistiocytosis must be reported in an expedited manner as a serious 
adverse event.   
 
8. 
REGISTRATION AND STUDY ENTRY  PROCEDURES 
8.1 Regulatory Requirements 
Please refer to the study-specific guide for investigators and research staff for detailed 
procedures regarding the following:  requirements for regulatory collection and RT 
credentialing. The RTOG Foundation 3505 Study Guide is posted on the RTOG website 
https://www.rtog.org/clinicaltrials/rtogfoundationstudies/rtogfoundationstudy3505.aspx  .  
8.2 RT  Registration Requirements  
For detailed information on the specific technology requirement required for this study, 
please refer to the study specific guide on the RTOG Foundation 3505 protocol page of the 
RTOG website, www.rtog.org. 
8.2.1 Pre-Registration Credentialing Requirements for IMRT/3DCRT  
See the study-specific guide on the RTOG Foundation 3505 protocol page of the RTOG 
website, www.rtog.org, for details of RT pre-registration credentialing requirements for 
IMRT/3DCRT.   
8.2.2 Pre-Registration Requirements for TRIAD Installation  
See the study-specific guide on the RTOG Foundation 3505 protocol page of the RTOG 
website, www.rtog.org, for details on TRIAD installation requirements needed prior to 
patient enrollment.  
 
8.3 Patient Enrollment 
See the study-specific guide on the RTOG Foundation 3505 protocol page of the RTOG 
website, www.rtog.org.  
 
9.0 DRUG INFORMATION  
9.1 
Investigational Study Agent 
Nivolumab, IND # 130197 
To supplement the toxicity information contained in this document, investigators must 
obtain the current version of the BMS-936558 (nivolumab) Investigator Brochure (IB) 
for comprehensive pharmacologic and safety information. Also see Appendix I. 
 
The IB can be accessed on the RTOG Foundation 3505 protocol page of the RTOG 
website, www.rtog.org. Sites must use their username and password to access the 
protocol page and the IB.   
 
 
 
 
 


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Table 
Product Description 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packagin
g 
(Volume)/ 
Label 
Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage Conditions 
(per label) 
Nivolumab BMS-
936558-01 
Solution for 
Injection* 
100 mg/vial 
(10 
mg/mL) 
Carton of 
5 or 10 
vials 
10cc Type 1 flint 
glass vial 
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles 
2 to 8 degreesC. 
Protect from light,  
freezing, and shaking 
*Nivolumab/placebo may be labeled as BMS-936558-01 Solution for Injection 
 
0.9% Sodium Chloride Injection solution is to be used as nivolumab/placebo. Placebo (0.9% 
Sodium Chloride Injection) and diluent solutions (0.9% sodium chloride injection, 5% 
dextrose injection) should also be sourced by investigative sites if available and permitted by 
local regulations. 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended 
safety measures for preparation and handling of nivolumab include laboratory coats and 
gloves. 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to Appendix I and the BMS-936558 
(nivolumab) Investigator Brochure section for “Recommended Storage and Use Conditions”  
9.1.1  Drug Ordering and Accountability 
Bristol-Myers Squibb will supply Nivolumab free of charge to patients on study in the U.S. 
and Canada. An on-site unblinded pharmacist will be responsible for mixing placebo per 
instructions provided in Appendix I.  The drug will be distributed by a third party vendor 
under contract to RTOG Foundation. Drug accountability records must be maintained at all 
sites according to good clinical practices. 
See the study-specific guide on the RTOG Foundation 3505 protocol page of the RTOG 
website, www.rtog.org , for details of drug shipment. 
 
9.2 Commercial Agent  
 
Cisplatin and Etoposide 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
9.2.1 Availability/Supply  
Please see Section 5 for administration instructions. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage. 
 


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10. PATHOLOGY/BIOSPECIMENS 
10.1 Tissue/Specimen Submission 
In this study, it is required that tissue be submitted to the Biospecimen Bank at UCSF for 
PD-L1 expression analysis for all patients. It is highly recommended (but optional for the 
patient) that if any tissue remains after analysis, it will be stored at the Biospecimen Bank 
at UCSF for future research. 
  
In addition, it is highly recommended (but optional for the patient) that serum and 
peripheral blood specimens be submitted for the two tests described in Section 10.3, 
Peripheral blood for phenotyping the lymphocytes and serum for banking at UCSF for 
future translational research.  
 
Tissue from a biopsy or surgical specimen will be obtained from formalin fixed and 
paraffin embedded (FFPE) in tissue blocks. Sites must verify that an archived tumor block 
is available prior to Step 1 registration to the trial although the actual submission can be 
immediately after Step 1 registration but at least 5 weeks prior to Registration Step 2. 
Institutions must ship FFPE tissue as outlined in Section 10.2 to the Biospecimen Bank at 
UCSF by overnight courier. 
 
As noted in section 3.2.15, we recognize the difficulty in submitting tissue from stage 3 
lung cancer patients in which the total available tissue may be small.  We have designed 
three possibilities: 
 
Preferred: H&E slide and archived tissue tumor block. If sites wish the block to be returned 
they may submit the block and the Biospecimen Bank will cut the unstained for the 
required study and then punch and return the block. 
 
Alternative:  If an archived tumor block sample cannot be shipped for this study, then two 
3mm punches from the core needle biopsy blocks may alternatively be provided for 
analysis in addition to the H&E slide. 
 
Minimum:  One (1) H&E stained slide (required) and five (5) positively charged unstained 
slides cut at 3-4 microns from the same block as the H&E. Unstained slides must be stored 
at 4C same day as being cut and shipped with a cold pack at 4C within 5 business days 
after being cut. The date that the unstained slides were cut must be noted on the ST form. 
Do NOT store or ship unstained slides at room temperature as they will not be able to be 
used for the mandatory testing. Please pack slides well to avoid breakage. If any slides are 
received broken the site must resubmit additional slides before the biobank can send for 
mandatory PDL1 testing.  
 
Ship FFPE biospecimens for mandatory central review and whole blood and serum 
samples for banking to:  
(do NOT ship fresh peripheral blood to this address) 
Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 


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415-476-7864;  RTOG@ucsf.edu  
 
Ship all fresh peripheral blood in heparin tubes to: 
Hooper Laboratory  
Attn.: Rhonda Kean (laboratory manager) or Craig Hooper, PhD 
JAH 454 
1020 Locust Street 
Philadelphia, PA 19107 
Phone:  215-503-1559 
 
See the tables below for mandatory and optional specimen collection. 
 
See further details of specimen collection/processing/shipping on the RTOG web site, 
http://www.rtog.org/LinkClick.aspx?fileticket=1SFlEVxSui4%3d&tabid=281.  
 
10.2     Mandatory Studies 
Mandatory Study: Tumor PD-L1 Expression for All Patients 
Specimens are being collected to determine if patients with PD-L1 positive tumors will 
have an improved PFS when treated with nivolumab in comparison to patients with 
PD-L1 negative tumors (see Section 2.7 for further details). 
 Required Form: ST form and Pathology report- must have all PHI redacted 
except date of procedure and pathology accession number. 
 Shipping costs: Paid for by sites. Return labels are provided for frozen 
biospecimens only. International sites are encouraged to have a Fed Ex 
Customs Broker to help with any custom issues. 
 At least 5 weeks prior to Registration Step 2. 
 H&E slide and residual FFPE material will remain at the bank for all patients 
who consent to banking. Blocks can be returned upon request but will be 
punched prior to returning.  
 
 
Ship specimens to: 
Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
For questions, contact:  
Biospecimen Bank at UCSF; RTOG@ucsf.edu; 415-476-7864/FAX 415-476-5271 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Representative 
H&E stained slides 
of the primary 
tumor 
Pre-treatment 
H&E stained slide 
(must match the 
block being 
submitted). Can be 
a duplicate cut 
Slide shipped 
ambient to the 
Biospecimen Bank 


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slide, does not have 
to be the diagnostic 
slide. 
 
A corresponding 
paraffin embedded 
tissue block, OR 
two 3mm 
embedded punches 
of the primary 
tumor OR 5 
unstained slides as 
specified in section 
10.1 
Pre-treatment 
Paraffin-embedded 
tissue block or 
punch biopsies 
from the block. If 
embedded punches 
are submitted the 
H&E from the 
punch block must 
also be submitted. 
If 5 unstained slides 
are being provided 
instead of the block 
they must be stored 
at 4⁰C and shipped 
at 4⁰C within 5 
business days after 
being cut. 
The date that the 
slides were cut must 
be noted on the ST 
form. See Section 
10.1 for details. 
 
Block or punches 
shipped ambient 
(ship with a cold 
pack during warm 
weather) to the 
Biospecimen Bank. 
NOTE:  Unstained 
slides must be 
shipped with cold 
pack by overnight 
courier. Pack slides 
well to avoid 
breakage, If slides 
are received broken 
this will delay 
testing and site will 
have to resubmit 
the slides. 
  
 
 
 
 
10.3 Optional Specimen Collection for RTOG 3505 Research and Banking 
Optional Study #1: SNP analyses and Serum for immune phenotype 
Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as 
specified in the protocol. Sites are not permitted to delete the specimen component from 
the protocol or from the sample consent. 
 
Specimens are being collected to determine immune phenotype, and co-stimulatory/co-
inhibitory receptors with clinical response. 
 Required Form: ST form 
 Biospecimen Kits: Available from the Biospecimen Bank at UCSF.  
 Shipping days for frozen specimens: Monday-Wednesday (U.S. sites); Monday-
Tuesday (Canada and Non-North American). 
 Shipping costs: Return labels are provided for peripheral blood or frozen 
biospecimens only. Batch shipping is encouraged for all sites with access to a -
70⁰C to -90⁰ Freezer. Canada and International sites will be required to have 
access to a -70⁰C to -90⁰Freezer to batch ship samples and may have to provide 


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their own outer shipping containers. International sites are encouraged to have a 
Fed Ex Customs Broker to help with any custom issues. 
 
 
Ship specimens to: 
Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
For questions, contact:  
Biospecimen Bank at UCSF; RTOG@ucsf.edu; 415-476-7864/FAX 415-476-5271 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Whole blood for 
DNA- collected in 
EDTA tube 
Pre-treatment only 
Invert tubes several 
times, then aliquot 
1ml per aliquot into 
1 ml cryovials (3-5 
per tube drawn). 
Store at -70⁰C to -
90⁰ until shipped. 
Sent frozen on dry 
ice via overnight 
carrier to the 
Biospecimen Bank 
 
Batch shipping of 
multiple cases in 
one shipment is 
encouraged. 
Serum: One 5 mL 
red top (clot) tube 
 Pre-treatment; 
 Post- 
chemoradiation/ 
before nivolumab/ 
placebo 
 60days after 
nivolumab/placebo 
 at study 
discontinuation for 
either toxicity or 
progression 
 
Serum centrifuged 
and aliquotted. 
Frozen serum 
samples containing 
minimum of 0.5mL 
per aliquot in 1 mL 
cryovials (5 per 
tube drawn).  
Samples should be 
frozen and stored at 
a -70⁰C to -90⁰; see 
Appendix III for 
processing 
instructions. 
Serum sent frozen 
on dry ice via 
overnight carrier to 
the Biospecimen 
Bank 
 
Batch shipping of 
all time points or 
multiple cases in 
one shipment is 
encouraged. 
 
 
Optional Study #2: Peripheral blood for immune phenotype 
 
Patients must be offered the opportunity to consent to optional specimen collection. If 
the patient consents to participate, the site is required to submit the patient’s specimens 
as specified in the protocol. Sites are not permitted to delete the specimen component 
from the protocol or from the sample consent. 
 


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Specimens are being collected to determine immune phenotype, and co-stimulatory/co-
inhibitory receptors with clinical response. 
 
 Required Form: Special Study specific ST form 
 Shipping days: Sites should only draw blood samples on Monday-Wednesdays 
and only ship Monday-Thursdays.   
 Shipping labels will be provided with kits for peripheral blood. Canada and 
International sites may have to provide their own outer shipping containers.  
 Sites must notify Rhonda Kean at Rhonda.Kean@jefferson.edu when they are 
shipping these samples 
Ship specimens to:  
Hooper Laboratory 
Attn.: Rhonda Kean (laboratory manager) or Craig Hooper, PhD 
JAH 454 
1020 Locust Street 
Philadelphia, PA 19107 
 
For questions, contact: 215-503-1559 
 
Specimen Type 
Collection Time Points 
Collection 
Information 
and 
Requirements 
Shipping 
Peripheral Blood 
Mononuclear 
Cells (PBMC) – 5 
Green top 
(heparin) tubes 
 Pre-treatment (day 
-14 to day 0) 
 After 
ChemoRT/before 
nivolumab/placebo 
 During 
nivolumab/placebo: 
Day 60  
 at study 
discontinuation for 
either toxicity or 
progression 
 
See Appendix 
IV for 
processing and 
shipping 
information  
Ship fresh at 
room temperature 
overnight for 
morning delivery 
to the Hooper 
Laboratory.  Ship 
Monday-
Thursday  
 
 
Optional Study #3: Tumor tissue for future research 
Patients must be offered the opportunity to consent to optional specimen collection. If 
the patient consents to participate, the site is required to submit the patient’s specimens 
as specified in the protocol. Sites are not permitted to delete the specimen component 
from the protocol or from the sample consent. 
 Required Form: ST form and Pathology report- must have all PHI redacted 
except date of procedure and pathology accession number 
 Shipping costs: Paid for by sites. Return labels are provided for frozen 


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biospecimens only. International sites are encouraged to have a Fed Ex 
Customs Broker to help with any custom issues. 
 
Ship specimens to: 
Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
For questions, contact:  
Biospecimen Bank at UCSF; RTOG@ucsf.edu; 415-476-7864/FAX 415-476-5271 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Representative 
H&E stained slides 
of the primary 
tumor 
At progression 
H&E stained slide 
(must match the 
block being 
submitted) 
 
Slide shipped 
ambient to the 
Biospecimen Bank 
A corresponding 
paraffin-embedded 
tissue block or two 
3 mm embedded 
punches of the 
primary tumor 
taken before 
initiation of 
treatment 
At progression 
Paraffin-embedded 
tissue block or 
punch biopsies 
from the block. If 
embedded punches 
are submitted the 
H&E from the 
punch block must 
also be submitted 
Block or punches 
shipped ambient 
(ship with a cold 
pack during warm 
weather) to the 
Biospecimen Bank 
 
 
 
11. SPECIAL STUDIES (NON-TISSUE) 
11.1  Toxicity, Patient-Reported Outcomes (PROs), and Health-Related Quality of Life 
(QOL)  
Objectives 
 
To characterize immune mediated toxicity from nivolumab following chemoradiation 
(CRT) for locally advanced  NSCLC; 
 
To evaluate the effect of immune mediated toxicity from nivolumab following CRT 
on QOL and patient reported fatigue. 
 
Hypotheses 
The primary HRQOL endpoint will be to determine if 15-month QOL (from start of 
nivolumab/placebo) using the Functional Assessment of Cancer Therapy - Trial Outcome 
Index for lung cancer (FACT-TOI) is correlated with overall survival (OS). The 
hypothesis is that long-term QOL using FACT-TOI at 15-month (from start of 
nivolumab/placebo) will be superior in the CRT followed by nivolumab arm compared to 
the CRT followed by placebo arm as the addition of nivolumab is expected to improve 
tumor response to CRT and improve disease-related QOL.  


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Secondary exploratory objectives are: 
 
To compare patient reported fatigue using the PROMIS fatigue short form between 
the consolidative nivolumab arm compared to placebo. The hypothesis is that acute fatigue 
at 3 months (from start of nivolumab/placebo) will be greater in the nivolumab arm 
compared to the placebo arm but will not impact long-term QOL outcome at 15 months 
(from start of nivolumab/placebo).  
 
To describe the levels and change in baseline at each assessment of the EQ-5D index 
and EQ-5D VAS in each of the study arms  
 
Background 
Health related quality-of-life (QOL) is an important endpoint in clinical trials to assess the 
overall disease burden and treatment effect from the patient’s perspective using patient 
reported outcomes (PROs). In this study, consolidative nivolumab/placebo will follow 
CRT. If the consolidative nivolumab arm shows superior OS compared to placebo, a new 
standard of care will be defined for locally advanced NSCLC, provided that the QOL and 
toxicity profiles are acceptable to the patient. Past efforts at treatment intensification such 
as concurrent chemotherapy cetuximab plus platinum-based CRT or induction 
chemotherapy regimens, have failed to improve survival yet have shown substantial 
increases in toxicity, unplanned treatment breaks or delays in therapy, all of which can 
lead to inferior QOL outcome and potential decreased efficacy, such that trials 
investigating further refinement of concurrent CRT regimens need to factor in QOL with 
toxicity outcome.  
 
The effects of nivolumab immunotherapy following standard CRT in lung cancer on QOL 
are currently unknown.  Hence, this study will provide a unique and critical opportunity to 
characterize the effects of this novel treatment on QOL. It is anticipated consolidative 
nivolumab will improve OS with minimal overlapping acute toxicities of nivolumab and 
CRT. Obtaining QOL data at baseline, during treatment, and follow up after treatment 
provides baseline prognostic data as well as reporting the effect of treatment on HRQOL 
from the patient’s perspective. Baseline QOL data was found to be a prognostic variable in 
addition to clinical factors in predicting survival in cancer patients (Quinten 2014, Urba 
2012) in a pooled analysis of 7417 cancer patients entered on randomized trials. These 
data suggest that obtaining baseline QOL data are of superior prognostic significance than 
obtaining physician graded performance scale scores such as Karnofsky performance 
scales or ECOG scales prior to initiation of treatment.  
 
The primary QOL and PRO objective in this study is to measure functional, physical and 
lung cancer specific QOL in lung cancer patients using the change from baseline of 
FACT-TOI at 15 months (using each patient as his or her own control). A clinically 
meaningful between group change from baseline is defined as FACT-TOI of ≥5 points 
between arms. The FACT-TOI instrument will also measure longitudinal QOL in both 
arms and will be administered at the following time points: baseline, prior to 
nivolumab/placebo, at 3, 6, 9 and 12 months during nivolumab/placebo treatment, and at 
15 and 18 months from start of nivolumab/placebo. 
 


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FACT-TOI 
 In order to analyze the difference in QOL between all arms, we plan to use a brief, 
validated instrument that is user friendly and has clinical relevance. FACT-TOI is a 
measure that sums the functional well-being (FWB), physical well-being (PWB), and the 
lung cancer subscale (LCS) of the Functional Assessment of Cancer Therapy – Lung 
(FACT-L) QOL instrument, which has been extensively used for measuring QOL in 
patients with lung cancer. In a review of literature reported that the FACT-L scale has 
been used in more than 5,000 patients and has been found to be sensitive to changes in 
performance status, treatment response. FACT has been translated into many languages 
and is available free of charge to institutions with the completion of an agreement to share 
data, accessible at http://www.facit.org/translation/licensure.aspx. The full FACT-L 
questionnaire can be completed in less than 10 minutes. This instrument has not only been 
shown to be prognostic for survival, but also sensitive to changes in QOL on serial 
evaluations throughout treatment. Importantly, the FACT-TOI has been associated with 
clinically meaningful changes in patients with lung cancer. The lung cancer sub-scale 
(LCS) consists of 9 items, involving lung cancer specific symptoms. All items are rated on 
a 5-item (point) Likert Scale, from 0 (not at all) to 4 (very much). It has been determined 
that a 5-point difference on the FACT-TOI is associated with a meaningful difference in 
clinical and subjective indicators. Thus, a difference of 5 points will be considered 
clinically significant. Handling of missing data will be in accordance with the FACIT 
Administration and Scoring Guidelines, described at www.facit.org. 
  
Fatigue in NSCLC 
Fatigue in lung cancer patients receiving consolidative nivolumab is caused by immune 
mediated effects combined with RT dose volume factors and chemotherapy toxicities.  
 
In melanoma studies investigating nivolumab, the most common toxicity described is 
fatigue. Other toxicities include dermatologic toxicity, gastrointestinal, symptoms 
(diarrhea/colitis, decreased appetite). Rare immunologic mediated toxicities from 
immunotherapy including nivolumab and ipilumumab have been described and include 
pneumonitis and endocrinopathies (pituitary, hypothalamus, thyroid, and adrenal disease). 
These immune-mediated toxicities may present with nonspecific symptoms such as 
fatigue, headache, mental status changes, abdominal pain, change in bowel habits, or 
hypotension.  In lung cancer, fatigue is one of the most common and distressing symptoms 
affecting up to 60% of patients. With concurrent chemoradiation, the majority of patients 
experience fatigue usually peaking during the first and second weeks after completion of 
CRT, which can remain higher than baseline in approximately half of patients long-term 
(Spratt 2012). Because approximately 25% of patients undergoing nivolumab 
monotherapy experience fatigue, the effect of consolidative nivolumab following CRT on 
patient-reported fatigue warrants study.  
 
Hence an exploratory objective is to evaluate patient reported fatigue using the PROMIS 
fatigue short form in patients receiving nivolumab following chemoradiation for lung 
cancer. 
 


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PROMIS-Fatigue: A Novel Short Form Fatigue Scale  
The National Institutes of Health (NIH) Patient-Reported Outcomes Measurement 
Information System (PROMIS) Roadmap initiative (www.nihpromis.org) was initiated. 
PROMIS is a 5-year cooperative group program of research designed to develop, validate, 
and standardize item banks to measure patient-reported outcomes (PROs) relevant across 
common medical conditions, including cancer [Cella, 2007; Garcia, 2007]. Integral to the 
work of this group, includes the creation of a PROMIS-derived fatigue short form (using 
limited questions to minimize patient burden) that was developed for ease of use in 
oncology populations. While the psychometric properties of this 7-question short fatigue 
scale have been validated in the general population [Garcia, 2007; Lai, 2008], validation 
in patients with cancer is ongoing. A “cross-walk” has been successfully developed 
between the PROMIS fatigue item bank and the PROMIS-Cancer fatigue item bank that 
produced the short form measure. These two item banks, sharing 54 common items, were 
linked by equating item parameters using items that held stable psychometric properties 
between the cancer and general population populations in which they were tested. Results 
showed that cancer patients reported more severe fatigue (1/3 standard deviation more 
severe, but the same scale characteristic curve slope) than the general population, which 
matches clinical expectations [Cella, 2008].   
 
The PROMIS fatigue will be completed at baseline, prior to nivo/placebo, at 3, 6, 9 and 12 
months during nivolumab/placebo treatment, and at 15 and 18 months from start of 
nivolumab/placebo.  
 
Quality-adjusted Survival, EuroQol (EQ-5D-5L)   
The EuroQol (EQ-5D) is a well-accepted instrument to measure general QOL and cost-
utility analysis (Pickard 2007) and will be used to assess quality-adjusted survival for this 
study. It is a two-part questionnaire that the patient can complete in 5 minutes (Schulz 
2002) and has been translated into multiple languages. The first part consists of 5 items 
covering 5 dimensions, including mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension can be graded on 3 levels including: 1-no problem, 2-
moderate problems, and 3-extreme problems. There are 243 potential health states.  The 
second part is a visual analogue scale (VAS) valuing current health state, measured on a 
20 cm, 10 point-interval scale.  Either the index score or the VAS score can be used in the 
quality-adjusted survival analysis (Wu 2002). The benefit of measuring quality-adjusted 
survival is that the product, quality-adjusted survival, can be compared to the outcomes of 
other interventions across disease sites and can be used by health policy makers to rank 
interventions. The EQ5D will be used to evaluate the effect of adding nivolumab to 
chemoradiation on quality-adjusted survival.  
 
Protocol-eligible patients will be included in the quality-adjusted survival analysis only if 
they have provided baseline and at least 1 subsequent measurement.  
 
Patients will complete the EQ-5D-5L version at the following time points:  
baseline, prior to starting nivolumab/placebo phase, at 3, 6, 9 and 12 months during  
nivolumab/placebo treatment, and at 15 and 18 months, 2, 3, 4, and 5 years from start of 
nivolumab/placebo. 


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12. MODALITY REVIEWS 
12.1 Radiation Therapy Quality Assurance Reviews 
The Radiation Oncology Co-Chair, James Urbanic, M.D. and delegates, will perform an 
RT Quality Assurance Review after the ACR Core Laboratory/RTQA has received 
complete data for the first 20 cases enrolled. Dr. Urbanic will perform the next review after 
the ACR Core Laboratory/RTQA has received complete data for the next 20 cases enrolled. 
Subsequent reviews will continue in a periodic and timely fashion.  The final cases will be 
reviewed within 3 months after this study has reached the target accrual or as soon as the 
ACR Core Laboratory/RTQA has received complete data for all cases enrolled, whichever 
occurs first. 
 
The goal of the review is to evaluate protocol compliance.  The review process is 
contingent on timely submission of radiotherapy treatment data as specified in Section 
13.2. The scoring mechanism is: Per Protocol, Variation Acceptable, and Deviation 
Unacceptable. 
12.2  Drug Quality Assurance Reviews 
The Principal Investigator/Medical Oncology, David Gerber, MD and Medical Oncology 
Co-Chair, Corey Langer, M.D., will perform a Chemotherapy Assurance Review of all 
patients who receive or are to receive chemotherapy in this trial.  The goal of the review is 
to evaluate protocol compliance.  The review process is contingent on timely submission of 
chemotherapy treatment data as specified in Section 13. The scoring mechanism is: Per 
Protocol, Acceptable Variation, Unacceptable Deviation, and Not Evaluable.   
 
Drs. Gerber and Langer will perform a Quality Assurance Review after RTOG 
Headquarters has received complete data for the first 20 cases enrolled. Drs. Gerber and 
Langer will perform the next review after RTOG Headquarters has received complete data 
for the next 20 cases enrolled. The final cases will be reviewed within 3 months after this 
study has reached the target accrual or as soon as RTOG Headquarters has received 
complete data for all cases enrolled, whichever occurs first. 
 
13. DATA AND RECORDS  
This study will utilize Medidata Rave. See the Data Management Plan in the study-
specific guide on the RTOG Foundation 3505 protocol page of the RTOG website, 
www.rtog.org, for further details. 
 
13.1    Summary of Dosimetry Digital RT Data Submission (Submit to ACR Core   
Laboratory/RTQA see the study-specific guide on the RTOG Foundation 3505 protocol 
page of the RTOG website, www.rtog.org, for details of TRIAD.) 
 
ALL DIGITAL RT DATA MUST BE IN DICOM FORMAT 
 
 
Item 
Due 
Treatment Planning Data exported from 
planning system and uploaded to TRIAD 
Within 1 week of start of RT 


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will include the following: 
 Planning CT 
Indicate “RT Digital Data” in 
Submission Type in TRIAD for all 
planning files 
 RT Structure File – all required 
structures included and labeled per 
tables in Section 5.2.5 and 5.2.6 
 
 RT Dose File (one file for total 
prescription dose) 
 
 RT Plan File 
 
 PET Scan – if used to aid 
contouring for treatment plan 
Indicate “Imaging-Baseline” in 
Submission Type in TRIAD 
Notes: 
 Upon submission of all digital RT data via TRIAD, complete an online Digital Data 
transmission 
form 
(DDSI) 
located 
on 
the 
RTOG 
Foundation 
3505 
websitehttps://www.rtog.org/clinicaltrials/rtogfoundationstudies/rtogfoundationstudy350
5.aspx 
 RTOG 3505 DVH Analysis Worksheet 
 
Note: Data will not be processed until DDSI form is received 
 Please include motion management technique in Comment section of DDSI Form 
 
13.2 Summary of Diagnostic Imaging Digital Data Submission (Submit to ACR Imaging 
Corelab; see the study-specific guide on the RTOG Foundation 3505 protocol page of the 
RTOG website, www.rtog.org, for details of TRIAD.))   
 
 
ALL DIGITAL DIAGNOSTIC IMAGING DATA MUST BE IN DICOM FORMAT 
 
 
Item 
Due (via TRIAD)1 
Contrast-enhanced CT of the Chest to 
include liver and adrenals (Baseline)2 
Within two weeks of acquisition  
Contrast-enhanced CT/MRI of the 
Brain (Baseline) 
Within two weeks of acquisition 
FDG-PET/CT Whole-Body (Baseline) 
Within two weeks of acquisition 
Contrast-enhanced CT of the Chest to 
include liver and adrenals (post-
chemoRT)2 
Within two weeks of acquisition 
Contrast-enhanced CT of the Chest to 
include liver and adrenals  (Follow-
Up)2 
Within two weeks of acquisition 
 Every three months for the first 
two years (e.g., Months 3, 6, 9, 
etc.) 
 Every six months for years 3-5 
 Annually thereafter 


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Contrast-enhanced CT of the Chest to 
include liver and adrenals in timepoints 
of site-determined PD2 
Within 3 days of acquisition 
FDG-PET/CT Whole-Body (Follow-up; 
perform as clinically indicated)3 
Within two weeks of acquisition 
Contrast-enhanced CT/MRI of the 
Brain (Follow-up; perform as clinically 
indicated)3 
Within two weeks of acquisition 
Notes: 
1All images should be accompanied by an Image Transmittal Worksheet (ITW). 
2If IV contrast is contraindicated, MRI Chest may be submitted in place of a contrast-enhanced CT 
Chest, along with a non-contrast-enhanced CT Chest.  
3 Patients with uncertain progression may require repeat imaging at 6 weeks rather than 3 months if 
disease status remains uncertain.    
 
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design 
Patients will be enrolled and randomized 1:1 between two arms. The treatment allocation 
scheme described by Zelen (1974) will be used. Patients will be stratified by Zubrod 
Performance Status (0 vs. 1); histology (squamous vs. non-squamous), as there may be a 
trend toward greater benefit of nivolumab in squamous histology (Topalian 2012); and 
tumor PD-L1 status. 
14.2 
Study Endpoints 
14.2.1  Primary endpoints:    
 Overall survival (OS) 
OS is defined as the time between the date of randomization and the date of death due to 
any cause. OS will be censored on the last date a subject is known to be alive. 
Progression free survival (PFS) based on Independent Radiology Review Committee 
(IRRC) according to RECIST 1.1  
 PFS is defined as the time between the date of randomization and the first date of 
documented progression, as determined by IRRC according to RECIST 1.1, or death due 
to any cause, whichever occurs first.  Please refer to Section 4 “Central Imaging Review” 
for details on IRRC PFS data generation and collection, and Section 14.3.2 for detailed 
definition of PFS events and censoring. 
14.2.2  Secondary endpoints: 
 Toxicities 
 Functional Assessment of Cancer Therapy - Trial Outcome Index for lung cancer (FACT-
TOI) at 15 months  
 OS and PFS in patients with (1) PD-L1-positive, (2) PD-L1-negative and PD-L1 not 
evaluable/undetermined tumors 
14.2.3  Exploratory endpoints 
 biomarker and biomarker correlatives 
 proportion of patients alive at 12 and 24 months 
 proportion of patients progression free at 12 and 24 months using investigational site 
assessments according to RECIST 1.1 


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 PROMIS fatigue at 3 months 
 Descriptive analysis of the EQ-5D utilities and the EQ-VAS by study arm before and 
after progression. 
 PFS based on investigator assessment. 
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypotheses and Endpoints 
The primary hypotheses of this study are (1) nivolumab increases OS with a hypothesized 
hazard ratio of 0.7; (2) nivolumab increases IRRC-determined PFS with a hypothesized 
hazard ratio of 0.667 (control arm is the reference level).  In particular, assuming OS and 
PFS are exponentially distributed (at least approximately), the alternative hypothesis for 
OS is that patients receiving the experimental regimen will have a median survival time 
of at least 34.3 months, while those receiving the control regimen will have a median 
survival time of 24 month. Similarly, the alternative hypothesis for PFS assumes the 
median times for PFS will be 12 and 18 months for the control and experimental arms, 
respectively. 
 
14.3.2 Statistical Analysis Plan for Primary Endpoints 
The primary analysis will be performed on an intent-to-treat (ITT) basis, such that all 
randomized cases will be included in the treatment arm to which they were randomized 
regardless of what treatment the patients actually received. This is the primary dataset for 
analyses of demography, protocol deviations, baseline characteristics, and efficacy 
outcome research.   
 
The study accounts for two primary endpoints: OS and PFS.  Overall (2-sided) alpha is 
0.05, which is split with 0.01 for evaluating PFS and with 0.04 for evaluating OS.   
 
The primary OS analysis will be conducted using a two-sided log-rank test stratified by 
histology, Zubrod and PD-L1 status in all randomized patients.  Hazard ratio (HR) and 
corresponding two-sided 96% confidence interval (CI) will be estimated using a Cox 
proportional hazard model, with treatment group as a single covariate, stratified by the 
above stratification factors. The stratification factors will be obtained at the time of 
randomization.  Results from an unstratified analysis will also be provided.  The rates at 
various timepoints (i.e., every 6 months after randomization) and medians of OS for each 
arm will be estimated using the Kaplan-Meier method (1958). The associated 95% 
confidence interval (CI) will be calculated using Greenwood’s formula and based on a 
log-log transformation applied on the survival function. 
 
The primary PFS analysis will be conducted using the same methods and stratification 
factors as OS analysis, except that the hazard ratio (HR) and corresponding two-sided 
99% confidence interval (CI) will be estimated using a stratified Cox proportional hazard 
model.   
 
PFS is defined as the time between the date of randomization and the first date of 
documented progression, regardless of discontinuation of study drug, or death due to any 
cause, whichever occurs first.  Progressive disease (PD) is determined by IRRC 


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according to RECIST 1.1.  Subjects who die without a reported progression will be 
considered to have the PFS event on the date of their death.  Subjects who do not 
progress or die will be censored on the date of their last evaluable tumor assessment as 
determined with radiographic evidence.  Subjects who do not have any on-study tumor 
assessments and do not die will be censored on their date of randomization.  For the 
primary PFS analysis, subjects who have palliative local therapy or initiate systematic 
anti-cancer therapy (aka new therapy) without a prior reported progression or a 
progression confirmed by IRRC, whichever occurs first, will be censored on the date of 
their last evaluable tumor assessment as determined with radiographic evidence prior to 
the permanent discontinuation of treatment or the initiation of subsequent anti-cancer 
therapy or palliative local therapy.   
 
Two sensitivity analyses will be performed to assess the robustness of the primary PFS 
analysis:  
1. Sensitivity analysis 1 is the same as the primary analysis except that for patients with 
a PFS event who miss two or more scheduled assessments immediately prior to the 
PFS event, data will be censored at the last tumor assessment as determined with 
radiographic evidence prior to the missed visits.   
2. Sensitivity analysis 2 is the same as the primary analysis except that it considers 
permanent discontinuation of study treatment (per Section 6.4) or initiation of 
palliative local therapy or systematic anti-cancer therapy, whichever occurs earlier, to 
be a PD event for subjects without a documented PD or death.   
 
The censoring rules for primary and sensitivity analyses are summarized in Table 3. 
 
Table 3: Censoring rules for Primary and Sensitivity Analyses of PFS 
Situation 
Primary Analysis 
Sensitivity  
Analysis 1 
Sensitivity  
Analysis 2 
No PD and no 
death; new 
therapy is not 
initiated 
Censored at last 
disease assessment 
Censored at last 
disease assessment 
Censored at last 
disease assessment 
if still on study 
therapy; otherwise 
progressed at 
treatment 
discontinuation 
No PD and no 
death; new 
therapy is 
initiated 
Censored at last 
disease assessment 
prior to new 
therapy 
Censored at last 
disease assessment 
prior to new 
therapy 
Progressed at date 
of new therapy or 
treatment 
discontinuation 
PD or death 
documented after 
≤1 missed disease 
assessments 
Progressed at date 
of documented PD 
or death 
Progressed at date 
of documented PD 
or death 
Progressed at date 
of documented PD 
or death 
PD or death 
documented after 
≥2 missed disease 
Progressed at date 
of documented PD 
or death 
Censored at last 
disease assessment 
immediately prior 
Progressed at date 
of documented PD 
or death 


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assessments 
to the ≥2 missed 
disease 
assessments 
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following 
classification variables: 
 Age category (≤65, >65 years) 
 Sex (female, male) 
 Race (white, non-white) 
 ECOG status (0, 1) 
 Histology (squamous, non-squamous) 
 Smoking status (never, former, current) 
The consistency of the treatment effect will be assessed descriptively via summary 
statistics by category for the classification variables listed above. 
 
14.3.3 Sample Size and Power Calculations:  
The study accounts for two primary endpoints: OS and PFS.  Overall (2-sided) alpha is 
0.05, which is split with 0.01 for evaluating PFS and with 0.04 for evaluating OS.  The 
study is event-driven and plans to randomize 550 patients with 1:1 ratio into the 
experimental and control arms.  Assuming a rate of 16.7% due to ineligibility and drop-
out between initial registration and randomization, a total of 660 patients will be enrolled 
to ensure 550 patients will be randomized after completion of chemoradiation. Assuming 
a uniform monthly accrual rate of 14.4 patients (12 eligible patients to be randomized), 
and minimal accrual in the first 6 months for ramp-up, the accrual is projected to last 52 
months (4.3 years) with additional 25 months follow up.  The overall study is projected to 
last 71 months (5.9 years) since the first patient first visit (FPFV), or 77 months (6.4 
years) since the study activation to reach the required number of events. If a higher rate 
of ineligible and drop-out is observed during the study conduct, the protocol may be 
amended to ensure at least 550 eligible patients to be randomized. 
 
The null hypothesis for IRRC-assessed PFS is that both arms will have a median survival 
time of 12 months. The alternative hypothesis for PFS is that patients receiving the 
experimental regimen will have a median survival time of at least 18 months, 
corresponding to a 33% relative hazard reduction (HR=0.667).  There is only one (final) 
PFS analysis planned and will be conducted after at least 363 PFS events are observed 
between the experimental and control arms.  The analysis is projected to occur after 50 
months from first patient first visit (FPFV) and 4 months after the completion of planned 
accruals.   If the initial accruals are slower than expected such that 363 PFS events are 
observed prior to the completion of planned patient accruals, then the analysis may be 
delayed for 6 months to allow all randomized subjects to have a reasonable amount of 
follow-up information for the primary PFS analysis.  With at least 363 PFS events, the 
study has ≥90% power to detect a hazard ratio of 0.667 for PFS at alpha=0.01 (2-sided) at 
this planned final PFS analysis.  A p-value less than 0.01 (1-sided 0.005) using stratified 
log-rank test for PFS approximately corresponds to an empirical hazard ratio of 0.763 (or 
approximately at least 15.7 months of median PFS in experimental vs. 12 months in 


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control, if PFS in both arms follow exponential distributions approximately). 
 
The null hypothesis for overall survival is that both arms will have a median survival 
time of 24 months. The alternative hypothesis for overall survival is that patients 
receiving the experimental regimen will have a median survival time of at least 34.3 
months, corresponding to a 30% relative hazard reduction (HR=0.7). Using a 2-sided test 
with alpha of 0.04 and two planned OS analyses, a total of 355 deaths (complete 
information of OS) and 550 analyzable patients are required to detect the hypothesized 
survival difference with 90% power.  There is one interim OS analysis and one final OS 
analysis is planned.  The interim analysis will be conducted at the same time of the final 
PFS analysis.  Based on the proportion of information available at the interim OS 
analysis, the Lan-DeMets implementation of O’Brien-Fleming boundary will be used to 
determine the critical value for the interim analysis. It is projected at the time of PFS final 
analysis, projected to occur after 50 months from first patient first visit (FPFV) and 4 
months after the completion of planned accruals, approximately 230 OS events or 65% 
cumulative information for OS will be observed. 
 
The final OS analysis will occur when complete information for overall survival, i.e., 
observing at least 355 deaths, is available.  The final OS analysis is projected to occur 
after 71 months from first patient first visit (FPFV).    
 
The trial will be declared positive if either the overall or progression-free survival 
comparison of the treatments is statistically significant favoring the experimental arm at 
0.04 and 0.01 (2-sided), respectively. For OS analysis, the boundary for statistical 
significance at the interim analysis and the final analysis will be determined based on the 
Lan-DeMets implementation of O’Brien-Fleming use function.  For example, with 2-
sided alpha of 0.04 and using stratified log-rank test, if 230 deaths have occurred at the 
time of the interim analysis, the statistical significance will be declared p≤0.008 (1-sided 
0.004, approximately corresponds to an empirical hazard ratio of 0.704); and if 355 
deaths have occurred at the time of the final OS analysis, statistical significance will be 
declared if p≤0.0376 (1-sided 0.0188, approximately corresponds to an empirical hazard 
ratio of 0.802).   
 
If the long-term clinical effect (“cure rate”) is present around 3 to 3.5 years since 
randomization, the study is anticipated to last 2 additional years of follow-up to observe 
the required number of events, i.e., the entire study duration may be 101 months (8.4 
years) or longer.   
 
The sample size and power calculation were performed in the software EAST. 
 
14.4 
Study Monitoring 
14.4.1  Interim Analysis for the DMC 
The RTOG Foundation Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and safety after enrollment of the first patient. An 
interim study summary report will be prepared at each meeting accordingly until the 
initial study results have been released.  In general, the interim reports will contain 


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information about patient accrual rate, a projected completion date for the accrual phase, 
patient exclusion rates and reasons following registration, compliance rate of treatment 
delivery, distributions of pretreatment characteristics and important prognostic baseline 
variables, and the frequencies and severity of treatment-related adverse events.  The 
interim reports will not contain the results from the treatment comparisons with respect to 
the efficacy endpoint. 
 
14.4.2 Interim Analysis for Safety  
To ensure the safety of this trial, the rates of protocol-specified adverse events between 
the arms will be compared after 13.3% and 26.7% of the eligible and evaluable patients 
who receive any protocol treatment (40 and 80 on each arm) have been accrued to the 
trial and observed for at least 180 days after the end of chemoradiation treatment (or die 
within 180 days). The As-Treated (AT) patient population will be used for the analysis of 
safety data in this study. The AT population consists of all randomized subjects who 
received at least one dose of study treatment (nivolumab or placebo). Subjects will be 
included in the treatment group corresponding to the trial treatment they actually received 
for the analysis of safety data.  
 
With a total of 160 patients approximately evenly receiving nivolumab and placebo, we 
will have at least 85% power to detect the following difference in the rates of protocol-
specified AE occurring within 180 days after the end of concurrent chemoradiation 
treatment at the significance level of 0.05 (2-sided): 5% vs.25%, 10% vs. 30%, and 15% 
vs. 35%. Using the Lan-DeMets implementation of O’Brien-Fleming boundary, if the p-
value related with this comparison is less than 0.003 and 0.049 (2-sided) the trial accrual 
(if applicable) will be suspended due to safety concerns. In the event of excessive 
protocol-specified adverse events such that the trial accrual suspension is warranted, 
RTOG Foundation DMC will hold a special meeting to review the study data and provide 
a recommendation as to whether the study may continue, whether amendment(s) to 
protocol should be implemented, or whether the study should be stopped.    
 
The difference in rates between the two treatment arms and their two-sided 95% CI, as 
well as associated odds-ratios will be estimated using the Cochron-Mantel-Haenszel 
(CMH) method of weighting (Agresti 2002), adjusting for the stratification factors.  
The difference in rate will also be compared using Cochron-Mantel-Haenszel (CMH) 
test, adjusting for the stratification factors, when 80 and 160 eligible and evaluable AT 
patients available from both treatments. 
 
Protocol-specified adverse events are defined as following: 
 
The development of grade 3 or higher adverse events definitely, probably, or possibly 
related to treatment for the following adverse events within 180 days after the end of 
concurrent chemoradiation treatment: 
 
ChemoRT Toxicity 
Notes 
Cardiac Disorders 
Grade 3 or higher:  Acute coronary 
syndrome, Atrial fibrillation, Atrial flutter, 


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Conduction disorder, Pericardial effusion, 
Pericarditis, Restrictive cardiomyopathy 
 
Gastrointestinal Disorders 
Grade 4 or higher:  Dysphagia, 
Esophagitis, Esophageal fistula,  
Esophageal obstruction,  Esophageal 
perforation,  Esophageal stenonsis,  
Esophageal ulcer,  Esophageal 
hemorrhage  
Injury, Poisoning, and Procedural 
Complications 
Grade 3 or higher:  Dermatitis radiation, 
Fracture (limited to rib fractures only) 
Nervous System Disorders 
Grade 3 or higher:  Brachial plexopathy, 
Recurrent laryngeal nerve palsy, Myelitis 
Respiratory, Thoracic, and Mediastinal 
Disorders 
Grade 3 or higher:  Atelectasis (grade 4-5 
only), Bronchopulmonary hemorrhage, 
Mediastinal hemorrhage, Pleural  
hemorrhage, Tracheal  hemorrhage, 
Bronchial fistula, Pulmonary  fistula, 
Bronchopleural  fistula, Tracheal  fistula, 
Hypoxia (provided gr.3 is worse than 
baseline), Bronchial obstruction, Tracheal 
obstruction, Pleural effusion, 
Pneumonitis, Pulmonary fibrosis 
Skin and Subcutaneous Disorders 
Grade 3 or higher:  Skin ulceration (thorax 
only) 
Changes in PFTs per the RTOG 
Pulmonary Toxicity Scale (see Section 
5.2.14) 
Grade 3 or higher:  FEV1 decline, Forced 
Vital Capacity decline, DLCO decline 
IMMUNE-MEDIATED Toxicity 
 Notes 
Skin Rash and Oral Lesions 
Grade 3 or higher:  Bullous dermatitis, 
Erythema multiforme, Erythroderma, 
Palmar-plantar erythrodysesthesia 
syndrome, Papulopustular rash, Pruritus, 
Purpura, Rash acneiform, Rash maculo-
papular, Skin ulceration, Stevens-Johnson 
syndrome, Toxic epidermal necrolysis,  
 
Liver Function, AST/ALT/T. Bili 
Grade 3 or higher 
Renal Function, Serum Creatinine 
Grade 3 or higher 
Diarrhea/Colitis 
Grade 3 or higher;  


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Pancreatitis, Amylase/Lipase 
Grade 3 with development of 
symptomatic pancreatitis or DM; Grade 4 
or higher 
Pneumonitis 
Grade 3 or higher 
Other GI (including N-V) 
Grade 3 and symptoms not resolving 
within 7 days with symptomatic 
treatment; Grade 4 or higher 
Neurologic Events 
Grade 3 or higher; any CNS events 
including aseptic meningitis, encephalitis, 
or myopathy, peripheral demyelinating 
neuropathy, cranial neuropathy (other than 
peripheral n. VII), GB syndrome, 
myasthenia gravis  
Endocrine, Hypophysitis, Adrenal 
Insufficiency 
Grade 3 or higher 
Uveitis/Ocular 
Grade 3 
Infusion Reaction 
Grade 3 or higher 
All Other Immune-Mediated Events 
Grade 3 or higher 
 
14.4.3 Interim Analysis for Efficacy  
The RTOG Foundation Data Monitoring Committee (DMC) will review the interim 
analysis for superiority based on OS and the primary analysis of PFS.  Both analyses are 
planned to occur and the results will be reviewed by DMC at the same time. If either the 
primary PFS analysis or the interim OS analysis is deemed to be positive per the 
respective rules, the study results will be unblinded and reported.  Otherwise, the study 
will remain open and the results will continue to remain blinded.  
  
The primary PFS analysis is planned after 363 PFS events are observed between the 
experimental and control arms.  The analysis is projected to occur after 50 months from 
first patient first visit (FPFV) and 4 months after the completion of planned accruals.   If 
the initial accruals are slower than expected such that 363 PFS events are observed prior 
to the completion of planned patient accruals, then the analysis may be delayed for 6 
months to allow all subjects to have a reasonable amount of follow-up for PFS analysis.   
The interim OS analysis will be based on the proportion of complete OS information 
available at the time of primary PFS analysis. It is projected that approximately 230 OS 
events or 65% cumulative information for OS (355 deaths) will be observed. 
 
14.5 
Accrual/Study Duration Considerations 
The study is event-driven and plans to randomize 550 patients with 1:1 ratio into the 
experimental and control arms. Assuming a uniform monthly accrual rate of 14.4 patients 
(12 eligible patients to be randomized), and minimal accrual in the first 6 months for 
ramp-up, the accrual is projected to last 52 months (4.3 years), and the study is projected 
to last 77 months (6.4 years) to reach the required number of events.  


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The above projected study durations are based on the hypothesized design parameters.  If 
the actual study parameters deviate from the hypothesized ones, the actual study duration 
may be different from the projection 
 
14.6 
Dose Level Guidelines 
 
 NA 
 
14.7 
Secondary Endpoints  
14.7.1 Toxicities 
The As-Treated (AT) patient population will be used for the analysis of safety data in this 
study. The AT population consists of all randomized subjects who received at least one 
dose of study treatment (nivolumab or placebo). Subjects will be included in the 
treatment group corresponding to the trial treatment they actually received for the 
analysis of safety data.  
 
Exposure to nivolumab treatment and length of safety follow-up will be summarized.  For 
each patient, the maximum severity reported will be used in the summaries. Adverse 
events will be summarized regardless of relationship to study drug as assessed by the 
investigator. All adverse events, adverse events leading to withdrawal of study drug, 
adverse events leading to dose reduction or interruption, Grade ≥ 3 adverse events, 
serious adverse events, and adverse events of special interest will be summarized. Deaths 
and cause of death will be summarized.  The rate of treatment-related adverse events 
using NCI Common Terminology Criteria for Adverse Events (CTCAE, v. 4) will be 
reported with the frequency and severity (e.g., type, grade, and attribution) by arm, the 
analysis will be performed at the time of primary endpoint analysis.  
 
14.7.2 Functional Assessment of Cancer Therapy - Trial Outcome Index for lung cancer (FACT-
TOI) at 15 months 
The QOL analyses will be performed based on all randomized patients. FACT-TOI 
complete rates will be summarized at each assessment point as the proportion of 
assessments actually received out of the expected number (i.e., the number of subjects 
still on treatment in follow-up). 
 
Baseline and FACT-TOI at each subsequent assessment, as well as their change from 
baseline will be summarized using descriptive statistics by treatment group as 
randomized. The summary at baseline and at each time point is based on all randomized 
subjects with a measurement at respective time point. The change from baseline analysis 
will only include subjects who have an assessment at baseline and at the subsequent time 
point. 
 
FACT-TOI deterioration rate at 15 months is defined as the proportion of randomized 
subjects who had 5 points or more decrease from baseline in FACT-TOI.  FACT-TOI 
deterioration rate at 15 months and associated 95% confidence interval will be calculated 
for each treatment group, based on all randomized subjects.  Clopper-Pearson method 
will be used for calculating 95% CI.  


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Based on prior trials in locally-advanced NSCLC, we expect about 40% patients will 
remain for evaluation at 15 months.  Based on RTOG 0617, the deterioration rate at 1 
year was about 50%. Therefore, assuming a 60% deterioration rate 15 months in control 
arm,  about 220 evaluable patients at 15 months will detect a 20% difference (e.g., 60% 
vs. 40%) in deterioration rate with about 85% power at a two-sided alpha of 0.05, after 
taking account of the potential treatment effects which may result in unequal number of 
patients between arms.  
 
 
The scores at baseline and subsequent time points, as well the associated changes from 
baseline for each treatment group will be compared using the two-sample t-test. If the 
parametric assumptions are not met, then the Mann-Whitney test will be used.  Effect size 
of FACT-TOI changes at different time points will be calculated based on Cohen’s d, i.e., 
dividing the difference between arms in mean score changes by the pooled standard 
deviation of the baseline score means.   
 
Longitudinal data analysis will also be performed to characterize the trend of scores over 
time across the two treatment groups using hierarchical formulation of the linear mixed 
model. The model will include treatment groups, stratification factors and time. 
 
14.7.3  OS and PFS in patients with 1. PD-L1-positive, 2. PD-L1-negative tumors and 3. PD-L1 
undetermined tumors 
If the trial is declared positive based on either OS or PFS in the overall ITT population, a 
step-down procedure will be applied to OS and PFS in the ITT subgroups in the 
following order: (1) PD-L1 positive (both ≥1% and ≥50% will be assessed); (2) PD-L1 
negative, (3) PD-L1 undetermined, and the overall 2-sided alpha 0.05 is recycled for each 
subgroup analysis.  Within each PD-L1 status group, OS and PFS will be analyzed using 
a 2-sided log-rank test stratified by histology and Zubrod in all randomized patients.  
Hazard ratio (HR) and corresponding two-sided 95% confidence interval (CI) will be 
estimated using a Cox proportional hazard model, with treatment group as a single 
covariate, stratified by histology and Zubrod. Results from an unstratified analysis will 
also be provided.  The rates at various timepoints (i.e., every 6 months after 
randomization) and medians of OS for each arm will be estimated using the Kaplan-
Meier method (1958). The associated 95% confidence interval (CI) will be calculated 
using Greenwood’s formula and based on a log-log transformation applied on the 
survival function. 
 
In the event that study is not declared positive based on either OS or PFS in the ITT 
population, the presence of qualitative interactions between PD-L1 status and nivolumab 
will be assessed by analyzing OS and PFS within each PD-L1 positive and negative 
subgroups separately for exploratory purposes. The statistical analysis plan will be same 
except that no formal hypothesis testing will be performed.  In addition, when assessing 
the presence of quantitative interactions is warranted based on exploratory subgroup 
analyses, an overall global interaction test for OS and PFS will be conducted.  This will 
be performed in the overall ITT population by comparing the fit of a Cox proportional 
hazards model including treatment, PD-L1 status, and treatment-by-PD-L1 status 


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interaction terms, stratified by histology and Zubrod, with one that excludes the 
interaction terms at the 2-sided 10% significance level.  If the fit of the model is not 
significantly improved with including the global interaction terms, then it will be 
concluded that the overall treatment effect is consistent across the PD-L1 status 
subgroups.  
 
If there are too few OS events and PFS events available for a meaningful analysis of a 
particular subgroup, e.g., less than 20 events in a subgroup, the aforementioned subgroup 
statistical analysis plan will not be performed for statistical inferences, and only 
descriptive summaries of OS and PFS will be provided.  
 
14.8 
Exploratory Hypothesis and Endpoints 
14.8.1  Biomarker analysis 
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these markers with study drug response, including efficacy and/or adverse 
events. The predictive and prognostic potential for the proposed biomarkers may become 
scientifically obsolete or the assay technology may evolve over time, making the 
technology outlined in the current protocol obsolete when the study is finished. As such, 
no marker assays will be conducted on the collected specimens. When sufficient 
information is available from the parent study, a full correlative study protocol for the 
marker studies detailing the scientific hypothesis, research plan, clinical outcome, assay 
methods for each biomarker, and a more complete statistical section (with adequate 
power justification and analysis plan) will be available. 
 
14.8.2 Proportion of patients alive and progression-free at 12 and 24 months  
The proportion of patients alive and progression-free at 12 and 24 months will be 
estimated by the Kaplan-Meier methodology for each arm, and the 95% CI will be 
calculated using Greenwood’s formula and based on a log-log transformation applied on 
the survival function in the ITT population.  
 
14.8.3 PROMIS fatigue 
 
Baseline and PROMIS at each subsequent assessment, as well as their change from 
baseline will be summarized using descriptive statistics by treatment group as 
randomized. The summary at baseline and at each time point is based on all randomized 
subjects with a measurement at respective time point. The change from baseline analysis 
will only include subjects who have an assessment at baseline and at the subsequent time 
point.  Changes in PROMIS fatigue at 3 months are of particular interest. 
 
14.8.4 EQ5D 
EQ-5D consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ 
VAS). The EQ-5D descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 
levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems. The EQ VAS records the subject’s self-rated health state on a 100-point 
vertical, visual analogue scale (0 = worst imaginable health state; 100 = best imaginable 
health state.   


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Subjects’ overall health state on a visual analog scale (EQ-VAS) at each assessment time 
point will be summarized using descriptive statistics by treatment group, as randomized. 
Proportion of subjects reporting problems for the five EQ-5D dimensions at each 
assessment time point will be summarized by level of problem and by treatment group, as 
randomized.  Percentages will be based on number subjects assessed at assessment time 
point.  
 
14.8.5 PFS based on investigator assessment  
PFS based on investigator assessment (inv-PFS) is defined similarly to the co-primary 
endpoint, IRRC-PFS, except that progressive disease (PD) is determined by investigator’s 
assessment based on RECIST criteria.  The intention of this analysis is to illustrate if the 
estimation and inferential results based on inv-PFS are concordant with those based on 
IRRC-PFS in order to reassure the applicability of the study results in clinical practice.   
The analysis will be considered as exploratory and descriptive in nature.  In addition to 
analyzing inv-PFS using the methods described in Section 14.3.2 for PFS primary 
analysis, the source of PFS events (PD vs. death) based on investigators’ assessment and 
IRRC will be summarized separately, and the censoring times distributions of inv-PFS 
and IRRC-PFS will be summarized separately.   
 
 
 
 
 
 
 
 


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Ezer N et al. Cisplatin vs. carboplatin-based chemoradiotherapy in patients >65 years of age with 
stage III non-small cell lung cancer.  Radiother Oncol. 2014;112: 272-8. 
 
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Garcia SF, Cella D, Clauser SB, et al. Standardizing patient-reported outcomes assessment in 
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Glasziou PP, Simes RJ, Gelber RD. Quality adjusted survival analysis. Stat Med. 1990; 
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Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent 
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Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of 
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2010; 37(Suppl 1): 48-53. 
 
Investigator Brochure:  Nivolumab (v.14). Bristol-Myers Squibb. 30 June 2015. 
 
Ivanova A, Qaqish BF, and Schell MJ. Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics. 61: 540-545, 2005. 
 
Iyengar P, Gerber DE. Locally advanced lung cancer: An optimal setting for vaccines and other 
immunotherapies. Cancer J. 19:247-62, 2013 
 
Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after 
concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell 
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Ku GY, Yuan J, Page DB, et al. Single-institution experience with ipilimumab in advanced 
melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates 
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Lai J-S, Cella D, Choi SW, et al.Developing a fatigue item bank from the patient-reported 
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Contexts (3MC). June 25-28, 2008. 
 
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21571656 
 
Le DT, et al. PD-1 blockade in tumors with mismatch-repair deficiency. NEJM. 372: 2509-20, 
2015. 
 
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Research & Therapy. 27 :153-60, 2011. 
 
Liakou CI, Kamat A, Tang DN, et al. CTLA-4 blockade increases IFNgamma-producing 
CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl 
Acad Sci U S A. 105:14987-92, 2008. 
 
Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin 
as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, 
double-blind, multicenter phase II study. J Clin Oncol. 30:2046-54, 2012. 
 
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blockade in non-small cell lung cancer. Science. 348: 124-8, 2015. 
 
Rizvi NA, Antonia SJ, Chow LQM, et al. A phase I study of nivolumab (anti-PD-1; BMS-936558, 
ONO-4538) plus platinm-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-
small cell lung cancer (NSCLC) patients (pts). J Clin Oncol. 31 (suppl; abstract 8072), 2013. 
 
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APPENDIX I 
Nivolumab (BMS-936558) Pharmacy Reference Manual 
 
1 
OBJECTIVE 
 
The objective of this procedure manual is to provide the study site with clear and detailed 
information for the storage, handling, preparation and administration of Nivolumab used in the 
RTOG 3505/CA209-333 study 
2 
BMS CLINICAL PRODUCT CONTACT 
If concerns regarding the quality or appearance of the study drug, or questions regarding 
administration arise, do not dispense the study drug and contact the Bristol-Myers Squibb 
immediately: 
 
Questions with regard to drug preparation and pharmacy manual content:  
 
Peter Trimboli, RPh 
Pharmacy Services, Drug Supply Management  
Bristol-Myers Squibb Research and Development 
Telephone: 609-252-4862 
Email: 
pharmacyservices@bms.com 
 
3 NIVOLUMAB INJECTION 
3.1 DESCRIPTION 
 
 
Product Name   
Nivolumab Injection (BMS 936558), 100 mg/vial (10 mg/mL)    
Product description 
and Packaging  
Packaging:  Vials assembled into white dispensing boxes containing 
100 mg vials.   
Vials:  10 cc Type I glass vial. 20 mm stopper and seal, respectively.  
Appearance: Clear to opalescent, colorless to pale yellow liquid, 
light (few) particulates may be present. 
Product Ingredients 
 Each vial contains 100 mg Nivolumab    
 
 
 
 
 
 
 
 
Continued on next page 
 
 


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APPENDIX I (Continued) 
 
3.2  Handling and Dose Preparation 
As with all injectable drugs, care should be taken when handling and preparing Nivolumab.  
Whenever possible, Nivolumab infusions should be prepared in a laminar flow hood, glovebox, 
or safety cabinet using standard procedures for the safe handling of intravenous agents applying 
aseptic techniques. Gloves are required. If nivolumab solution comes in contact with the skin or 
mucosa, immediately and thoroughly wash with soap and water. 
Dose Preparation and administration 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale yellow solution. Discard the 
vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a 
few translucent-to-white, proteinaceous particles. Do not shake the vial. 
Preparation 
 Withdraw the required volume of Nivolumab and transfer into an intravenous 
container.  
 Dilute Nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP to prepare an infusion with a final concentration ranging 
from 1 mg/mL to 10 mg/mL (see example below) 
 Mix diluted solution by gentle inversion. Do not shake. 
 Discard partially used vials or empty vials of Nivolumab. 
Storage of Infusion 
The product does not contain a preservative. After preparation, store the Nivolumab 
infusion either: 
 at room temperature for no more than 4 hours from the time of 
preparation. This includes room temperature storage of the infusion in the 
IV container and time for administration of the infusion  
or 
 under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours 
from the time of infusion preparation. 
Do not freeze. 
Administration 
Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-
pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Do 
not coadminister other drugs through the same intravenous line. Flush the intravenous line at 
end of infusion with appropriate amount of diluent (e.g. 15-20 ml) to ensure that the total 
dose is administered. Total infusion and flush time should equal to 30. 
Dose selection for Nivolumab should be assigned per subject as outlined in the clinical protocol 
study drug dosing section of the clinical protocol. The examples below use a total volume of 60  


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APPENDIX I (Continued) 
ml to allow for a practical administration rate, however other volumes may be used for 
Nivolumab preparation so as long as the final concentration remain between 1 - 10 mg/ml (e.g. 
100 ml). 
NOTE: When Nivolumab Placebo is required, placebo shall be considered an equal volume of 
drug diluent alone (NS, D5W) which is standard to site practice for mixing active Nivolumab 
(60 ml, or 100 ml) and should be infused at the same rate (30 minutes). 
Preparation example 240 mg dose; 
 
Nivolumab 240 mg (24 ml Nivolumab 10mg/ml solution, local rounding rules applicable) may be 
mixed with 36 ml NS or D5W to a total volume = 60 ml which can be infused over 30 minutes at 
2 ml/min followed by flush.  
 
Preparation example 480 mg dose; 
Nivolumab 480 mg (48 ml Nivolumab 10mg/ml solution, local rounding rules applicable) may be 
mixed with 12 ml NS or D5W to a total volume = 60 ml which can be infused over 30 minutes at 
2 ml/min followed by flush.  
 
3.3 Product Storage and Stability 
Nivolumab 100 mg vials for injection should be refrigerated at 2°C to 8°C (36°F to 46°F). 
Protected from light and should not be frozen. Do not use beyond the expiration date on the 
vial.  Protect the vials from light by storing in the original package until time of use.  Vials do 
not contain preservative and thus are intended for single use only and should be discarded after 
use and product reconciliation. 
Nivolumab should not be infused concomitantly in the same intravenous line with other agents. 
No physical or biochemical compatibility studies have been conducted to evaluate the co-
administration of Nivolumab with other agents. 
 
4 
SITE TEMPERATURE EXCUSIONS AND TRANSIT 
 
Drug must be stored under the proper conditions as listed on the clinical supply label.   If any 
temperature excursions are encountered during on site storage, please report these to BMS for 
assessment as outlined in the Bristol-Myers Squibb, “Investigational Medicinal Product (IMP) 
handling at Investigational Sites: Shipment, Receipt, Storage, Use Date Extension and 
Return/Destruction” guideline using the Temperature Excursion Response Form. See Form 1 
Proper storage conditions must be maintained during movement of inventory within an  
 
 
 
 
 


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APPENDIX I (Continued) 
 
investigational site. Storage conditions for medications requiring storage at 2ºC to 8ºC (36ºF-
46ºF) must be maintained throughout the transport with documentation maintained within the 
site files. Where controlled storage conditions (for example, temperature, relative humidity, light, 
etc.) are required during transit, the necessary environmental controls must be in place to ensure 
that the drug product remains within the acceptable temperature range. Temperature monitoring 
devices such as min max device must be implemented during transit.  
 
5 
PRODUCT RECEIPT, ACCOUNTABILITY, AND DESTRUCTION 
 
Drug Receipt 
Shipment Inspection Instructions 
1. Open box immediately upon receipt.  
2. Carefully inspect kits ensuring all of the supplies were received in good condition, correct 
quantity received, and all of the container ID #s were received as noted on packing slip.   
3. Sign and date (date of receipt) packing slip and file with study-specific documents. 
4. Log in all supplies in each shipment on the appropriate Inventory log Form  
 
Accountability 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product accountability and reconciliation is maintained at each study site where 
study drug is inventoried and dispensed.  
 
In addition, records or logs must comply with local regulations and guidelines for the conduction 
and handling of clinical supplies should include but not limited too: 
 
 Amount received and placed in storage area 
 Amount currently in storage area 
 Label ID number or batch number 
 Amount dispensed to and returned by subject, including unique subject identifiers 
 Amount transferred to another area/site for dispensing or storage 
 Non-study disposition (e.g. lost, wasted) 
 Amount destroyed at study site, if applicable 
 Amount returned to the Sponsor, if applicable 
 Dates and initials of person responsible for Investigational Product (IP) 
 Dispensing/accountability, as per the Site Signature and Delegation Log. 
 
Study Drug Destruction 
Study drugs can be destroyed on site if local policies allow to do so. It is the Investigator’s  
 
 
 


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APPENDIX I (Continued) 
 
responsibility to ensure that arrangements have been made for the disposal, procedures for proper 
disposal have been established according to applicable regulations, guidelines and institutional 
procedures, and appropriate records of the disposal have been documented.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Form 1 
Bristol-Myers Squibb 
Temperature Excursion Response Form for Investigational Medicinal Products 
 
Section A.  To be completed by the site at the time of Site Storage Temperature Excursion: 
Protocol Number: 
Site Number/Investigator Name/Country: 
 
Description of Drug Products involved in Excursion: 
 
Batch number (s) printed on label: 
Container numbers: 
 
 
 
 
 
 
Description of Excursion (temperature highs/lows and duration): 
Below label storage lower limit …...°C                    Duration:………….                           Low extreme t°:  …..°C 
 
Above label storage upper limit ….. °C                    Duration:………...                           High extreme t°:  …..°C 
 
Reason for excursion: 
 
 
Has the issue been resolved? 
 
Have these specific containers been involved in a previous excursion?               NO 
       YES  
   
 If yes, please provide: 
Batch number (s): 
Container numbers: 
Temperature highs/lows and duration 
 
 
 
 
 
 
 
 
 
When is the next planned patient visit when these supplies may be dispensed? 
 
 
Excursion information submitted by: _________________________________________ Date: ____________     
 
 
 
 
 
        Print/Signature/Title of site staff 
Section B.  Usage Decision to be made by Bristol-Myers Squibb: 
 
Temperature excursion details for the products listed above have been evaluated.  Usage decision is based on the temperature data 
that were made available by the investigational site.  
Conclusion (and comments): 
 
 All products are suitable for continued use 
______________________________________________________________________________________   
______________________________________________________________________________________ 
 
 All products are NOT suitable for further dispensation.  Please remove supplies from available inventory and work with your 
Site Manager/Site Monitor to have supplies destroyed and IVRS updated if applicable. 
______________________________________________________________________________________   
______________________________________________________________________________________ 
 
Assessment completed by:_______________________________________________      Date ___________ 
                                                                           Print/Signature/Title 
Send completed form to: Peter Trimboli, RPh at pharmacyservices@bms.com 
 


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Templates as provided via separate attachment or below may serve as a sample for dosage calculations 
and may be printed out and used to document any calculations and infusion times as required by the clinical 
study team. Content in this attachment may be added or omitted. 
 
Drug Dose and Volume Calculator  
for IV Infusion 
  
  
Drug Product : 
 
Protocol number 
 
Patient name or ID: 
 
Preparation date and time: 
 
  
 
Drug Strength (mg/mL) 
 
Subject body weight (kg) 
 
1Dose in mg 
 
Volume of Drug (mL) 
 
Total Volume of infusion (mL) 
 
Volume of Diluent (mL) NS or D5W 
 
Infusion duration (min) 
 
Infusion Rate (mL/min) 
 
Infusion hang time 
  
Infusion completion time 
  
Note: If required, flush line with separate volume of same diluent (e.g. 15-20 ml) as outlined 
in the study pharmacy manual 
  
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX II 
 
1.1 
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 
 
1.1.1   Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
1.1.2   Measurable lesions  
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
1.1.3  Non-measurable lesions  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
1.1.4  Malignant lymph nodes 
1.1.1.1  To be considered pathologically enlarged and measurable, a lymph node must be >15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed. 
 
1.1.5   Baseline documentation of “Target” and “Non-Target” lesions  
Target lesions.  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the  


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APPENDIX II (continued) 
 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
Non-target lesions.  
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
1.1.6  Response Criteria 
Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 
mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX II (continued) 
 
Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note: If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression of non-target 
lesions should not normally trump target lesion 
status. It must be representative of overall disease 
status change, not a single lesion increase. 
 
* Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail. 
 
Evaluation of best overall response 
The best overall response is the best time point response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the participant's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Table 3: Response Assignment 
Target Lesions 
Non-Target lesion 
New Lesion 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
 
Not evaluated 
No 
PR 
PR 
Non-CR/ Non-PD/ not 
evaluated 
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
APPENDIX II (continued) 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment  
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
1.1.7  Definitions for Response Evaluation –RECIST version 1.1 
 
1.1.7.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
1.1.7.2 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented, taking as reference for progressive 
disease the smallest measurements recorded since treatment started. 
 
1.1.7.3 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that progressive disease is objectively documented. 
 
1.1.7.4 Objective response rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST v1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 
1.1.7.5 Progression Free Survival 
A measurement from the start of the treatment until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs, taking as reference the smallest measurements recorded 
since the treatment started.  
 
Progression free survival will be measured from the date of initial treatment to the earliest date of 
disease progression, resection of measurable tumor or death for subjects who fail; and to the date 
of last contact for subjects who remain at risk for failure. 
 
1.2 Methods of Measurement 


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All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and  
 
APPENDIX II (continued) 
 
never more than 28 days before the beginning of the treatment. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s)  
being followed cannot be imaged but are assessable by clinical exam. The same imaging 
modality must be used throughout the study to measure disease. 
 
1.2.1 CT and MRI 
CT and MRI are the best currently available and most reproducible methods for measuring target 
lesions. This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less. If 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 
in certain situations (e.g. for body scans).  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  
 
1.2.2 Chest X-Ray 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by an aerated lung (CT is preferable).  
 
1.2.3 Clinical Examination 
Clinically detected lesions will only be considered measurable when they are superficial (e.g. 
skin nodules and palpable lymph nodes). For skin lesions, documentation by color photography, 
including a ruler to estimate size of the lesion, is recommended. Photographs should be retained 


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at the institution. 
 
 
APPENDIX II (continued) 
 
1.2.4 Cytology and Histology 
Cytologic and histologic techniques can be used to differentiate between complete and partial 
responses in rare cases (e.g. after treatment to differentiate residual benign lesions and residual  
malignant lesions in germ cell tumors). Cytologic confirmation of the neoplastic nature of any 
effusion that appears or worsens during treatment is required when the measurable tumor has met 
response or stable disease criteria.  
 
 
 


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APPENDIX III 
 
Biospecimen Bank at UCSF:  Biospecimen Collection, Processing, and Shipping 
Instructions for FFPE and Serum 
 
 FFPE Specimens: 
o Slides should be shipped in plastic slide holder/slide box. Place a small wad of padding 
in top of the container. If you can hear slides shaking they can break during shipping.  
o Unstained slides must be stored at 4C after cutting and shipped to the Biospecimen 
bank with cold packs at 4C within 5 business days from cutting. The date that the slides 
were cut should be noted on the ST form. 
o FFPE Blocks can be shipped in a plastic block holder or wrapped with paper or placed 
in a paper envelope, and placed in a cardboard box with padding. Do not wrap blocks 
with bubble wrap or gauze. Place padding in top of container so that if you shake the 
container the blocks are not shaking. If you can hear blocks shaking they may break 
during shipping.  During warm weather months the use of cold packs is recommended 
to prevent wax from melting. 
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United 
States Postal Service (USPS) to the USPS address (94143) or by Courier to the Street 
Address (94115). Do NOT ship on Dry Ice.  
o Urgent overnight shipments (central review) should always be sent by Courier. 
o If patients consented to banking DO NOT ship FFPE specimens with a return request. 
We cannot accept or bank samples that we cannot keep. Always send what can be 
banked (duplicate H&Es, Blocks or punches as specified in the protocol). We can 
punch and return blocks if noted in the protocol. Punch kits can be requested from us by 
email (RTOG@ucsf.edu) for sites that wish to punch the block themselves.  
 
 Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a 
separate bag and clearly identified. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry 
ice (at least 7 lbs.). There should be plenty of dry ice under and above the specimens. If 
the volume of specimens is greater than the volume of dry ice then ship in a larger 
Styrofoam box, or two separate boxes. Any Styrofoam box can be used, as long as it is 
big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be 
discarded and the site will be notified.  
o Send frozen specimens via overnight courier to the address above. Frozen specimens 
should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to 
prevent thawing due to delivery delays. Saturday or holiday deliveries cannot be 
accepted. Samples can be stored frozen at -80°C until ready to ship.  
 
 For Questions regarding collection/shipping please contact the Biospecimen Bank at 
UCSF by e-mail: RTOG@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271. 
 
 


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APPENDIX III (Continued) 
 
Shipping Instructions for FFPE and Serum: (See Appendix III for processing and shipping 
information for peripheral blood) 
 
US Postal Service Mailing Address:  
Use only for non-urgent ambient 
specimens- FFPEs, slides, blocks: 
 
Courier Address (FedEx, UPS, etc.):  
For Frozen, Urgent or Trackable Specimens: 
Biospecimen Bank at UCSF 
UCSF-  Box 1800 
2340 Sutter St, room S341 
San Francisco, CA 94143-1800 
Biospecimen Bank at UCSF 
University of California San Francisco 
2340 Sutter St, room S341 
San Francisco, CA 94115 
 
 Include all required specimen paperwork in pocket of biohazard bag.  
 Check that the Specimen Transmittal (ST) Form has been completely filled out  
 Check that all samples are labeled with the study and case number, and include date of 
collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
Blood Collection Kit Instructions 
This Kit is for collection, processing, storage, and shipping of serum and whole blood for 
first 3 timepoints. Recurrence/ toxicity patients- site should request follow-up kits 
separately for these patients. 
 
 
Kit contents:  For 3 timepoints 
 Five 1 ml cryovials per timepoint. 
(Twenty per kit)  
 Biohazard bag (4) 
 ST Form and Kit Instructions 
Note: sites will have to provide their own 
EDTA for whole blood and standard Red 
Top tube for serum blood draw unless 
specifically requested. 
 Absorbent shipping material (4) 
 1 Styrofoam container (inner) and 
Cardboard shipping (outer) box for 
batch shipping 
 UN1845 DRY Ice Sticker and 
UN3373 Biological Substance 
Category B Stickers 
 
Preparation and Processing of Serum 
 
Serum: Red Top Tube 
 Label as many 1ml cryovials (5 to 8) for each time point as necessary for the serum 
collected.  
Label tubes with the RTOG Foundation study and case number, time point, 
collection date and time, and clearly mark cryovials “serum”. 
 
 
 


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APPENDIX III (Continued) 
 
Preparation and Processing of Serum (continued) 
Process: 
1. Allow one red top tube (not provided in kit) to clot for 30 minutes at room 
temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4°C 
(preferred). If sites are unable to process samples at 4°C then spinning at room 
temperature is acceptable if done within 2 hours of draw but must be noted on the ST 
Form. 
3. Aliquot 0.5 ml serum into five (5) labeled cryovials. Make sure tubes are labeled as 
specified above. 
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90C. Store 
frozen until ready to ship. See below for storage conditions. 
 
Whole Blood for DNA Purple Top EDTA tube (EDTA tube is not provided) 
 Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label 
them with the RTOG study and case number, collection date/time, and time point, and 
clearly mark cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
Blood can also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many labeled cryovials as are 
necessary for the blood collected (3 to 5). Make sure tubes are labeled as specified 
above. 
3. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C. Store 
frozen until ready to ship on dry ice. See below for storage conditions 
PLEASE make sure EVERY SPECIMEN IS LABELED and include collection time point 
on ST Form. 
 
PLEASE make sure EVERY SPECIMEN IS LABELED and include collection time point 
on ST Form. 
 
Freezing and Storage: 
 Freeze Serum and whole blood samples in a -80C Freezer or on Dry Ice or snap freeze 
in liquid nitrogen. 
 Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for up 
to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday 
only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 


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APPENDIX III (Continued) 
 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday 
only; Canada: Monday-Tuesday only). 
 Please indicate on Specimen Transmittal Form the storage conditions used and time 
stored. 
 
Shipping/Mailing: 
 Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from 
Canada) to prevent thawing due to delivery delays. Saturday and holiday deliveries 
cannot be accepted.  
 Include all required paperwork in sealed plastic bag taped on outside top of the 
Styrofoam box. 
 Wrap frozen specimens of same time point together in absorbent shipping material and 
place specimens from separate time points or cases  in a separate biohazard bag.  Place 
specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs./3.5kg 
minimum).  Add padding to avoid the dry ice from breaking the tubes.  
 Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 
and UN1895 dry ice stickers to outer cardboard box. Fill out the UN1895 Label 
COMPLETELY. 
 


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APPENDIX III (Continued) 
 
Preparation and Processing of Serum 
Shipping/Mailing:(Continued) 
 Multiple cases may be shipped in the same cooler, but make sure each one is in a 
separate bag and that there is enough room for plenty of dry ice. Add padding to avoid 
the dry ice from breaking the tubes. 
 For questions regarding collection, shipping or to order a Serum Collection Kit, 
please e-mail RTOG@ucsf.edu or call (415) 476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
Biospecimen Bank UCSF 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: RTOG@ucsf.edu    
 
 
Note: See Appendix IV for processing and shipping information for peripheral blood.  
 
 


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APPENDIX IV 
 
Hooper Laboratory: Preparation, Processing and shipping of Peripheral Blood 
 
Kit Contents: 
5 Heparin Blood (green top) draw tubes per time point  
Tube holder 
Outer box for tube holder 
Study Specific ST Form 
Fed Ex Clinical Pak with label 
 
Processing: 
1. Sites should only draw blood samples on Monday-Wednesdays and only ship Monday-
Thursdays.   
2. Draw blood in 5 green heparin tubes. 
3. Mix gently. 
4. Place tubes in tube holder and outer box provided with Kit. 
5. Seal up tube holder box and place in Fed Ex Clinical Pak provided 
6. Ship the blood at room temperature on the same day for overnight delivery if possible.  
7. Blood samples drawn too late in the day for overnight shipping, should be refrigerated 
overnight and shipped the following day for same day delivery. 
8.  Ship same day to Hooper Laboratory- Label is provided on the Clinical Pak. 
 
Shipping Address: Note: Do NOT ship peripheral blood to Biospecimen Bank at UCSF. 
Hooper Laboratory 
Attn.: Rhonda Kean (lab manager) or Craig Hooper, PhD 
JAH 454 
1020 Locust Street 
Philadelphia, PA 19107 
For questions, contact: 215-503-1559 
 
 
 
 
 

ICF_001.pdf: 
RTOG FOUNDATION 
 
 
RTOG 3505 
 
(ClinicalTrials.gov NCT #: 02768558) 
 
 
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND 
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY 
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG 
CANCER 
 
 
Amendment 2:  January 30, 2017 


Sample consent form version: January 30, 2017 
To be attached to protocol version:January 30, 2017 
RTOG 3505 
Page 1 of 15 
 
RTOG Foundation 3505 
 
TITLE:  
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN 
AND ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED 
BY NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL 
CELL LUNG CANCER 
 
SHORT TITLE:  
Testing the addition of the immune activating drug, nivolumab, after 
chemoradiotherapy for lung cancer. 
 
PROTOCOL NO.: 
RTOG 3505 
 
WIRB® Protocol #20160677 
 
SPONSOR: 
RTOG Foundation Collaboration with Bristol-Myers Squibb 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Name 
 
Number (24-hour number required) 
 
 
The purpose of this consent form is to help you decide if you want to be in the research study.  Before any 
study-related procedures are performed, you will be asked to read and sign this consent form if you wish to 
participate. 
 
If you have any questions or do not understand something in this form, you should ask the study doctor or study 
staff. You should also discuss your participation with anyone you choose in order to better understand this study 
and your options. You should not join this research study until all of your questions are answered. 
 
What is the usual approach to my lung cancer? 
You are being asked to take part in this study because you have locally advanced non-small cell lung cancer. 
People who are not in a study are usually treated with chemotherapy and radiation therapy. There are several 
FDA-approved chemotherapy drugs that are commonly used along with the radiation therapy, such as cisplatin 
and etoposide. For patients who receive the usual approach for this cancer, about 15 out of 100 are free of 
cancer at five years. 
 


Sample consent form version: January 30, 2017 
To be attached to protocol version:January 30, 2017 
RTOG 3505 
Page 2 of 15 
 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
 you may choose to have the usual approach described above 
 you may choose to take part in a different study, if one is available 
 or you may choose not to be treated for cancer but receive care that is intended to maintain your 
comfort and dignity. 
 
 Why is this study being done? 
We will test whether or not receiving nivolumab after the usual chemotherapy (cisplatin and etoposide) with 
radiation will improve survival for patients with non-small cell lung cancer. Nivolumab can help the immune 
system recognize cancer cells. Nivolumab following chemotherapy and radiation is not part of the usual 
treatment for lung cancer. Nivolumab is already FDA-approved for treating patients with metastatic (stage 4) 
lung cancer, but is investigational, (not approved) for locally advanced (stage 3) lung cancer.  
 
In this study, half of the patients will receive nivolumab and the other half will receive placebo. The placebo 
will look the same as nivolumab, but it is a non-active substance and will have no effect on your cancer. This 
study will allow the researchers to know whether the addition of nivolumab is better, the same, or worse than 
the usual chemotherapy and radiation.  If better, the new approach should improve survival compared to the 
usual approach. 
 
There will be about 660 people taking part in this study. 
 
What are the study groups? 
All patients will receive cisplatin and etoposide chemotherapy with radiation. After completion of 
chemoradiotherapy, eligible patients will be randomized to be in one of two groups  (nivolumab or placebo). A 
computer will by chance assign you to treatment groups in the study.  This is called randomization.  This is 
done by chance because no one knows if one study group is better or worse than the other. You will have an 
equal chance of being placed in either group. 
 
You and your doctors will not know if you are assigned to the nivolumab or placebo group. This is called being 
“masked.” Masking assures that the researchers are able to compare the experience of patients in each group  
without bias or a preference for one treatment over the other. In the event of an emergency, the study doctor can 
find out what you are receiving. 
 
After completion of chemoradiotherapy: 
 Nivolumab Group 1 will get nivolumab 240 mg every 2 weeks for 16 weeks, then 480 mg every 4 
weeks for 36 weeks for a total of one year. 
 Placebo Group 2 will get placebo every 2 weeks 16 weeks, then every 4 weeks for 36 weeks for a 
total of for one year. 
 
 


Sample consent form version: January 30, 2017 
To be attached to protocol version:January 30, 2017 
RTOG 3505 
Page 3 of 15 
Another way to find out what will happen to you during this study is to read the chart below. Start reading at the 
left side and read across to the right, following the lines and arrows. 
How long will I be in this study? 
You will receive chemotherapy and radiation for 6 weeks. After completion of chemoradiotherapy and if your 
cancer has not progressed, you will receive nivolumab or placebo every 2 weeks for 16 weeks and then every 4 
weeks for 36 weeks for a total of one year. After you finish nivolumab or placebo, you will be seen regularly by 
your doctors.  During these visits, they will check the status of your cancer and your side effects from treatment.  
These visits will occur every 3 months from the end of treatment for years 1 and 2, every 6 months for years 3, 
4, and 5, then once a year for your lifetime. 
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer. However, 
there are some extra tests and procedures that you will need to have if you take part in this study. 
 
Before you begin the study, you will need to have the following extra tests: 
 
You must have the tumor tissue from your previous biopsy tested for PD-L1, an immune system 
marker, using a test that is for research purposes only as the test has not been approved by the FDA 
for your type of cancer.  The role of PD-L1 in cancer is not fully understood and researchers want to 
use the information from this investigational test of your tumor tissue to help them understand the 
immune system’s response to cancer. The result of the PD-L1 test does not impact the treatment you 
will receive for your cancer. Your privacy is very important and the researchers will make every 
effort to protect it.  Your test results will be identified by a unique code and the list that links the 
code to your name will be kept separate from your sample and health information. If any of your 
tissue is left over from this extra test, it will be stored for biobanking, if you agree. There is more 
information about biobanking in the optional study section. 
 You will need to have blood tests to screen for health problems that might increase the side effects of 
treatment. This would include tests for liver problems, an under- or over-active thyroid, and 
inflammation of the pancreas. These blood tests will be repeated during treatment to monitor for side 
effects of nivolumab. 
 You will be asked to fill out 3 forms with questions about your physical and emotional well-being. 
Researchers will use this information to learn more about how cancer and cancer treatment affects 
people. Each form will take about 5 to 10 minutes to complete. The forms will ask about things like 
 
You agree to 
take part in 
the study 
Usual care:  
chemotherapy 
with radiation 
 
Randomization         
(The computer will 
randomly put you in a 
study group, and you 
will not know which 
group you are in) 
 
Nivolumab 
Placebo 


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tiredness and social and emotional well-being. You may feel uncomfortable answering some of the 
questions, and you can skip any you do not want to answer. 
 You will be asked to fill out the three forms 8 times:  before chemotherapy and radiation treatment, 
before nivolumab/placebo treatment, at 3, 6, 9,12, 15 and 18 months from start of 
nivolumab/placebo treatment. For one of the forms, you will be asked to fill it out 4 more times at 
years 2, 3, 4, and 5 from start of nivolumab/placebo treatment  Each form will take about 5 to 10 
minutes to complete. The forms will ask about things like tiredness and social and emotional well-
being. You may feel uncomfortable answering some of the questions, and you can skip any you do 
not want to answer. 
 
During the study: 
 You will need to have blood tests to monitor your liver and thyroid function, and to monitor for 
inflammation of the pancreas. 
 Women who can have children must have a negative pregnancy test every 4 weeks in order to 
continue to take part in the study. 
 You will be asked to fill out the same 3 forms with questions about your physical and emotional 
well-being before nivolumab/placebo treatment, at 3, 6, 9,12, 15 and 18 months from start of 
nivolumab/placebo treatment. For one of the forms, you will be asked to fill it out 4 more times at 
years 2, 3, 4, and 5 from start of nivolumab/placebo treatment. Each form will take about 5 to 10 
minutes to complete. The forms will ask about things like tiredness and social and emotional well-
being. You may feel uncomfortable answering some of the questions, and you can skip any you do 
not want to answer. 
 
What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
 The study drug(s)/study approach may not be better, and could possibly be worse, than the usual 
approach for your cancer. 
 You may lose time at work or home and spend more time in the hospital or doctor’s office than usual 
 You may be asked sensitive or private questions which you normally do not discuss 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important points about side effects: 
 The study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect. 
 The study doctor may be able to treat some side effects. 
 The study doctor may adjust the study drugs to try to reduce side effects. 
 


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The tables below show the most common and the most serious side effects that researchers know about. There 
might be other side effects that researchers do not yet know about. If important new side effects are found, the 
study doctor will discuss these with you.  
 
Possible side effects of cisplatin, etoposide, and radiation to the lung which are the usual approach for this type 
of cancer: 
 
Possible Side Effects of Cisplatin, Etoposide 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, Etoposide, more than 20 and up to 100 may have: 
 Infection, especially when white blood cell count is low 
 Anemia which may require blood transfusions 
 Bruising, bleeding 
 Kidney damage which may cause swelling, may require dialysis 
 Hearing loss including ringing in ears 
 Hair loss 
 Sores in mouth which may cause difficulty swallowing 
 Diarrhea, loss of appetite, nausea, vomiting 
 Tiredness 
 Fever, chills 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, Etoposide, from 4 to 20 may have: 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the 
face or throat 
 Confusion 
 Difficulty with balance 
 Heart failure or heart attack which may cause chest pain, shortness of breath, swelling of ankles, and 
tiredness 
 Severe skin rash with blisters and peeling which can involve inside of mouth and other parts of the body 
 Liver damage which may cause yellowing of eyes and skin, swelling 
 
RARE, AND SERIOUS 
In 100 people receiving Cisplatin, Etoposide, 3 or fewer may have: 
 Cancer of bone marrow (leukemia) caused by chemotherapy later in life 
 Seizure 
 
 
Possible Side Effects of Lung Radiation 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving lung radiation, more than 20 and up to 100 may have: 
 Swelling and redness, tanning, thickening, numbness, or peeling of the skin in the area of radiation 
 Difficulty and/or pain with swallowing 
 Hair loss in the treatment area, may be permanent 
 Shortness of breath 
 Cough with or without increased phlegm production 


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COMMON, SOME MAY BE SERIOUS 
In 100 people receiving lung radiation, more than 20 and up to 100 may have: 
 Tiredness 
 Diarrhea, nausea 
 Anemia, which may require blood transfusion 
 Infection, especially when white blood cell count is low 
 Bleeding, bruising 
 Rib pain, increased risk of rib fracture 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving lung radiation, from 4 to 20 may have: 
 Inflammation of the lung that may cause difficulty breathing and can be life-threatening 
 Narrowing of the throat which may cause vomiting, difficulty swallowing 
 Scarring in the lung  
 Lung collapse 
 Fluid around lungs 
 Bleeding from the lungs which may cause coughing up blood  
 Fever  
 Narrowing of the esophagus which may cause difficulty swallowing 
 Pain in chest wall 
 
RARE, AND SERIOUS 
In 100 people receiving lung radiation, 3 or fewer may have: 
 Abnormal opening in internal organs which may cause pain and bleeding 
 Irritation of the heart causing heart failure, heart attack, chest pain, abnormal heartbeat, shortness of breath, 
swelling of ankles, cough or tiredness 
 Transverse myelitis – irritation of the spinal cord causing weakness, tingling or numbness of the lower 
body and legs, or paralysis of the lower half of the body 
 Brachial plexopathy – irritation of the nerves controlling the arm, causing weakness or paralysis 
 Bleeding from the airway (windpipe) 
 Narrowing of the airway causing shortness of breath 
 Death 
 Lung damage, may be life threatening 
 Damage to the large blood vessels surrounding the heart, which could cause coughing up of blood and 
possibly death  
 Sores and skin damage causing bleeding and severe pain and may lead to an open wound 
 
The risks below are those known to occur with the drug, nivolumab, when given alone. It is unknown if giving 
nivolumab after chemotherapy and radiation will result in more severe or new side effects or if side effects will 
worsen more rapidly than expected. Therefore, it is important to promptly notify your study doctor of any side 
effects even if they are mild.  
Possible Side Effects of Nivolumab 
 
Nivolumab may cause one or more of the side effects listed below.  This information is based on data from 
cancer subjects in other clinical trials with nivolumab.  In addition, there may be side effects that are not yet 


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known that may occur.  You should tell your doctor or nurse right away about any possible side effects you 
experience. 
 
PLEASE NOTE THE FOLLOWING IN REVIEWING THESE RISKS: 
Nivolumab increases the immune system response and may result in severe and possibly fatal immune-related 
side effects.  Immune-related side effects have been reported in patients receiving nivolumab. Most immune-
related side effects are reversible and managed with treatment. It is important to promptly notify your study 
doctor if you experience any side effects even if they are mild. You will receive a Subject Alert Card with the 
contact details of your study doctor. 
 
Special precautions 
Side effects of nivolumab may happen anytime during treatment or even after your treatment 
has ended. Call or see your healthcare provider right away if you develop any problems 
listed below or the symptoms get worse. 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving nivolumab, more than 20 and up to 100 may have: 
 
Tiredness 
 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving Nivolumab, from 4 to 20 may have: 
 Anemia which may require blood transfusion 
 Swelling and redness of the eye  
 Pain in belly 
 Diarrhea, nausea, loss of appetite 
 Dry mouth 
 Fever 
 Swelling and redness at the site of the medication injection 
 Bruising, bleeding 
 Pain or swelling of the joints  
 Reaction during or following a drug infusion which may cause fever, chills, rash  
 
Nivolumab may cause your immune system to attack normal organs and cause side effects in 
many parts of the body.  These problems may include but are not limited to: 
 
 Lung problems (pneumonitis and pleural effusion).  Symptoms may include: new or 
worsening cough, chest pain, shortness of breath. 
 Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine.  
Signs and symptoms of colitis may include: diarrhea or increase in bowel movements, 
blood in your stools or dark, tarry, sticky stools, severe belly pain or tenderness. 
 Skin: itching; rash, blisters including inside the mouth; loss of skin pigment  
 Liver problems (hepatitis) which can cause liver failure.  Signs and symptoms of 
hepatitis may include: yellowing of your skin or the whites of your eyes, severe 
nausea or vomiting; drowsiness; pain in the right upper belly.  
 Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and 


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pancreas).  Signs and symptoms may include: headaches that will not go away or 
unusual headaches, extreme tiredness or changes in mood or behavior decreased sex 
drive; weight loss or weight gain; excessive thirst or urine; dizziness or fainting. 
 
 
 
RARE, AND SERIOUS 
In 100 people receiving Nivolumab, 3 or fewer may have: 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath,  swelling of the face or throat 
 
Nivolumab may cause your immune system to attack normal organs and cause side effects in 
many parts of the body.  These problems may include but are not limited to: 
 
 Visual disturbances which may cause double vision, blurred vision, or loss of vision 
with a chance of blindness 
 A condition with high blood sugar which leads to tiredness, frequent urination, 
excessive thirst, headache, nausea and vomiting, and can result in coma 
 Kidney problems, including nephritis and kidney failure requiring dialysis.  Signs of 
kidney problems may include: decrease in the amount of urine, blood in your urine, 
ankle swelling.  
 Heart problems including inflammation and heart failure.  Symptoms and signs of 
heart problem may include: Shortness of breath, swelling of the ankle and body.   
 Problem of the muscle, including inflammation, which can cause muscle pain and 
severe muscle weakness sometimes with dark urine 
 Inflammation of the brain (meningitis/encephalitis), which may cause: headache, 
confusion, sleepiness, seizures, and stiff neck  
 Problem of the nerves that can cause paralysis.  Signs and symptoms may include: 
numbness, tingling of hands and feet; weakness of the arms, legs and facial muscle 
movement. 
 Complications associated with stem cell transplant using donor stem cells (allogeneic 
stem cell transplant).  These complications are caused by attack of donor cells on the 
host organs (inducing liver, skin and gut), and can lead to death.  If you are 
considering an allogeneic stem transplant after participating in this study, please tell 
your doctor that you have received nivolumab therapy, since the risk and severity of 
transplant-associated complications may be increased.  
 
 
Lung Inflammation (pneumonitis):  Inflammation of the lung is a rare side effect of nivolumab.  Lung 
inflammation may occur without symptoms but may be seen on x-ray or CT scan. In some cases, lung 
inflammation may lead to symptoms that may be mild to severe. In rare cases, death has occurred as a result of 
lung inflammation.  Signs and symptoms of lung inflammation may include difficulty breathing, pain or 
discomfort while breathing, chest pain, cough, shortness of breath, increased rate of breathing, fever, low blood 
oxygen levels, or fatigue.   
   


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Your study doctor and nurse will watch you closely for changes in your ability to breathe and for other signs or 
symptoms that might show you are developing this type of lung inflammation. If needed, additional tests or 
procedures may be required to assess your lungs.  
 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the following: 
 Any new or increased shortness of breath; 
 Any new or increased chest pain; 
 Any new or increased pain/difficulty while breathing; 
 Any new or increased cough or any significant change in your type of cough; for example any new or 
increased mucous or blood in your cough;   
 Any change in the amount of oxygen you require; 
 Any fever, fatigue, or other symptoms that occur at the same time as any changes to your breathing or 
other lung symptoms.  
 
Damage to the body by the immune system caused by nivolumab may also include: 
 
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis 
may include: 
 diarrhea (loose stools) or more bowel movements than usual 
 blood in your stools or dark, tarry, sticky stools 
 severe stomach area (abdomen) pain or tenderness 
 
Liver problems (hepatitis). Signs and symptoms of hepatitis may include:  
 yellowing of your skin or the whites of your eyes  
 severe nausea or vomiting  
 
Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:  
 decrease in the amount of urine  
 blood in your urine  
 swelling in your ankles  
 loss of appetite  
 
Hormone gland problems (especially the thyroid and pituitary glands). Signs and symptoms that your hormone 
glands are not working properly may include:  
 headaches that will not go away or unusual headaches  
 extreme tiredness, changes in mood, or behavior decreased sex drive,  
 dizziness or fainting  
 
Other Problems: 
 rash  
 changes in eyesight  
 severe or persistent muscle pain, weakness or joint pains  
 
Getting medical treatment right away may keep these problems from becoming more serious.  
 


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There may be risks or side effects which are unknown at this time.   
 
Let your doctor know of any questions you have about possible side effects. You can ask the study doctor 
questions about side effects at any time.  
 
Certain drugs may increase the severity of these side effects if taken during the study.  Ask your study doctor 
for a full list of prohibited medications. 
 
Risks to Reproduction, Unborn Babies and Nursing Infants  
You must use an adequate method to avoid pregnancy for the duration of this study and after the last dose of 
study drug. Women who are able to become pregnant must not be pregnant or breastfeeding and should not 
become pregnant or breastfeed while taking the study treatments and for up to 5 months after the last dose of 
study drug. Male subjects who are sexually active with a woman of child bearing potential should also use an 
adequate method of birth control to avoid pregnancy of their partner for up to 7 months after the last dose of 
study drug. You should immediately contact your study doctor if there is a change in your method to avoid 
pregnancy, if you start any prescription drug or other medication (including over-the-counter drugs and herbal 
supplements) not prescribed by the study doctor, or if you become pregnant, suspect pregnancy or if you missed 
your period or it is late, or if you have a change in your usual menstrual cycle (e.g., heavier bleeding during 
your period or bleeding between periods). There may be unknown risks to you, your unborn baby or nursing 
infant if you are or become pregnant during this study or are breastfeeding during this study.  
 
If you are a woman of childbearing potential, you will have a pregnancy test at the start of treatment with 
chemotherapy and radiation and again prior to start of treatment with nivolumab/placebo, then every 4 weeks 
during treatment and during your first two follow up visits. Pregnancy will be determined on basis of either a 
urine or blood test. 
 
Should you become pregnant during this study, you will immediately have the study medication permanently 
discontinued and be referred for obstetric care; unless, after further discussion between your physician and the 
Sponsor of this research, it is decided that the benefit of continuing therapy would outweigh the risk for 
stopping therapy. You will continue to be followed for any side effects or potential benefits of the study 
treatment, provided it is safe for you and your unborn baby to do so. Your doctor will discuss this with you, as 
well as options for additional appropriate care for your cancer. The sponsor has not set aside any funds to pay 
for any aspects of obstetric, child or related care and does not plan to pay for them. 
 
Let your study doctor know of any questions you have about possible side effects. You can ask the study doctor 
questions about side effects at any time. 
 
What possible benefits can I expect from taking part in this study? 
It is not possible to know at this time if the study drug(s)/study approach is better than the usual approach so 
this study may or may not help you. This study will help researchers learn things that will help people in the 
future. 
 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let the 
study doctor continue to provide your medical information to the organization running the study. 
 


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The study doctor will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
The study doctor may take you out of the study: 
 If your health changes and the study is no longer in your best interest 
 If new information becomes available 
 If you do not follow the study rules 
 If the study is stopped by the sponsor, IRB or FDA. 
 
What are my rights in this study? 
 
Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, 
there will be no penalty or loss of benefits to you. You will not lose medical care or any legal rights. 
 
 
What are the costs of taking part in this study? 
Nivolumab will be supplied by Bristol-Myers Squibb at no charge while you take part in this study. The cost of 
getting nivolumab ready and giving it to you is not paid by the study sponsor so you or your insurance company 
may have to pay for this. It is possible that nivolumab may not continue to be supplied while you are on the 
study. Although not likely, if this occurs, your study doctor will talk to you about your options. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs treating your cancer 
while in this study, including the cost of tests, procedures, or medicines to manage any side effects, unless you 
are told that certain tests are provided at no charge. Before you decide to be in the study, you should check with 
your health plan or insurance company to find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell your 
study doctor. 
 
If you are injured as a result of this study, you do not give up your right to pursue a claim through the legal 
system. The study sponsor agrees to pay for the reasonable cost of necessary medical treatment for any physical 
injury or illness that is a direct result of receiving study drug, provided that the study plan was followed, and 
your insurance does not cover the injury services. A study-related injury does not include injuries directly 
caused by any of the following:  any standard of care medical treatments; the natural course of your disease or 
medical condition; or if you or the study staff did not follow the study plan. 
 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. Your information 
may be given out if required by law. For example, certain states require doctors to report to health boards if they 
find a disease like tuberculosis. However, the researchers will do their best to make sure that any information 
that is released will not identify you. Some of your health information, and/or information about your specimen, 


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from this study will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make sure your 
information is kept private, unless required by law to provide information. Some of these organizations are: 
 The study sponsor, RTOG Foundation 
 The drug company supporting the study, Bristol-Meyers Squibb (its current or future research partners, 
collaborators, assignees, licensees or designees and their affiliates, agents, and employees) 
 The Institutional Review Board, IRB, is a group of people who review the research with the goal of 
protecting the people who take part in the study. 
 The Food and Drug Administration in the U.S. and similar ones if other countries are involved in the 
study. 
 
Where can I get more information? 
 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general information 
about cancer. You may also call the NCI Cancer Information Service to get the same information at: 1-800-4-
CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to report side 
effects or injuries. Contact the study [insert name of study doctor] at [insert telephone number]. 
 
For questions about your rights while in this study, or if you have concerns or complaint about the research, 
contact the Western Institutional Review Board (WIRB®) at 1019 39th Avenue SE Suite 120, Puyallup 
Washington 98374-2115, Telephone: 1-800-562-4789 or 360-252-2500, E-mail: Help@wirb.com. 
 
WIRB is a group of people who perform independent review of research.  WIRB will not be able to answer 
some study-specific questions, such as questions about appointment times. However, you may contact WIRB if 
the research staff cannot be reached or if you wish to talk to someone other than the research staff. 
 
 
 
ADDITIONAL STUDIES SECTION: This section is about optional studies you can 
choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in. You will not get 
health benefits from any of these studies. The researchers leading this optional study hope the results will help 
other people with cancer in the future. 
 
The results will not be added to your medical records and  you or your study doctor will not know the results. 
 


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You will not be billed for these optional studies. You can still take part in the main study even if you say “no” 
to any or all of these studies. If you sign up for but cannot complete any of the studies for any reason, you can 
still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
 
Optional Sample Collections for Laboratory Studies and Biobanking for Possible Future 
Studies 
Researchers are trying to learn more about cancer  and other health problems. Much of this research is done 
using samples from your tissue, blood, urine, or other fluids. Through these studies, researchers hope to find 
new ways to prevent, detect, treat, or cure health problems. 
 
Some of these studies may be about genes. Genes carry information about features that are found in you and in 
people who are related to you. Researchers are interested in the way that genes affect how your body responds 
to treatment. 
 
If you choose to take part in this study, the study doctor for the main study would like to collect blood and 
tumor tissue for research on genetic markers of response to the immunotherapy, including activation of the 
immune system. If you choose to take part, blood will be drawn and a sample of tissue from your previous 
biopsy will be collected. Also, if your tumor progresses and you undergo a biopsy, tissue will be collected. 
 
In addition, the researchers ask your permission to store and use your samples and related health information 
(for example, your response to cancer treatment, results of study tests and medicines you are given) for medical 
research. The research that may be done is unknown at this time. Storing samples for future studies is called 
“biobanking”. The Biobank is being run by and supported by the RTOG Foundation. 
 
WHAT IS INVOLVED? 
If you agree to take part, here is what will happen next: 
1) Over five time-points, a total of 10 tablespoons of blood will be collected from a vein in your 
arm:  before treatment, after chemotherapy and radiation, before nivolumab or placebo, 60 days 
after start of nivolumab/placebo, and at the time of progression or severe side effects. In addition, 
a sample from the tissue that was collected at the time of your biopsy will be sent to the Biobank.   
2) Your sample and some related health information will be sent to a researcher for use in the study 
described above. Remaining samples may be stored in the Biobank, along with samples from 
other people who take part. The samples will be kept until they are used up. 
3) For future unspecified research:Your tumor tissue sample and some related health information 
may be stored in the Biobank, along with samples and information from other people who take 
part. The samples will be kept until they are used up. Information from your medical record will 
be updated from time to time. 
4) Qualified researchers can submit a request to use the materials stored in the Biobanks. A science 
committee at the RTOG-Foundation will review each request. There will also be an ethics review 
to ensure that the request is necessary and proper. Researchers will not be given your name or any 
other information that could directly identify you.  
5) Neither you nor your study doctor will be notified when research will be conducted or given 
reports or other information about any research that is done using your samples.  


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6) Some of your genetic and health information may be placed in central databases that may be 
public, along with information from many other people. Information that could directly identify 
you will not be included.  
 
WHAT ARE THE POSSIBLE RISKS? 
1) The most common risks related to drawing blood from your arm are brief pain and possibly a bruise.  
2) There is a risk that someone could get access to the personal information in your medical records or 
other information researchers have stored about you. 
3) There can be a risk in knowing genetic information.  New health information about inherited traits  
that might affect you or your blood relatives could be found during a research study. Even though your 
genes are unique, you share some of the same genes with your blood relatives. Although we are not able 
to know all of the risks from taking part in research on inherited traits, we believe that the risks to you 
and your family are very low, because your samples will be coded. Research results will not be returned 
to you or your doctor. 
 
Very rarely health or genetic information could be misused by employers, insurance companies, and 
others. For example, life insurance companies may charge a higher rate based on this information. 
 
Many states have laws to protect against genetic discrimination. Additionally, a federal law called the 
Genetic Information Non-Discrimination Act, or GINA, is in effect.  This law prohibits health insurer or 
employer discrimination (if the employer has 15 or more employees).  The law does not include other 
types of misuse by life insurance, disability, or long term care insurance. To learn more about the GINA 
Law, please ask the study team.   
 
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE? 
Your privacy is very important to the researchers and they will make every effort to protect it. Here are just a 
few of the steps they will take: 
1) When your sample(s) is sent to the researchers, no information identifying you (such as your name) 
will be sent. Samples will be identified by a unique code only.  
2) The list that links the unique code to your name will be kept separate from your sample and health 
information. Any Biobank and RTOG Foundation staff with access to the list must sign an 
agreement to keep your identity confidential. 
3) Researchers to whom RTOG Foundation sends your sample and information will not know who you 
are. They must also sign an agreement that they will not try to find out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not be used. 
 
WHAT ARE THE POSSIBLE BENEFITS? 
You will not benefit from taking part. The researchers, using the samples from you and others, might make 
discoveries that could help people in the future.  
 
ARE THERE ANY COSTS OR PAYMENTS? 
There are no costs to you or your insurance. You will not be paid for taking part. If any of the research leads to 
new tests, drugs, or other commercial products, you will not share in any profits. 
 


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WHAT IF I CHANGE MY MIND? 
If you decide you no longer want your samples to be used, you can call the study doctor, [insert name of study 
doctor] at [insert telephone number], who will let the researchers know. Then, any sample that remains in the 
bank will no longer be used and related health information will no longer be collectd. Samples or related 
information that have already been given to or used by researchers will not be returned. 
 
WHAT IF I HAVE MORE QUESTIONS? 
If you have questions about the use of your samples for research, contact the study doctor, [insert name of study 
doctor] at [insert telephone number], at _____________________ (insert telephone number of study doctor for 
main trial). 
 
Please circle your answer to show whether or not you would like to take part in each option (include only 
applicable questions): 
 
SAMPLES FOR THE LABORATORY STUDIES: 
I agree to have my specimen collected and I agree that my specimen sample(s) and related information 
may be used for the laboratory study(ies) described above. 
 
 
YES 
 
NO 
 
 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
 
My samples and related information may be kept in a Biobank for use in future health research. 
 
 
YES 
 
NO 
 
I agree that my study doctor, or their representative, may contact me or my physician to see if I wish to 
participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My Signature Agreeing to Take Part in the Main Study 
 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions 
have been answered. I will be given a signed copy of this form. I agree to take part in the main study and any 
additional studies where I circled ‘yes’.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
Signature of person(s) conducting the informed consent discussion___________________________________ 
 
Date of signature____________________________________