Clinical trial NCT03043599
Conditions: Small Cell Lung Cancer Extensive-stage Small Cell Lung Cancer
Keywords: Thoracic Radiotherapy Platinum Based Chemotherapy Immunotherapy Ipilimumab Nivolumab Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC)
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2017-02-13; Completion date: 2023-11-16
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the safety run in Phase I portion of this study is to confirm the recommended Phase II dose of ipilimumab and nivolumab among participants treated with combined thoracic radiation therapy (30 Gy in 10 fractions) and nivolumab/ipilimumab following standard treatment with 4-6 cycles of platinum-based chemotherapy.

The purpose of the Phase II portion of this study is to estimate the 6-month Progression Free Survival (PFS) rate among participants treated with ipilimumab and nivolumab with thoracic radiation therapy (30 Gy in 10 fractions) after standard treatment with 4 to 6 cycles of platinum based chemotherapy.

Detailed description:
This study is a nonrandomized, phase II, single arm, multicenter trial evaluating safety and efficacy of thoracic radiation therapy followed by nivolumab and ipilimumab in participants with Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) who have completed a first-line platinum-based chemotherapy regimen and achieved ongoing complete response (CR), partial response (PR), or stable disease (SD). This study will determine whether nivolumab and ipilimumab delivered 2 weeks following consolidative thoracic radiation therapy demonstrates acceptable toxicity and whether the treatment regimen will improve 6-month progression-free survival (PFS) compared with a similar historical control cohort in this participant population. Additional objectives include further characterization of overall survival, adverse event profile, patterns of failure analysis, and potential predictive biomarkers of response to nivolumab in combination with ipilimumab and thoracic radiation therapy in patients with ED-SCLC.

Arms: arm 1: Consolidative Ipilimumab and Nivolumab with Thoracic Radiotherapy after Platinum Based Chemotherapy. Radiotherapy, followed by a 14 to 21 day break between radiotherapy and the beginning of study drug treatment.
Interventions: intervention 1: Thoracic Radiation Therapy intervention 2: Ipilimumab intervention 3: Nivolumab
Intervention descriptions: intervention 1: All participants will receive radiation therapy (3Gy x 10 fractions) to the chest for 10 days (Monday through Friday for 2 weeks). intervention 2: Ipilimumab 3 mg/kg (90 minute IV infusion) will be administered every 3 weeks for 4 doses. intervention 3: Nivolumab 1 mg/kg (30 minute IV infusion) will be administered every 3 weeks for 4 doses, followed by nivolumab 480 mg every 4 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 Consolidative Ipilimumab and Nivolumab with Thoracic Radiotherapy after 
Platinum Based Chemotherapy for Patients with Extensive-Stage Small Cell Lung 
Cancer 
NCT03043599 
 
Version 9 
June 21, 2019 


1 
 
Protocol Title: Consolidative Ipilimumab and Nivolumab with Thoracic Radiotherapy after 
Platinum Based Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer 
BMS Protocol Number: CA209-840 
Moffitt Protocol Number: MCC 18914 
Principal Investigator:  
 
Bradford A Perez, MD 
Moffitt Cancer Center  
12902 USF Magnolia Dr, Tampa, FL 33612  
Email: bradford.perez@moffitt.org 
Phone: 813-745-4380 
Fax: 813-745-4371 
 
 
Biostatistician:  
Dr. Michael Schell , PhD 
Moffitt Cancer Center 
12902 USF Magnolia Dr, Tampa, FL 33612  
Email: michael.schell@moffitt.org 
Phone: 813-745-6061 
Fax: 813-449-8333 
 
Trial Registration Number: NCT03043599 
 
 
 
Version 9:  06/21/2019 
 
 


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TABLE OF CONTENTS 
Study Synopsis ...................................................................................................................................................... 2 
TABLE OF CONTENTS ...................................................................................................................................... 3 
1 INTRODUCTION .......................................................................................................................................... 8 
 
Study Rationale ................................................................................................................................... 8 
1.1
1.1.1 
Rationale for Investigating First-Line Maintenance Therapy in SCLC .................................... 8 
1.1.2 
Rationale for Immuno-Oncology Therapeutic Approaches in SCLC ........................................ 9 
1.1.3 
Rationale for Nivolumab (1 mg/kg)/Ipilimumab (3 mg/kg) Combination in SCLC .................. 9 
1.1.4 
Rationale for Consolidative Thoracic Radiation Therapy ...................................................... 10 
1.1.5 
Rationale for Omission of Prophylactic Cranial Irradiation .................................................. 11 
1.1.6 
Rationale for Nivolumab/Ipilimumab with Thoracic Radiation Therapy ............................... 11 
1.1.7 
Rationale to Support Nivolumab Monotherapy “Flat” Dose of 480 mg Every 4 Weeks ........ 13 
1.1.8 
Rationale for Permitting Continued Treatment in Select Cases of Progressive Disease ........ 14 
 
Background ....................................................................................................................................... 14 
1.2
1.2.1 
Nivolumab Mechanisms of Action ........................................................................................... 14 
1.2.2 
Ipilimumab Mechanisms of Action .......................................................................................... 15 
1.2.3 
Product Development Background .......................................................................................... 15 
 
Research Hypothesis ......................................................................................................................... 16 
1.3
 
Overall Risk/Benefit Assessment ..................................................................................................... 16 
1.4
2 Objectives ..................................................................................................................................................... 17 
 
Primary Objective ............................................................................................................................. 17 
2.1
2.1.1 
Part 1: Safety Run In Phase I .................................................................................................. 17 
2.1.2 
Part 2: Phase II ....................................................................................................................... 17 
 
Secondary Objectives........................................................................................................................ 17 
2.2
 
Exploratory Objectives ..................................................................................................................... 17 
2.3
3 Ethical Considerations .................................................................................................................................. 18 
 
Good Clinical Practice ...................................................................................................................... 18 
3.1


4 
 
 
Institutional Review Board/Independent Ethics Committee............................................................. 18 
3.2
 
Informed Consent.............................................................................................................................. 18 
3.3
4 Investigational Plan ....................................................................................................................................... 20 
 
Safety Lead in Design ....................................................................................................................... 20 
4.1
 
Phase I/II Study Design and Duration .............................................................................................. 20 
4.2
4.2.1 
Study Phases ............................................................................................................................ 22 
 
Post-Study Access to Therapy .......................................................................................................... 24 
4.3
 
Study Population ............................................................................................................................... 24 
4.4
4.4.1 
Inclusion Criteria .................................................................................................................... 24 
4.4.2 
Exclusion Criteria.................................................................................................................... 27 
4.4.3 
Women of Childbearing Potential ........................................................................................... 30 
 
Concomitant Treatments ................................................................................................................... 30 
4.5
4.5.1 
Prohibited and/or Restricted Treatments ................................................................................ 30 
4.5.2 
Other Restrictions and Precautions ........................................................................................ 31 
4.5.3 
Permitted Therapy ................................................................................................................... 31 
 
Discontinuation of Participants Following Any Treatment with Thoracic Radiation Therapy or 
4.6
Study Drug(s) ................................................................................................................................................ 32 
 
Post-Study Drug Study Follow-up .................................................................................................... 33 
4.7
4.7.1 
Withdrawal of Consent ............................................................................................................ 33 
4.7.2 
Lost to Follow-Up .................................................................................................................... 33 
5 Radiation therapy .......................................................................................................................................... 34 
 
Thoracic Radiation Dose Specifications ........................................................................................... 34 
5.1
 
Radiation Treatment Schedule .......................................................................................................... 34 
5.2
 
Technical Factors .............................................................................................................................. 35 
5.3
5.3.1 
Beam Energy ............................................................................................................................ 35 
5.3.2 
Beam Shaping .......................................................................................................................... 35 
 
Localization, Simulation, and Immobilization.................................................................................. 35 
5.4


5 
 
 
Treatment Planning/Target Volumes ................................................................................................ 35 
5.5
 
Target Volume and Critical Structure Constraints with Compliance Criteria .................................. 37 
5.6
 
Documentation Requirements ........................................................................................................... 38 
5.7
 
Radiation Therapy Quality Assurance Reviews ............................................................................... 39 
5.8
 
Radiation Therapy Adverse Events .................................................................................................. 39 
5.9
5.9.1 
Acute Reactions ....................................................................................................................... 39 
5.9.2 
Late Reactions ......................................................................................................................... 39 
5.9.3 
Treatment of Radiation Adverse Events .................................................................................. 40 
6 Study Drugs .................................................................................................................................................. 40 
 
Investigational Product ..................................................................................................................... 40 
6.1
 
Non-investigational Product ............................................................................................................. 41 
6.2
 
Storage of Study Drug ...................................................................................................................... 41 
6.3
 
Method of Assigning Participant Identification ................................................................................ 41 
6.4
 
Selection and Timing of Dose for Each Participant .......................................................................... 42 
6.5
6.5.1 
Dosing Windows ...................................................................................................................... 43 
6.5.2 
Study Medications.................................................................................................................... 43 
6.5.3 
Dose Modifications and Delays ............................................................................................... 43 
6.5.4 
Management Algorithms for Immuno-Oncology Agents ......................................................... 46 
6.5.5 
Treatment Beyond Disease Progression .................................................................................. 46 
6.5.6 
Treatment of Nivolumab- or Ipilimumab-Related Infusion Reactions .................................... 47 
 
Treatment Compliance ...................................................................................................................... 49 
6.6
 
Destruction or Return of Investigational Product ............................................................................. 49 
6.7
7 STUDY ASSESSMENTS AND PROCEDURES ........................................................................................ 50 
 
Flow Chart/Time and Event Schedule .............................................................................................. 50 
7.1
7.1.1 
Retesting During Screening ..................................................................................................... 57 
 
Study Materials ................................................................................................................................. 57 
7.2
 
Safety Assessments ........................................................................................................................... 58 
7.3


6 
 
7.3.1 
Imaging Assessment for the Study ........................................................................................... 58 
 
Efficacy Assessments........................................................................................................................ 58 
7.4
7.4.1 
Primary and Secondary Efficacy Assessments ........................................................................ 60 
 
Biomarker Assessments .................................................................................................................... 60 
7.5
7.5.1 
Tumor Tissue Specimens ......................................................................................................... 61 
7.5.2 
Characterization of Tumor Infiltrating Lymphocytes (TILS) and Tumor Antigens................. 61 
7.5.3 
DNA and RNA Genomic Assessment ....................................................................................... 61 
7.5.4 
Tumor Sample Collection Details............................................................................................ 61 
7.5.5 
Peripheral Blood Markers ....................................................................................................... 62 
7.5.6 
Single Nucleotide Polymorphisms (SNPs) ............................................................................... 62 
7.5.7 
Serum Soluble Factors............................................................................................................. 62 
7.5.8 
Peripheral Blood Mononuclear Cells ...................................................................................... 62 
7.5.9 
Peripheral Blood DNA and RNA Genomic Assessment .......................................................... 62 
8 ADVERSE EVENTS .................................................................................................................................... 63 
 
Serious Adverse Events .................................................................................................................... 63 
8.1
8.1.1 
Serious Adverse Event Collection and Reporting .................................................................... 64 
 
Nonserious Adverse Events .............................................................................................................. 66 
8.2
8.2.1 
Nonserious Adverse Event Collection and Reporting ............................................................. 66 
 
Laboratory Test Result Abnormalities .............................................................................................. 66 
8.3
 
Pregnancy .......................................................................................................................................... 66 
8.4
 
Overdose ........................................................................................................................................... 67 
8.5
 
Potential Drug-Induced Liver Injury (DILI) ..................................................................................... 67 
8.6
 
Other Safety Considerations ............................................................................................................. 68 
8.7
 
Protocol Monitoring Committee ....................................................................................................... 68 
8.8
9 STATISTICAL CONSIDERATIONS.......................................................................................................... 68 
 
Lead in Safety Observation ............................................................................................................... 68 
9.1
 
Phase I/II Sample Size Determination .............................................................................................. 69 
9.2


7 
 
9.2.1 
Accrual Justification ................................................................................................................ 69 
 
Populations for Analyses - Data Set Descriptions ............................................................................ 69 
9.3
 
Endpoints .......................................................................................................................................... 70 
9.4
9.4.1 
Primary Endpoints ................................................................................................................... 70 
9.4.2 
Secondary Endpoint ................................................................................................................. 70 
9.4.3 
Exploratory Endpoints ............................................................................................................. 71 
 
Analyses ............................................................................................................................................ 71 
9.5
9.5.1 
Demographics and Baseline Characteristics .......................................................................... 71 
9.5.2 
Efficacy Analyses ..................................................................................................................... 71 
9.5.3 
Safety Analyses ........................................................................................................................ 71 
10 
STUDY MANAGEMENT ..................................................................................................................... 72 
 
Compliance ....................................................................................................................................... 72 
10.1
10.1.1 
Compliance with the Protocol and Protocol Revisions ........................................................... 72 
10.1.2 
Monitoring ............................................................................................................................... 72 
10.1.3 
Source Documentation ............................................................................................................ 72 
 
Records ............................................................................................................................................. 73 
10.2
10.2.1 
Records Retention .................................................................................................................... 73 
10.2.2 
Study Drug Records ................................................................................................................. 73 
10.2.3 
Case Report Forms .................................................................................................................. 73 
 
Clinical Study Report and Publications ............................................................................................ 74 
10.3
11 
List of Abbreviations .............................................................................................................................. 74 
12 
tsh ............................................................................................................. Error! Bookmark not defined. 
13 
References ............................................................................................................................................... 80 
14 
Appendix 1: Study Calendar ................................................................................................................... 83 
15 
Appendix 2: Management Algorithms for Immune Adverse Events ..................................................... 85 
 
 
 
 
 


8 
 
1 INTRODUCTION 
MCC18914 is a nonrandomized, phase II, single arm, multicenter trial evaluating safety and efficacy of 
thoracic radiation therapy followed by nivolumab and ipilimumab in participants with Extensive-Stage Disease 
Small Cell Lung Cancer (ED-SCLC) who have completed a first-line platinum-based chemotherapy regimen 
and achieved ongoing complete response (CR), partial response (PR), or stable disease (SD). This study will 
determine whether nivolumab and ipilimumab delivered 2 weeks following consolidative thoracic radiation 
therapy demonstrates acceptable toxicity and whether the treatment regimen will improve 6-month 
progression-free survival (PFS) compared with a similar historical control cohort in this participant population.  
Additional objectives include further characterization of overall survival, adverse event profile, patterns of 
failure analysis, and potential predictive biomarkers of response to nivolumab in combination with ipilimumab 
and thoracic radiation therapy in patients with ED-SCLC. 
 Study Rationale 
1.1
1.1.1 Rationale for Investigating First-Line Maintenance Therapy in SCLC  
SCLC accounts for 15 to 20% of new cases of lung cancer and is associated with poor outcomes. SCLC is 
traditionally classified as Limited Stage Disease (LD-SCLC: TNM stages I to IIIB) and Extensive Stage 
Disease (ED-SCLC: TNM stage IV with distant metastases (M1) including malignant pleural effusions). For 
LD-SCLC, a combined therapeutic approach of radiotherapy, chemotherapy and (rarely) surgery is used with 
curative intent[1]. Most patients at diagnosis have ED-SCLC and are treated with four to six cycles of etoposide 
plus platinum-based therapy (EP), which remains the standard chemotherapy regimen for LD- and ED-
SCLC[2]. Overall survival (OS) remains poor with median survival for LD-SCLC at 18 to 30 months[3] and for 
ED-SCLC in the range of 9 to 12 months[4-7]. Despite high initial response rates, in particular in patients with 
ED-SCLC, the disease does recur or progress rapidly after completion of chemotherapy, with median PFS of 
only 2-3 months[7, 8]. A Dutch randomized phase III of patients with ED-SCLC treated with thoracic radiation 
therapy following EP reported a significant improvement in PFS at 6 months (24% vs 7%, HR 0.73) and a 
significant improvement in 2 year OS (13% vs 3%, p=0.004) with the addition of thoracic radiation therapy[5]. 
There are no other established standard of care treatments for subjects with ED-SCLC who complete first line 
therapy with EP and have achieved stable disease or response. In a phase 3 trial of topotecan versus observation, 
topotecan did not show an OS prolongation for SCLC patients after completion of EP[8]. Recently, sunitinib 
showed an improved PFS in a Phase 2 trial of sunitinib vs placebo in SCLC patients after completion of EP[7]. 
Despite the extensive chemotherapy regimens administered to ED-SCLC patients, approximately 75-90% of 
patients have persistent intrathoracic disease and though consolidative RT alone to the residual thoracic disease 
can improve time to progression in the thorax, 2 year OS is still only 13% among patients treated with TRT [5]. 
This underscores the need for more effective treatment options in this devastating malignancy. 
Considering the short median OS for patients who have completed first line platinum-based treatment, as well 
as the even shorter PFS experienced in this disease, new treatments complementary to SCLC standard first-
line platinum-based treatment are required. 


9 
 
1.1.2 Rationale for Immuno-Oncology Therapeutic Approaches in SCLC 
SCLC has classically been associated with immune-mediated paraneoplastic processes, such as cerebellar 
degeneration, limbic encephalitis and Lambert-Eaton myasthenic syndrome [9]. For example, antibodies 
generated against human neuronal RNA-binding proteins (e.g. Hu), which are expressed on neurons and SCLC 
tumors, leads to an encephalomyelitis [10]. Interestingly, SCLC patients that present with these ‘early’ 
paraneoplastic syndromes have a more favorable prognosis [11, 12], suggesting that an underlying immune 
response is being generated against these onconeural antigens.  
Proof of an active immune environment in SCLC has been described in a few analyses of patient samples. First, 
analysis of sixty-four SCLC tumors demonstrated that a wide range of CD45+ cells infiltrated the tumor, an 
average of 40 immune cells/field, and that high CD45+ counts were associated with a better prognosis [13]. 
Secondly, a separate study found that various tumor-infiltrating lymphocyte (TIL) subsets were present in 
SCLC brain metastases and that programmed death ligand 1 (PD-L1) was heterogeneously expressed [14]. 
Finally, evaluation of peripheral blood cells in 35 SCLC patients demonstrated a high CD4+ effector T cell to T 
regulatory (Treg) cell ratio in patients with LD-SCLC vs. ED-SCLC [15]. This implies that in some respect, 
SCLC pathology integrates with the immune response.  
Furthermore, SCLC is known to have one of the highest mutational loads [16], which is thought to be a 
reflection of myriad insults inflicted by carcinogens from smoking. Additionally, comprehensive genomic 
profiling of SCLC tumors has identified that the vast majority lack functional p53 (90%) and Rb1 (65%) [17]. 
This universal genetic aberration facilitates poor genomic stability [18], thus perpetuating the generation of 
tumor-associated antigens (TAAs). Interestingly, recent studies have highlighted that the clinical efficacy of 
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade in melanoma 
and non-small cell lung cancer (NSCLC), respectively, are partially driven by the mutational burden of the 
tumor and the presence of neoantigens [19, 20]. Thus, the high mutational burden in SCLC may facilitate 
enhanced immune recognition. Though SCLC pathology appears to be intertwined with the immune response 
and is predisposed by a substantial mutational load, prior evidence indicates that major histocompatibility 
complex (MHC) surface expression is reduced in SCLC [21, 22], which may preclude robust immune 
recognition.   
These data support the notion that there is an active immune microenvironment within primary and metastatic 
SCLC lesions. Finally, a phase I/II non-randomized trial (CheckMate 032) evaluated nivolumab with or without 
ipilimumab in LD-SCLC/ED-SCLC patients that failed platinum-based therapy. This study reported a response 
rate of 23% at the most efficacious dose level of ipilimumab 3mg/kg and nivolumab 1mg/kg. This study also 
reported a tolerable safety profile for patients treated at the aforementioned dose level. Considering the immune 
response seen in SCLC patients, and the results of early phase studies utilizing checkpoint inhibitors nivolumab 
and ipilimumab in SCLC patients in later treatment lines, it is reasonable to expect that nivolumab and 
ipilimumab combination therapy are likely to also provide benefit as first line maintenance therapy in SCLC. 
 
1.1.3 Rationale for Nivolumab (1 mg/kg)/Ipilimumab (3 mg/kg) Combination in SCLC 
In a phase I/II study of nivolumab and nivolumab/ipilimumab for treatment of recurrent SCLC (CA209032), 
participants who were platinum sensitive or refractory and had progressive disease were enrolled regardless of 


10 
 
tumor PD-L1 status or number of prior chemotherapy regimens [23]. This open-label study randomized 
participants to nivolumab 3 mg/kg IV every 2 weeks or nivolumab + ipilimumab (1 + 1 mg/kg, 1 + 3 mg/kg or 3 
+ 1 mg/kg) IV every 3 weeks for 4 cycles followed by nivolumab 3 mg/kg every 2 weeks. The primary 
objective was objective response rate. Other objectives were safety, PFS, OS and biomarker analysis.  
All participants had prior platinum-based first-line treatment and progression after the most recent treatment 
regimen. Baseline characteristics were typical for a SCLC population with respect to age, smoking history, and 
gender.  
Safety. While the incidence of drug-related adverse events (AEs) in the nivolumab 1 mg kg/ipilimumab 3 
mg/kg cohort (79% any grade, 30% grade 3-4) was higher than in the nivolumab monotherapy group (53% any 
grade, 13% grade 3-4), the treatment discontinuation rate for treatment-related AEs was only 11% (nivolumab 1 
mg/kg / ipilimumab 3 mg/kg): 5 patients with diarrhea, myasthenia gravis [subsequently developing 
complications with fatal outcome], pneumonitis, cardiomyopathy, and 1 patient with hypothyroidism, 
hyperglycemia, and increased ALT levels).  
The most frequent (≥10%, any grade) drug-related AEs were diarrhea, fatigue, rash, pruritus, hypothyroidism, 
rash maculo-papular, nausea, hyperthyroidism, and increased lipase levels. One treatment-related death in the 
nivolumab 1 mg/kg / ipilimumab 3 mg/kg cohort occurred. This participant developed myasthenia gravis 
(reported as grade 4) after treatment start and suffered from complications resulting in death. Limbic 
encephalitis was reported in 3 participants, which resolved with immunosuppressive treatment in 2 cases. 
Another participant had a minor response to immunosuppressive treatment and eventually died due to the 
underlying tumor disease. 
Efficacy. Patients treated at the recommended phase III dose of ipilimumab 3mg/kg and nivolumab 1mg/kg 
(n=61) were noted to have an overall response rate (ORR) of 23%, and the disease control rate (CR + PR + SD) 
was 44%. Objective responses were long lasting, with a median duration of response of 7.7 months in the 
nivolumab 1mg/ipilimumab 3 mg combination group. The median PFS was 2.6 months (95% CI: 1.4, 4.1) The 
median OS was 7.7 months (95% CI: 3.6, 18) in the nivolumab 1 mg /ipilimumab 3 mg combination group, 
which compares favorably with historical controls [8].  There is an ongoing phase III randomized, placebo-
controlled study (CA209-451) evaluating PFS and OS among patients with ED-SCLC with at least stable 
disease after 4 cycles of EP chemotherapy.  More than 800 patients are to be randomized to placebo, nivolumab 
240 mg delivered every 2 weeks, or ipilimumab 3 mg + nivolumab 1 mg combination therapy for 4 cycles 
followed by nivolumab 240 mg every 2 weeks until progression. Patients will be carefully monitored on this 
protocol, and we expect results from our study with comparable inclusion criteria to be available in the coming 
years.   
1.1.4 Rationale for Consolidative Thoracic Radiation Therapy 
In a phase III study of consolidative thoracic radiation therapy for treatment of patients with ED-SCLC in the 
first line, participants who had any response to systemic 4-6 cycles of EP chemotherapy were enrolled in a 
randomized fashion to either no further treatment or to receive a 30-Gy dose of radiation delivered in 10 daily 
fractions to any residual intrathoracic disease including all initially involved hilar and mediastinal lymph node 
stations[5].  All patients also received prophylactic cranial irradiation as part of the study protocol. Baseline 
characteristics were typical for a SCLC population with respect to age, smoking history, and gender.  


11 
 
Safety. Consolidative thoracic radiation therapy was well tolerated in the above study. Ninety-five percent of 
patients completed the protocol-specified radiation therapy without interruption, with only 1 patient 
discontinuing treatment.  The rate of grade 3 and higher toxic effects was only 10.5% compared with 7.2% in 
the control arm that received no thoracic radiation therapy.  The incidence of grade 3 dyspnea or cough was 
only 1.2% in the thoracic radiation therapy group. 
Efficacy. The multi-center study from Slotman et al. described above enrolled 498 patients.  The study reported 
a significant improvement in PFS at 6 months (24% vs 7%, HR 0.73) and a significant improvement in 2-year 
OS (13% vs 3%, p=0.004) with the addition of TRT. Another randomized study by Jeremic et al., which 
included 206 patients with ED-SCLC who were treated with 3 cycles of EP, reported complete response at 
distant sites and at least a partial response in the chest [6]. Patients were randomized to thoracic radiation 
therapy with low-dose chemotherapy versus chemotherapy alone for 4 additional cycles. Patients who received 
thoracic radiation therapy reported significantly increased OS compared with chemotherapy alone (median 17 
vs 11 months, 5-year OS of 9% vs 4%). 
1.1.5 Rationale for Omission of Prophylactic Cranial Irradiation 
Prophylactic cranial irradiation (PCI) remains controversial for patients with ED-SCLC.  One randomized 
controlled study evaluating the efficacy of PCI by Slotman et al. demonstrated a survival benefit with treatment. 
In that study, the hazard ratio for death was 0.68 (95% CI, 0.52-0.88) [24].  One major criticism of the study 
design is that brain imaging was not part of the standard staging or follow-up procedures unless neurologic 
symptoms were present.  Given the high incidence of clinically undetected brain metastases, presumably some 
magnitude of benefit seen in this study could be attributable to treatment of patients with clinically undetected 
brain metastases.   
Another more recent Japanese phase III randomized study evaluating the role of PCI in patients with ED-SCLC 
did enroll patients to determine whether PCI (25 Gy in 10 fractions) could affect survival [25]. In this study, 
brain MRI was required prior to initiation of PCI, and all patients who did not receive PCI underwent brain MRI 
every 3 months while enrolled on the study.  The study reported a non-significant trend toward longer survival 
in patients who did not receive PCI (15.1 months in the control group vs. 10.1 months in the PCI group; 
P=0.09).  On the basis of an interim analysis with these findings, the study was terminated for futility.  Because 
patients in this study will undergo repeat staging with MRI brain prior to study enrollment after EP 
chemotherapy, we will not allow PCI.  
Finally, recent studies suggest that anti-PD-1 therapy may penetrate the blood brain barrier to treat brain 
metastases in patients with NSCLC[26].  Among 11 NSCLC patients with untreated brain metastases, the brain 
metastasis response rate was 45% in the absence of any radiation therapy or surgical intervention.  The duration 
of response was at least 12 weeks for 4 of 5 responders.   This data suggests that treatment with immune 
checkpoint therapy as part of our clinical protocol may help to further reduce the incidence of clinically relevant 
brain metastases in patients with ED-SCLC.    
1.1.6 Rationale for Nivolumab/Ipilimumab with Thoracic Radiation Therapy  
The excellent response rates and OS rates with combined immune checkpoint blockade in the second line 
treatment of ED-SCLC outlined in Section 1.1.3 demonstrates that the immune system is actively involved in 


12 
 
SCLC tumor pathology. However, these responses are somewhat limited to patients that have preexisting T 
cells primed to target the tumor. Radiation therapy (RT) by itself has demonstrated clinical efficacy in multiple 
malignancies, including SCLC, by improving tumor control with limited toxicity and evolving evidence 
suggests RT may be a promising modality to combine with immunotherapy to amplify the immune response 
[27].  
Cancer cells treated with noxious stimuli (e.g. chemotherapy or RT) undergo various forms of cell death, which 
results in differential antigenic presentation and clearance by the host [28]. Accumulating evidence indicates 
that RT can trigger an additional type of cellular demise termed immunogenic cell death (ICD) [29]. ICD is 
characterized by cell surface presentation and release of cryptic antigens, which have been termed danger-
associated molecular patterns (DAMPs), into the surrounding tumor microenvironment [30]. RT-induced 
DAMP exposure has been demonstrated in various models in vitro and in vivo and is emerging as a therapeutic 
approach to increase the immune response. Prior studies have demonstrated that cancer cells that were treated 
with RT were able to prime a durable immune response to phenotypically similar cells when challenged in the 
opposite flank of a mouse [31]; this effect was found to be dependent on induced DAMP exposure. RT has also 
been found to increase MHC I expression [32], increase ligands that promote immune activity and enhance the 
profile of inflammatory soluble mediators in the tumor microenvironment [33].  Thus, it is hypothesized that RT 
is inducing an in situ vaccine of the targeted tumor and is aiding in overcoming the immunosuppressive 
environment.  
In addition to the tumor targeted with RT, a burgeoning amount of evidence indicates tumors outside of the 
radiation field are also affected by the generation of this locally produced in situ vaccine. This phenomenon, 
though rare, is termed the abscopal effect and is thought to be mediated by the immune system [34]. This was 
first demonstrated in irradiated lung cancer cells which were inoculated into the footpads of mice followed by 
treatment with a dendritic cell (DC) growth factor; this study identified that the combination of immune 
stimulation and RT led to regression of pulmonary metastases, which were outside the irradiated field, and this 
was dependent on an intact immune system [35]. These findings were confirmed in other model systems [36, 
37] and subsequent studies demonstrated that RT also increases T cell expansion, DC activation and cytokine 
release [38].  
Though RT alone changes the antigen repertoire of the treated tumor and influences the distribution of immune 
effector cells, clinically this is not sufficient to maintain robust local responses and is unable to induce the 
abscopal effect in the majority of scenarios. Therefore, investigators have begun to combine RT with immune 
checkpoint blockade to create synergism between two highly effective tumor controlling modalities. This was 
first examined by combining RT with CTLA-4 blockade in a breast cancer model, which demonstrated that 
combination treatment compared to either alone resulted in improved local and distant control of the tumor 
burden [39]. Also, PD-1 deficient mice or PD-1 blockade lead to an abscopal effect in melanoma and renal cell 
cancer models [40]. Importantly, these preclinical findings have demonstrated merit in clinical studies. The 
abscopal effect has been recognized in combination with CTLA-4 blockade in melanoma [41] and NSCLC [42]. 
A recent retrospective study of melanoma patients also identified that RT + ipilimumab resulted in almost a 
doubling of OS and abscopal events were present in about 20% of patients [43].  The results of these clinical 
findings are encouraging and improved outcomes are likely as a more thorough understanding of the 
relationship between RT and immunotherapy evolves.   


13 
 
The organ(s) at risk in the treatment region must also be taken into consideration when combining RT with 
immunotherapy. In the setting of consolidative thoracic radiation therapy for SCLC, the most critical structure 
is the normal surrounding lung. This is important as both RT and immunotherapy separately have been shown 
to cause pneumonitis. Preclinical data of partial volume lung RT in rats revealed cytokine and immune cell 
responses were initiated at 1 hr following treatment and cyclic patterns of these responses were sustained up to 
sixteen weeks [44]. How these inflammatory responses induced by RT in the lung influence toxicity with 
immunotherapy are not known, but clinical data suggests that RT combined with immunotherapy may not lower 
the tolerance of the lung too drastically.  
A retrospective study evaluating 16 patients with NSCLC who were prospectively enrolled in a phase 2 trial 
with phased ipilimumab and chemotherapy identified that adjuvant RT did not lead to any grade ≥ 3 toxicity 
[45]. Additionally, NSCLC patients that received RT followed by nivolumab [46] or a single patient in a case 
report who received concurrent RT and ipilimumab [42] did not have increased lung toxicity. Finally, a recent 
retrospective report of melanoma patients also indicated that patients that received RT before, during or after 
ipilimumab had no increased toxicity in the lung [43]. Combining RT, which can instigate a robust immune 
response, with checkpoint inhibition may provide synergism in immune-mediated destruction of SCLC tumors. 
By treating intrathoracic disease with consolidative RT after standard of care chemotherapy, the targeted tumor 
burden will be low and this may be the optimal time to amplify synergism between RT and immunotherapy. 
1.1.7 Rationale to Support Nivolumab Monotherapy “Flat” Dose of 480 mg Every 4 
Weeks 
Nivolumab monotherapy has been extensively studied in NSCLC patient populations and in other solid tumor 
indications with body weight-normalized dosing (mg/kg). Nivolumab pharmacokinetics (PK) and exposures of 
participants in these studies have been characterized by population pharmacokinetic (PPK) analysis of data 
collected in these studies, together with PK data from several phase I, II, and III 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 patients, relative to 
the exposures in lighter patients. It should be noted that a dose of 480 mg nivolumab across typical body 
weights leads to peak nivolumab concentrations that are less than 10mg/kg which has been previously shown to 
be safe and well tolerated across multiple clinical studies.  Based on clinical modeling and simulation 
approaches using population PK (PPK) and exposure analyses of data from studies in multiple tumor types, a 
dose of 480mg delivered every 4 weeks is expected to be similarly efficacious compared to previously utilized 
dose strategies including 3mg/kg delivered every 2 weeks or 240mg flat dose delivered every 2 weeks.  
Nivolumab monotherapy has been extensively studied in multiple tumor types with body weight normalized 
dosing (mg/kg). 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 was 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. Flat dosing is expected to reduce prescription 
dosing errors, shorten pharmacy preparation time, and improve ease of administration. Extending the dosing 
interval to 4 weeks provides numerous benefits to patients including increased flexibility between clinical visits, 


14 
 
as compared to a 2 week dosing schedule. A flat dose of 480 mg every 4 weeks was selected based on 
equivalence to the approved 3 mg/kg every 2 weeks at the median body weight of ~ 80 kg in nivolumab-treated 
subjects. A PPK model predicted overall nivolumab average exposures across subjects with a wide range of 
body weight from 480 mg Q4W to be similar to that from 3 mg/kg Q2W. Although the flat dose is expected to 
lead to higher exposure in lighter patients relative to the exposure in heavier patients given the relationship 
between nivolumab PK and body weight, the predicted median and 95th percentile of exposures are maintained 
below those in 10 mg/kg every 2 weeks, which was established as a safe and well-tolerated dose across multiple 
tumor types. There was no clinically meaningful relationship between nivolumab exposure or body weight and 
frequency or severity of adverse events. Therefore, a flat dose of 480 mg every 4 weeks is expected to be safe 
and tolerable in patients. In terms of efficacy, 480 mg every 4 weeks is expected to result in similar efficacy 
given a flat exposure-response relationship and same dose intensity. Overall, the benefit-risk profile of 
nivolumab 480 mg Q4W is expected to be similar to the approved regimen 3 mg/kg Q2W, and it is 
recommended for further investigation in this study.  Additionally, this simplified dose strategy will limit the 
number of visits and overall treatment administration inconvenience.    
Taken together, the PK, safety, and efficacy data indicate that the safety and efficacy profile of 480 mg 
nivolumab every 4 weeks will be similar to that of 3 mg/kg nivolumab every 2 weeks. Based on these clinical 
results, a flat dose of 480 mg every 4 weeks will be utilized for the maintenance dosing following completion of 
nivolumab/ipilimumab combination. 
1.1.8 Rationale for Permitting Continued Treatment in Select Cases of Progressive 
Disease 
Accumulating clinical evidence indicates some patients treated with immune system stimulating agents may 
develop progression of disease (by conventional response criteria) before demonstrating clinical objective 
responses and/or stable disease. This phenomenon was observed in a phase I study of nivolumab [47] and also 
in combination with ipilimumab [48]. Two hypotheses have been put forth to explain this phenomenon. First, 
enhanced inflammation within tumors could lead to an increase in tumor size, which would appear as enlarged 
index lesions and as newly visible small non-index lesions. Over time, both the malignant and inflammatory 
portions of the mass may then decrease leading to overt signs of clinical improvement. Alternatively, in some 
individuals, the kinetics of tumor growth may initially outpace anti-tumor immune activity. 
With sufficient time, the anti-tumor activity will dominate and become clinically apparent. Therefore 
participants will be allowed to continue study therapy after initial investigator-assessed Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1)-defined progression if they are assessed to be deriving clinical benefit 
and tolerating study drug. Such participants must discontinue study therapy upon evidence of further 
progression. 
 Background 
1.2
1.2.1 Nivolumab Mechanisms of Action 
Nivolumab is a fully humanized, IgG4 (kappa) isotype monoclonal antibody (mAb) that binds PD-1 on 
activated immune cells and disrupts engagement of the receptor with its ligands PD-L1 (B7-H1/CD274) and 
PD-L2 (B7-DC/CD273), thereby abrogating inhibitory signals and augmenting the host antitumor response. PD-


15 
 
1, (CD279), a 55-kDa type I transmembrane protein, is a member of the CD28 family of T-cell co-stimulatory 
receptors that also includes CD28, CTLA 4, ICOS, and BTLA. PD-1 contains an intracellular membrane 
proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal immunoreceptor tyrosine-
based switch motif (ITSM). Two ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and 
PD L2 (B7-DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T cell activation on binding to 
PD-1 in both murine and human systems. PD-1 delivers a negative signal by the recruitment of SHP-2 to the 
phosphorylated tyrosine residue in the ITSM in its cytoplasmic region. PD-1 is primarily expressed on activated 
T cells, B cells, and myeloid cells. Further evidence for a negative regulatory role of PD-1 comes from studies 
of PD-1-deficient mice. PD 1-deficient mice develop various autoimmune phenotypes, including dilated 
cardiomyopathy, a lupus-like syndrome with arthritis and nephritis, and accelerated diabetes mellitus. The 
emergence of these autoimmune phenotypes is dependent on the genetic background of the mouse strain, and 
many of these phenotypes emerge at different times and show variable penetrance. In addition to the phenotypes 
of null mutations, PD-1 inhibition by antibody-mediated blockade in several murine models has been found to 
play a role in the development of autoimmune diseases such as encephalomyelitis, graft-versus-host disease, 
and type I diabetes. Taken together, these results suggest that PD-1 blockade has the potential to activate anti-
self T-cell responses, but these responses are variable and dependent on various host genetic factors. Thus, PD-
1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self-antigens. 
Preclinical animal models of tumors have shown that blockade by PD-1 by mAbs can enhance the anti-tumor 
immune response and result in tumor rejection. Antitumor activity by PD-1 blockade functions in PD-L1-
positive tumors as well as in tumors that are negative for the expression of PD-L1. This suggests that host 
mechanisms (i.e., expression of PD-L1 in antigen-presenting cells) limit the antitumor response. Consequently, 
both PD-L1 positive and negative tumors may be targeted using this approach. In humans, constitutive PD-L1 
expression is normally limited to macrophage-lineage cells, although expression of PD-L1 can be induced on 
other hematologic cells as well, including activated T cells. However, aberrant expression of PD-L1 by tumor 
cells has been reported in a number of human malignancies. PD-L1 expressed by tumor cells has been shown to 
enhance apoptosis of activated tumor-specific T cells in vitro. Moreover, the expression of PD-L1 may protect 
the tumor cells from the induction of apoptosis by effector T cells. Additional details are available in the 
Nivolumab Investigator Brochure.  
 
1.2.2 Ipilimumab Mechanisms of Action 
Ipilimumab is a fully humanized,  IgG1 (kappa) isotype mAb that binds to the CTLA-4 antigen expressed on a 
subset of T cells from human and nonhuman primates. CTLA-4 is a negative regulator of T-cell activity. 
Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of 
CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and 
proliferation of TILs. Inhibition of CTLA-4 signaling can also reduce Treg cell function, which may contribute 
to a general increase in T-cell responsiveness, including the anti-tumor response. 
1.2.3 Product Development Background 
Nivolumab is in clinical development for the treatment of patients with NSCLC, RCC, glioblastoma, and other 
cancer types. Recently, nivolumab was approved by the FDA for the treatment of patients with advanced 


16 
 
NSCLC and melanoma. Nivolumab is also approved for the treatment of advanced melanoma in Europe, Japan, 
and other countries. 
In the phase I/II trial (CA209-032), in participants with heavily pretreated SCLC, nivolumab monotherapy 
showed an ORR of 10%, whereas the combination of nivolumab-1 and ipilimumab-3 demonstrated an ORR of 
30% [23]. Study CA209-451 is the second phase III study in the clinical development program for nivolumab in 
SCLC and will evaluate the efficacy and safety of nivolumab monotherapy and nivolumab and ipilimumab 
combination therapy, as maintenance treatment following first line platinum-based chemotherapy in patients 
with ED-SCLC. 
 Research Hypothesis 
1.3
For patients with ED-SCLC and at least stable disease after 4 to 6 cycles of platinum-based chemotherapy, we 
hypothesize that ipilimumab and nivolumab with thoracic radiation therapy (30 Gy in 10 fractions) will improve 
6-month PFS by at least 20% compared with a 6-month historical PFS rate of 24% among patients treated in a 
similar fashion without combined checkpoint blockade [5]. 
 Overall Risk/Benefit Assessment 
1.4
ED-SCLC is a disease with high unmet medical need. Despite robust initial response rates to first-line platinum-
containing chemotherapy regimens, subsequent progression is typically rapid and overall survival rates are 
poor. Furthermore, there are currently no systemic agents approved in the maintenance setting for patients who 
respond to first-line therapy. The clinical activity of nivolumab and ipilimumab combination therapy, observed 
in the CA209-032 study, suggests the potential for improved clinical outcomes relative to a current standard 
practice of consolidative thoracic radiation therapy without nivolumab and ipilimumab combination therapy.  
Furthermore, thoracic radiation therapy delivered in close proximity to the nivolumab and ipilimumab 
combination therapy may lead to improved systemic anti-tumor response with the use of combined checkpoint 
blockade. 
Nivolumab in combination with ipilimumab can cause clinically relevant AEs, including liver toxicities, 
thyroiditis, pneumonitis, and diarrhea. Most concerning when delivering the combination in conjunction with 
thoracic radiation therapy is the risk of clinically significant pneumonitis.  We plan to carefully evaluate safety 
and tolerability of the proposed study regimen with a 6-9 patient safety lead in phase and a 13-week safety 
observation period prior to proceeding with our phase II study.  Furthermore, completion of this single-arm 
phase II study will not only provide robust efficacy estimates but also robust safety data to help guide the design 
of future phase III randomized controlled trials for first-line treatment of patients with ED-SCLC. 
 


17 
 
2 OBJECTIVES 
 Primary Objective 
2.1
2.1.1 Part 1: Safety Run In Phase I 
The safety run in phase I is to confirm the recommended phase II dose of ipilimumab and nivolumab among 
patients treated with combined thoracic radiation therapy (30 Gy in 10 fractions) and nivolumab/ipilimumab 
following standard treatment with 4-6 cycles of platinum-based chemotherapy.   
2.1.2 Part 2: Phase II 
Phase II objective is to estimate the 6-month PFS rate among patients treated with ipilimumab and nivolumab 
with thoracic radiation therapy (30 Gy in 10 fractions) after standard treatment with 4 to 6 cycles of platinum-
based chemotherapy.  
 
 Secondary Objectives 
2.2
1. To estimate the median PFS among patients treated with ipilimumab and nivolumab with thoracic 
radiotherapy (30 Gy in 10 fractions) after standard treatment with 4-6 cycles of platinum-based 
chemotherapy. 
2. To estimate 1-year OS rate among patients treated with ipilimumab and nivolumab with thoracic 
radiotherapy after standard treatment with 4-6 cycles of platinum-based chemotherapy. 
3. To estimate median OS among patients treated with ipilimumab and nivolumab with thoracic radiotherapy 
after standard treatment with 4-6 cycles of platinum-based chemotherapy. 
 
 Exploratory Objectives 
2.3
1. To document and explore patterns of radiographic response and progression both inside and outside the 
treated radiotherapy field. 
2. To bank and store formalin-fixed, paraffin-embedded diagnostic tumor biopsy specimens for future 
potential predictive and/or prognostic biomarkers. 
3. To bank and store peripheral blood specimens for future rigorous evaluation of future potential predictive 
and/or prognostic biomarkers.   
 


18 
 
3 ETHICAL CONSIDERATIONS 
 Good Clinical Practice 
3.1
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the International 
Conference on Harmonisation (ICH) and in accordance with the ethical principles underlying European Union 
Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) and 
applicable local requirements. The study will be conducted in compliance with the protocol. The protocol and 
any amendments and the participant informed consent will receive Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study. All potential serious 
breaches must be reported to Moffitt Cancer Center through the MCRN Coordinating Center immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the participants of 
the study or the scientific value of the study.  
Personnel involved in conducting this study will be qualified by education, training, and experience to perform 
their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
 
 Institutional Review Board/Independent Ethics Committee 
3.2
Before study initiation, the investigator must have written and dated approval/favorable opinion from the 
IRB/IEC for the protocol, consent form, participant recruitment materials (eg, advertisements), and any other 
written information to be provided to participants. The investigator should also provide the IRB/IEC with a 
copy of the Investigator Brochure or product labeling information to be provided to participants and any 
updates. The investigator should provide the IRB/IEC with reports, updates, and other information (eg, 
expedited safety reports, amendments, and administrative letters) according to regulatory requirements or 
institution procedures. 
 
 Informed Consent 
3.3
Investigators must ensure that participants are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which they volunteer to participate. In situations where consent 
cannot be given to participants, their legally acceptable representatives (as per country guidelines) are clearly 
and fully informed about the purpose, potential risks, and other critical issues regarding clinical studies in which 
the patient volunteers to participate. The main site study team will provide the investigator with an appropriate 
sample informed consent form, which will include all elements required by ICH, GCP, and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles that have their 
origin in the Declaration of Helsinki. 


19 
 
Investigators must:  
1. Provide a copy of the consent form and written information about the study in the language in which the 
participant is most proficient prior to clinical study participation. The language must be non-technical and 
easily understood. 
2. Allow time necessary for participant or participant's legally acceptable representative to inquire about the 
details of the study. 
3. Obtain an informed consent signed and personally dated by the participant or the participant's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form and any 
other information to be provided to the participants, prior to the beginning of the study, and after any 
revisions are completed for new information. 
5. If informed consent is initially given by a participant’s legally acceptable representative or legal guardian, 
and the participant subsequently becomes capable of making and communicating his or her informed 
consent during the study, consent must additionally be obtained from the participant. 
6. Revise the informed consent whenever important new information becomes available that is relevant to the 
participant's consent. The investigator, or a person designated by the investigator, should fully inform the 
participant or the participant's legally acceptable representative or legal guardian, of all pertinent aspects of 
the study and of any new information relevant to the participant's willingness to continue participation in the 
study. This communication should be documented. 
The confidentiality of records that could identify participants must be protected, respecting the privacy and 
confidentiality rules applicable to regulatory requirements, the participant's signed ICF and, in the US, the 
participant’s signed HIPAA Authorization. 
The consent form must also include a statement that the study sponsor, Moffitt Cancer Center, BMS and 
regulatory authorities have direct access to patient records. Participants unable to give their written consent 
(e.g., stroke or participants with severe dementia) may only be enrolled in the study with the consent of a legally 
acceptable representative. The participant must also be informed about the nature of the study to the extent 
compatible with his or her understanding, and should this participant become capable, he or she should 
personally sign and date the consent form as soon as possible. The explicit wish of a participant who is unable 
to give his or her written consent, but who is capable of forming an opinion and assessing information to refuse 
participation in, or to be withdrawn from, the clinical study at any time should be considered by the 
investigator. 
The rights, safety, and well-being of the study participants are the most important considerations and should 
prevail over interests of science and society. 
 
 


20 
 
4 INVESTIGATIONAL PLAN 
The principal investigator is ultimately responsible for appropriate study coordination.   
 Safety Lead in Design 
4.1
All patients for the entire study will be treated on the same schedule outlined in Section 4.2. We will utilize a 6 
to 9 patient safety lead in endpoint as described in the Section 9.1 with a safety observation period of 13 weeks 
after initiation of thoracic radiation therapy.  We will initially enroll 6 patients and wait until completion of the 
13-week safety observation period following initiation of ipilimumab + nivolumab combination treatment.  No 
additional patients will be enrolled until the safety lead in phase is complete. 
If 0 or 1 of 6 patients develops unacceptable toxicity:  
then we will proceed with the study as outlined below (to accrue an additional 44 patients).   
If 2 patients develop unacceptable toxicity:  
then we will enroll an additional 3 patients to determine the rate of unacceptable toxicity with 9 patients.   
If 3 or more patients develop unacceptable toxicity during any portion of the safety lead in phase, 
then we will discontinue the study.   
Additionally, we will be continually assessing toxicity throughout the study and if at any time 3 of the first 9 
patients or greater than 33% of patients experience unacceptable toxicity within the 13-week safety observation 
period, we will discontinue the study. After the 13-week safety observation period, toxicity will be assessed on 
an ongoing basis for all patients prior to each dose of ipilimumab/nivolumab or nivolumab alone until study 
completion.  If unacceptable toxicity occurs outside the 13 week safety observation period, that patient will 
discontinue treatment on the study according to discontinuation criteria (Section 6.5.3.4).  The protocol 
monitoring committee will evaluate all patients who discontinue the study due to unacceptable toxicity on a 
monthly basis.  If the monitoring committee feels that the study regimen is unsafe, we will discontinue the 
study.   
 Phase I/II Study Design and Duration 
4.2
This is a non-randomized, single-arm, multicenter, phase I/II study in adult patients with ED-SCLC, who 
achieved stable disease, partial response, or complete response after completion of platinum-based first-line 
chemotherapy. Fifty participants will be enrolled to receive thoracic radiation therapy (30 Gy in 10 fractions) 
followed by nivolumab/ipilimumab combination therapy for 4 cycles and then maintenance nivolumab until 
progression. The study design schematic is presented in Figure 4.2-1. 
 
 
 


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22 
 
 
The treatment regimen is as follows: 
At least 3 weeks, but not longer than 8 weeks after completion of systemic chemotherapy, patients will initiate 
thoracic radiation therapy targeting the initially involved supraclavicular, hilar and mediastinal lymph node 
stations as well any other residual intrathoracic disease seen on restaging CT or PET-CT after completion of 
systemic therapy.  Details of the Radiotherapy Treatment Schedule are outlined in Table 5.2-1.  At least 14 days 
and not more than 21 days after completion of RT, patients will commence nivolumab 1 mg/kg (30-minute IV 
infusion) and ipilimumab 3 mg/kg (90-minute IV infusion) every 3 weeks for 4 doses, followed by nivolumab 
480 mg every 4 weeks, as described in Table 6.5-1.  
Τhe detailed 3-part schedule of investigational treatments is as follows:  
1) Monday to Friday: thoracic radiation therapy at a dose of 3 Gy daily for 10 treatments 
2) After at least 14 days but not more than 21 days, initiate combined nivolumab 1 mg/kg + ipilimumab 
3 mg/kg every 3 weeks for 4 doses; 
3) After part 2 of treatment, initiate maintenance nivolumab at least 42 days but not more than 56 days, 
delivered every 4 weeks at a dose of 480 mg/cycle. 
Patients will undergo ongoing 4-week cycles until discontinuation criteria are met (Section 4.6). The full study 
schedule calendar is outlined in Appendix 1. 
On-study tumor assessments commence 4 weeks after initiation of thoracic radiation therapy and will be 
conducted according to the study calendar schedule(+/-5 days) for the first 33 weeks. After week 36, 
radiographic tumor assessments will be performed every 12 weeks (+/-5 days) until disease progression (See 
Tables 7.4-1 and 7.4-2). 
The total duration of the study from start to final analysis of overall survival is expected to be 30 months (18 
months of accrual + 12 months of follow-up), assuming an increasing accrual rate from 2 participants/month for 
the first 6 months, then increasing accrual rate (5 participants/month during 18 months). PFS will be analyzed 
before OS (Section 9). Additional survival follow-up may continue for up to 5 years from the primary analysis 
of survival. The study will end once survival follow-up has concluded. Participant safety will be monitored on 
an ongoing basis as described fully in Section 7.  
The start of the trial is defined as first visit for the first participant screened. The end of trial is defined as the 
last visit for the last participant. Study completion is defined as the final date on which data for the primary 
endpoint was collected. 
4.2.1 Study Phases 
The study is divided into the following phases: Screening, Treatment, and Follow-up. 
The study calendar is outlined in Appendix 1. 


23 
 
1. Screening: Screening begins after the participant signs the informed consent form (ICF) and is enrolled on 
the study through the Moffitt Clinical Research Network (MCRN) at Moffitt Cancer Center. 
• Whenever possible, tumor tissue (archival or recent tumor biopsy 10 slides or tissue block) should be 
submitted to the central lab for correlative studies. Participants must consent to allow the acquisition of 
tumor tissue by study personnel for performance of the correlative studies. 
• Baseline assessments must be performed within the timeframes described in Table 7.1-1. 
 
• For patients with known brain metastases at presentation, brain radiotherapy (whole brain radiation 
therapy (WBRT) or stereotactic radiation) may be offered, per local standard of care. Patients with 
asymptomatic brain metastases at initial diagnosis may be treated with chemotherapy alone at the 
discretion of the patient’s treating physician.  A 4 week disease stable interval as confirmed by MRI or 
CT brain w/ contrast (Table 7.4-2) is required after treatment of brain metastases before initiation of 
thoracic radiation therapy. 
• Prophylactic Cranial Irradiation (PCI) is not allowed.  
• Treatment initiation must be > 3 weeks but ≤ 8 weeks from the last dose of chemotherapy for all 
participants.  
• The screening phase either ends with confirmation of full eligibility and initiation of study treatment or 
with the confirmation that the participant is a screen failure.  
• This study permits the re-enrollment of a participant that has discontinued the study as a pretreatment 
failure before enrollment If re-enrolled, the participant must be reconsented. A new participant 
identification number will be assigned at the time of re-enrollment. 
 
2. Treatment: The treatment phase begins with a study initiation call to the MCRN. Treatment is to begin 
within 3 business days of study initiation. 
Study therapy is administered as described in Tables 5.2-1 and 6.5-1 until disease progression, discontinuation 
due to toxicity, withdrawal of consent, the study ends, or other criteria for discontinuation are met, as described 
in Section 4.6 and Section 6.5.3.4. Patients may be treated beyond initial progression as specified in Section 
6.5.5. 
Participants will be evaluated for response according to RECIST 1.1 criteria. Radiographic assessments will be 
obtained according to the study calendar schedule for the first 33 weeks and subsequently every 12 weeks, or 
more frequently as clinically indicated, until disease progression (or until discontinuation of study drug(s) in 
patients treated beyond progression) or withdrawal of study consent. 
The treatment phase ends when the participant is discontinued from study drug(s) 
Study assessments while on treatment are to be collected as outlined in Tables 7.1-1, 7.1-2, and 7.1-3. 
 


24 
 
3. Follow-up. Follow-up begins when the decision to discontinue a participant from study therapy is made. 
Participants who discontinue study therapy for reasons other than disease progression will continue to have 
radiographic assessments according to the study calendar(± 5 days)for the first 33 weeks, and subsequently 
every 12 weeks, until disease progression or withdrawal of study consent. 
Follow-up visits occur as follows: 
− X01 Follow-up Visit 1 = 35 days ± 7 days from last dose; 
− X02 Follow-up Visit 2 = 80 days ± 7 days from X01 Follow-up Visit 1; 
− Survival Follow-Up visits begin after the X02 Follow-up Visit 2. 
For Survival Follow-up Visits, contact of participants will occur (in person or by telephone) every 12 weeks 
upon entry into this phase to evaluate OS and collect data on the initiation of subsequent therapy for the 
treatment of SCLC.  
 
 Post-Study Access to Therapy 
4.3
At the conclusion of the study, participants assigned to active study drug who continue to demonstrate clinical 
benefit will be eligible to receive BMS-supplied study drug. Study drug will be provided via an extension of the 
study, a rollover study requiring approval by responsible health authority and ethics committee, or through 
another mechanism at the discretion of BMS. 
BMS reserves the right to terminate access to BMS-supplied study drug if any of the following occur: 1) the 
marketing application is rejected by responsible health authority; 2) the study is terminated due to safety 
concerns; 3) the participant can obtain medication from a government-sponsored or private health program; or 
4) therapeutic alternatives become available in the local market. 
 
 Study Population 
4.4
For entry into the study, the following criteria MUST be met. 
4.4.1 Inclusion Criteria 
1. Signed Written Informed Consent 
a) Participants must have signed and dated an IRB/IEC-approved written informed consent form in accordance 
with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-
related procedures that are not part of normal patient care. 
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests 
and other requirements of the study. 


25 
 
2. Target Population 
a) Patients with SCLC documented by histology or cytology from brushing, washing, or needle aspiration of a 
defined lesion, but not from sputum cytology alone;  
b) Participants must have presented at initial diagnosis with extensive-stage disease (defined as Stage IV (T any, 
N any, M1a/b) per NCCN Guidelines Version 1.2015, AJCC Cancer Staging Manual, 7th Edition, 2010); 
c) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 (see http://ecog-
acrin.org/resources/ecog-performance-status for details) 
d) Participants must have received 4-6 cycles of platinum-based first-line chemotherapy and must have an 
ongoing response of complete response (CR), partial response (PR), or stable disease (SD) after completion of 
chemotherapy. Acceptable combinations, as recommended per NCCN guidelines, include cisplatin or 
carboplatin combined with either etoposide or irinotecan; 
i) As an exception to the above criterion, participants receiving only 3 cycles of chemotherapy due to 
toxicity are eligible, if they have an ongoing PR or CR after the 3rd cycle  
ii) Participants who have received > 6 cycles of platinum-based first-line chemotherapy are not eligible 
e) Participants must initiate study treatment with thoracic radiation therapy ≤ 8 weeks (56 days) from the last 
dose of platinum-based first line chemotherapy; 
i) Thoracic radiation therapy must not be administered < 3 weeks (21 days) from the last dose of 
platinum-based first line chemotherapy 
ii) Ipilimumab/nivolumab study therapy must not be administered < 13 days and not more than 21 days 
from the last dose of thoracic radiotherapy 
f) Whenever possible, a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or 10 unstained slides of 
tumor sample (archival or recent) for biomarker evaluation should be made available and submitted to the 
central lab for correlative studies;  
g) Patient re-enrollment: This study permits the re-enrollment of a participant who has discontinued the study 
due to pre-treatment failure (ie, participant has not been treated). If re-enrolled, the participant must be re-
consented. 
3. Age and Reproductive Status 
a) Men and women ≥ 18 years of age; 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of thoracic radiation therapy; 
c) Women must not be breastfeeding; 


26 
 
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with 
study drug(s) plus 5 half-lives of study drug (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) 
for a total of 5 months post-treatment completion; 
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception 
for the duration of treatment with study drug (s) plus 5 half-lives of the study drug (half-life up to 25 days) plus 
90 days (duration of sperm turnover) for a total of 7 months post-treatment completion; 
f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements. However they must still undergo pregnancy testing as described in this section. 
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise 
on the use of highly effective methods of contraception, which have a failure rate of < 1% when used 
consistently and correctly.  
Regarding male participants, age 18 years or greater: 
a) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception 
for the duration of treatment with study drug(s) study therapy plus 5 half-lives of the study drug study therapy 
up to 25 days plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion; 
b) Azoospermic males are exempt from contraceptive requirements; 
c) Male participants must be willing to refrain from sperm donation during the entire study and for 5 half-lives 
of study drug plus 90 days (duration of sperm turnover).  
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
At a minimum, participants must agree to the use of one highly effective method of contraception as listed 
below: 
Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. 
WOCBP participants and female partners of male participants who are WOCBP are expected to use one of the 
highly effective methods of contraception listed below. Male participants must inform their female partners who 
are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception 
with their partner. Contraception methods are as follows: 
• Progestogen-only hormonal contraception associated with inhibition of ovulation. 
• Hormonal methods of contraception, including oral contraceptive pills containing combined estrogen + 
progesterone, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena 
• Nonhormonal IUDs, such as ParaGard 
• Bilateral tubal occlusion 


27 
 
• Vasectomized partner with documented azoospermia 90 days after procedure 
o Vasectomized partner is a highly effective birth control method provided that partner is the sole 
sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical 
assessment of the surgical success. 
• Intrauterine hormone-releasing system (IUS) 
• Complete abstinence 
o Complete abstinence is defined as the complete avoidance of heterosexual intercourse  
o Complete abstinence is an acceptable form of contraception for all study drugs and must be used 
throughout the duration of the study treatment (plus 5 half-lives of the investigational drug plus 30 
days); 
o It is not necessary to use any other method of contraception when complete abstinence is elected; 
o Participants who choose complete abstinence must continue to have pregnancy tests, as specified in 
Section 7. 
o Acceptable alternate methods of highly effective contraception must be discussed in the event that the 
participant chooses to forego complete abstinence. 
o The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the participant. 
UNACCEPTABLE METHODS OF CONTRACEPTION 
1) Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
2) Withdrawal (coitus interruptus) 
3) Spermicide only 
4) Lactation amenorrhea method (LAM) 
 
4.4.2 Exclusion Criteria 
1. 
Target Disease Exceptions 
a) Participants with previous brain metastases are eligible provided that they are treated and asymptomatic not 
requiring steroids or anticonvulsants, and have stable disease at the screening tumor assessment. A 4 week 
disease stable interval as confirmed by MRI or CT brain w/ contrast (Table 7.4-2) is required after treatment of 
brain metastases before initiation of thoracic radiation therapy.  In addition, subjects must have been either off 
corticosteroids, or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent).  


28 
 
 
b) Participants who have received prior chest radiation which at the discretion of the treating radiation 
oncologist precludes delivery of protocol radiation therapy as outlined in section 5 . 
c) Carcinomatous meningitis 
d) Pleural effusion that cannot be controlled with appropriate interventions 
e) All toxicities attributed to prior anti-cancer therapy must have been resolved to Grade 1 (NCI CTCAE 
Version 4) or baseline before administration of study drug(s) other than: 
i) Patients with toxicities attributed to prior anti-cancer therapy that either are not expected to resolve 
and/or result in long-lasting sequelae, such as neuropathy after platinum-based therapy, or are not 
expected to interfere with treatment on study, such as fatigue,alopecia, or grade 2 hematologic 
toxicityare eligible. 
2.  
Medical History and Concurrent Diseases 
a) Women who are pregnant or breastfeeding 
b) Active, known, or suspected autoimmune disease. Patients with an autoimmune paraneoplastic syndrome 
requiring concurrent immunosuppressive treatment are excluded. Patients with type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not 
requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll 
c) A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or 
other immunosuppressive medications within 14 days of study initiation. Corticosteroids with minimal systemic 
absorption (inhaled or topical steroids) and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent are permitted in the absence of active autoimmune disease  
d) Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including 
ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways) 
e) Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected 
drug-related pulmonary toxicity 
f) Any patient requiring supplemental oxygen therapy 
g) Previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, 
gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved 
at least 2 years prior to study entry AND no additional therapy is required during the study period  
h) Known medical condition that, in the investigator’s opinion, would increase the risk associated with study 
participation or study drug(s) administration or interfere with the interpretation of safety results 


29 
 
i) Major surgery or significant traumatic injury that is not recovered at least 14 days before the initiation of 
thoracic radiation therapy.  
3. Physical and Laboratory Test Findings 
a) Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or positive test for 
hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic 
infection 
i) Individuals with a positive test for HCV antibody but no detection of HCV RNA indicating no current 
infection are eligible  
b) Known medical history of testing positive for human immunodeficiency virus (HIV) or known medical 
history of acquired immunodeficiency syndrome (AIDS) 
c) Inadequate hematologic function defined by: 
i) Absolute neutrophil count (ANC) < 1,000/mm3. 
ii) Platelet count < 100,000/mm3, or 
iii) Hemoglobin level < 8.0 g/dL 
d) Inadequate hepatic function as defined by either: 
i) Total bilirubin level ≥ 1.5 times the ULN (except patients with Gilbert Syndrome, who are excluded if 
total bilirubin ≥ 3 times ULN), or 
ii) AST and ALT levels ≥ 2.5 times the ULN or ≥ 5 times the ULN if liver metastases are present 
e) Inadequate pancreatic function as defined by either: 
i) Lipase > 1.5 ULN. Participants with lipase > 1.5 ULN may enroll if there are neither clinical nor 
radiographic signs of a pancreatitis 
ii) Amylase > 1.5 ULN. Participants with amylase > 1.5 ULN may enroll if there are neither clinical nor 
radiographic signs of a pancreatitis 
4. Allergies and Adverse Drug Reaction 
a) History of allergy or hypersensitivity to any of the study drugs or study drug components 
5. Other Exclusion Criteria 
a) Prisoners or individuals who are involuntarily incarcerated 
b) Individuals who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious 
disease) illness 


30 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and 
that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria. 
 
4.4.3 Women of Childbearing Potential 
A woman of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who 
has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other 
biological or physiological causes. In addition, females under the age of 55 years must have a serum follicle 
stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause.  Females treated with hormone 
replacement therapy (HRT) are likely to have artificially suppressed FSH levels and may require a washout 
period in order to obtain a physiologic FSH level. The duration of the washout period is a function of the type of 
HRT used. The duration of the washout period below are suggested guidelines and the investigators should use 
their judgment in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time during the 
washout period, the woman can be considered postmenopausal: 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
Postmenopausal women may continue HRT after FSH testing is completed and postmenopausal status is 
confirmed. Other parenteral products may require washout periods as long as 6 months. 
 
 Concomitant Treatments 
4.5
4.5.1 Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study: 
• Immunosuppressive agents (except to treat a drug-related AE or an autoimmune paraneoplastic 
syndrome). Participants with an autoimmune paraneoplastic syndrome at enrollment requiring 
concurrent immunosuppressive treatment are not eligible; 
• Systemic corticosteroids > 10 mg daily prednisone equivalent, except as stated in Section 4.4.2 or to 
treat a drug-related AE; 
• Any concurrent systemic antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
standard or investigational agents for the treatment of cancer); 
• Supplemental oxygen therapy 
• Surgical resection of tumor; 


31 
 
• Note: in addition to the study prescribed thoracic radiotherapy, the following radiotherapy is 
permitted: 
− Palliative bone radiotherapy as described in Section 4.5.2 
− Palliative radiotherapy to a single metastatic site, other than bone, in participants who do not 
require immediate initiation of second-line systemic anti-cancer therapy. See Section 4.5.2 for 
additional restrictions. 
 
4.5.2 Other Restrictions and Precautions 
Treatment breaks must be resumed ≤ 6 weeks from the last dose or the participant must be permanently 
discontinued from the study. (See exceptions in Sections 4.6 and 6.5.3)  
Non-target bone lesions that do not include lung tissue in the planned radiation field may receive palliative 
radiotherapy at any time while on study treatment. Radiotherapy to non-bone lesions is permitted only as 
described in Section 4.5.2, but must not be given during or 2 weeks after study therapy. Details of palliative 
radiotherapy should be documented in the source records and case report form (CRF). Details in the source 
records should include: dates of treatment, anatomical site, dose administered and fractionation schedule, and 
AEs. 
Participants requiring palliative radiotherapy should be carefully assessed for disease progression. Participants 
considered to have progressive disease are required to discontinue study participation, unless eligible to 
continue treatment beyond progression per the guidance in Section 6.5.5 (Treatment Beyond Disease 
Progression). 
Imaging Restrictions and Precautions 
It is the local imaging facility’s responsibility to determine, based on patient attributes (e.g., allergy history, 
diabetic history, and renal status), the appropriate imaging modality and contrast regimen for each participant. 
Imaging contraindications and contrast risks should be considered in this assessment. Participants with renal 
insufficiency should be assessed as to whether they should receive contrast and, if so, what type and dose of 
contrast is appropriate. Specific to MRI, patients with severe renal insufficiency (i.e., estimated glomerular 
filtration rate (eGFR) < 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast 
should not be given to this population. In addition, participants are excluded from MRI if they have tattoos, 
metallic implants, pacemakers, etc. The ultimate decision to perform MRI in an individual in this study rests 
with the site radiologist, the investigator, and the standard set by the local Ethics Committee. 
 
4.5.3 Permitted Therapy 
Participants are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with 
minimal systemic absorption). Adrenal replacement steroid doses including 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 


32 
 
allergen) is permitted. Postmenopausal women may continue HRT after FSH testing is completed and 
postmenopausal status is confirmed. Concomitant palliative and supportive care for disease-related symptoms 
(including bisphosphonates and RANK-L inhibitors) are allowed. See Section 4.5.2 for guidance on 
concomitant palliative radiotherapy.  Caution should be used regarding the use of herbal medications as there 
may be as yet unknown interactions with study therapy. Discontinuation of the use of herbal medications prior 
to study initiationis encouraged. 
 
 Discontinuation of Participants Following Any Treatment with Thoracic 
4.6
Radiation Therapy or Study Drug(s) 
Participants MUST discontinue investigational product (and non-investigational product at the discretion of the 
investigator) for any of the following reasons: 
• Disease progression as assessed by RECIST 1.1 criteria, unless the participant meets criteria for 
treatment beyond progression (Section 6.5.5) 
• Participant requests to stop study treatment 
• Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness that, in the opinion of 
the investigator, indicates that continued participation in the study is not in the best interest of the 
participant 
•  Discontinuation of study support by Bristol-Myers Squibb (BMS) 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration for 
treatment of either a psychiatric or physical (e.g., infectious disease) illness 
• Additional protocol-specified reasons for discontinuation, as described in Section 6.5.3.4 
In the case of pregnancy, the investigator must immediately notify the primary investigator or designee of this 
event. In most cases, study drug(s) will be permanently discontinued in an appropriate manner. If the 
investigator determines a possible favorable benefit/risk ratio that warrants continuation of study drug(s), a 
discussion between the primary investigator or designee, the IRB, and the Sponsor or designee must occur. All 
participants who discontinue study drug(s) should comply with protocol specified follow-up procedures as 
outlined in Section 7. The only exception to this requirement is when a participant withdraws consent for all 
study procedures including post-treatment study follow-up or loses the ability to consent freely (ie, is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical illness). 
Participants must be followed for at least 100 days after the last dose of study therapy. Follow-up visit 1 (FU1) 
occurs approximately 35 days (+/- 7 days) after last dose of coinciding with the date of discontinuation (+/- 7 
days) if the date of discontinuation is greater than 35 days after the last dose. Follow-up visit 2 (FU2) occurs 
approximately 80 days (+/- 7 days) after FU1. Survival visits are every 3 months from FU2 up to 5 years and 
may be conducted during a clinic visit or via the phone. The primary endpoint of this study is PFS with a 
secondary endpoint of OS so tracking reporting the participant’s status in the follow-up setting according to the 
protocol guidelines for disease progression and survival are critical to the final study analysis. The importance 
of follow-up should be clearly communicated to study participants. If the study drug(s) is discontinued prior to 


33 
 
the patient completion of the study, the reason for the discontinuation must be documented in the patient’s 
medical records and entered on the appropriate case report form (CRF) page. 
 
 Post-Study Drug Study Follow-up 
4.7
In this study, overall survival is a key endpoint of the study. Post-study follow-up is of critical importance and 
is essential to preserving participant safety and the integrity of the study. Participants who discontinue study 
drug must continue to be followed for collection of outcome and/or survival follow-up data as required and in 
line with Section 7 until death or the conclusion of the study. The primary investigator may request that survival 
data be collected on all participants outside of the protocol-defined window (see Table 7.1-5). At the time of 
this request, each participant will be contacted to determine their survival status unless the participant has 
withdrawn consent for all contact. 
 
4.7.1 Withdrawal of Consent 
Participants who request to discontinue study therapy will remain on the study and must continue to be followed 
for protocol-specified follow-up procedures. The only exception to this is when a participant specifically 
withdraws consent for any further contact with him/her or persons previously authorized by the participant to 
provide this information. Participants should notify the investigator of the decision to withdraw consent from 
future follow-up in writing, if possible. The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is from further treatment with study therapy only or 
also from study procedures and/or post-treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance with local law. 
 
4.7.2 Lost to Follow-Up 
All reasonable efforts must be made to locate participants to determine and report their ongoing status. This 
includes follow-up with those authorized by the particpant as noted above. Lost to follow-up is defined as the 
inability to reach the participant after a minimum of three documented phone calls, faxes, or emails as well as 
lack of response by participant to one registered mail letter. All attempts should be documented in the 
participant’s medical records. If it is determined that the participant has died, the site will use permissible local 
methods to obtain the date and cause of death. 
If investigator’s use of third-party representative to assist in the follow-up portion of the study has been 
included in the participant’s informed consent, then the investigator may use a third-party representative to 
assist site staff with obtaining participant’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult publicly available 
sources, such as public health registries and databases, to obtain updated contact information. If after all 
attempts the participant remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the participant’s medical records. 


34 
 
 
5 RADIATION THERAPY 
 Thoracic Radiation Dose Specifications 
5.1
Patients will receive thoracic radiation to residual intrathoracic disease including mediastinal, supraclavicular 
(SC), and hilar lymph node sites involved at the time of diagnosis. The treating physician will have discretion to 
limit treatment volume if there is concern for excess of normal tissue irradiation.  
The total dose of 30 Gy will be given in 10 daily fractions of 3 Gy prescribed to the planning target volume 
(PTV) with at least 95% of the PTV receiving 30 Gy. An acceptable variation is at least 90% of the PTV 
receiving 30 Gy. The maximum dose for any contiguous volume of no more than 0.03 cc inside the PTV must 
not exceed 120% of the prescribed dose. An acceptable deviation is a maximum dose inside the PTV of up to 
125% of the prescribed dose. The minimum dose (0.03 cc) to the PTV volume should be no less than 28.5 Gy.  
An acceptable deviation is a minimum PTV dose of 27.9 Gy.  All radiation doses will be calculated with 
inhomogeneity corrections.  
 
 Radiation Treatment Schedule 
5.2
Localization, Simulation, and Immobilization for radiation treatment planning, as outlined in Section 5.4, will 
be performed no more 21 days and no less than 1 day before the first day of thoracic radiation treatment.  The 
patient can initiate treatment any day of the week.  Treatment will be delivered daily for 10 consecutive 
working days (generally Monday-Friday).  Disruptions to the planned radiation treatment schedule should be 
avoided if at all possible.  Any unexpected treatment break lasting > 1 day should be reported to the principal 
investigator.       
 
Table 5.2-1. Radiation Treatment Schedule 
Thoracic RT Planning 
Simulation 
Radiation 
Treatment 1-5 
Radiation 
Treatment 6-10 
Between Day -21 and 
Day 0  
Week 1 
Week 2A 
AIf thoracic radiation therapy is started later in week 1, then radiation 
treatments will continue into week 3. 
 
 


35 
 
 Technical Factors 
5.3
5.3.1 Beam Energy 
Six- to 10-MV photons are recommended for mediastinal and lung irradiation; however, beam energy and type 
will be left to the discretion of the treating radiation oncologist in order to obtain the best dose distribution for 
the site being treated.  
5.3.2 Beam Shaping 
Multi-leaf collimation (MLC) or individually shaped custom blocks should be used to protect normal tissues 
outside of the target volume. 
 Localization, Simulation, and Immobilization 
5.4
A volumetric treatment planning computed tomography (CT) study (intravenous contrast preferred, if possible) 
will be required for treatment of primary disease and regional lymphatics. A four-dimensional CT to account for 
respiratory motion may be beneficial and should be utilized whenever possible to limit the overall size of the 
planning target volume. PET-CT performed for restaging may also assist with radiation treatment planning 
target delineation.  Evaluation and/or fusion (according to each institution’s standard practice) of the initial 
diagnostic PET-CT or CT chest will assist with delineation of any initially involved hilar or mediastinal nodal 
sites.     
Each patient will be positioned in an immobilization device in the treatment position on a flat table. Contiguous 
CT slices with a no more than 3-mm thickness will be obtained through the regions harboring gross disease and 
the entirety of all organs in the treatment field. This is necessary for proper radiation planning.  
 
 Treatment Planning/Target Volumes 
5.5
The definitions of volumes will be in accordance with the 1993 ICRU Reports #62. 
Definition of GTV: Gross tumor volume (GTV) will include known disease as determined by physical 
examination and post-chemotherapy imaging studies. The Uniform Tissue Naming scheme for this study is 
available in Table 5.6-2. 
Definition of CTV:  The clinical target volume (CTV) will be defined as any residual intrathoracic disease 
contoured as GTV plus 0-1cm (preferable 0.7cm) expansion volume accounting for anatomic boundaries. 
Additionally, the CTV volume will include any SC, hilar or mediastinal lymph node sites that were involved at 
the time of initial diagnosis.  This is not the same as pretreatment volume.  For example, if the patient had a 10 
cm mediastinal mass that involved the paratracheal and subcarinal lymph nodes and had a complete response to 
chemotherapy, the CTV would not necessarily be a 10 cm volume but rather a carefully defined volume 
including the subcarinal and paratracheal tissues. CTVs will be labeled to correspond to the appropriate GTV or 
in cases where there is no GTV, the CTV will be labeled according to Uniform Tissue Naming scheme in Table 


36 
 
5.6-2.CTV may be modified to exclude intrathoraic pulmonary nodules as well as nodal regions if they 
contribute to excess normal tissue toxicity. 
Definition of PTV: The planning target volume (PTV) is the CTV plus a margin to account for treatment set-up 
uncertainty and organ motion. The most appropriate PTV margin is to be determined by the treating radiation 
oncologist and could range from 0.3 to 2.0 cm depending on the use of respiratory motion management and 
image guided radiation therapy techniques.  
Utilization of advanced planning techniques including 3D conformal radiation therapy (3DCRT) or intensity 
modulated  radiation therapy (IMRT) to minimize dose to normal tissues (especially lung) is encouraged.   
Respiratory Motion Assessment and Management:  
Utilization of advanced planning techniques to account for respiratory motion can limit the volume of normal 
tissue (specifically lung).  By utilizing respiratory motion management, the PTV margin that accounts for organ 
motion can be made smaller.  4D-CT based planning to account for any residual tumor motion as well as hilar-
mediastinal motion is one form of respiratory motion management.  Alternative options to account for 
respiratory motion include but are not limited to fiducial marker placement, gating and breath hold approaches.   
Internal Target Volume (ITV) Approach: 
If a 4D-CT was collected at the time of simulation for respiratory motion management, then an ITV approach 
can be utilized to account for internal motion.  Utilization of an ITV approach allows for limiting PTV 
expansion as outlined above.  ITV approach can be utilized to account for motion of any residual intrathoracic 
tumor through designation of GITV or it can be utilized to delineate CTV motion at the hilar or mediastinal 
sites through designation of a CITV.   
3DCRT Treatment Planning:  
The PTVs are to be treated with any combination of coplanar or non-coplanar 3-dimensional conformal fields 
shaped to deliver the specified dose while restricting the dose to normal tissues. Field arrangements will be 
determined by the 3D planning to produce the optimal conformal plan in accordance with volume definitions. 
The treatment plan used for each patient will be based on an analysis of volumetric dose, including DVH 
analysis of the cumulative dose to each PTV and all critical normal structures.  
IMRT Treatment Planning:  
IMRT is allowed at the discretion of the treating radiation oncologist.  If IMRT is used, it is highly encouraged 
that a 4D-CT is also performed. 
 
 
 
 


37 
 
 
 Target Volume and Critical Structure Constraints with Compliance 
5.6
Criteria 
 
Table 5.6-1. Target Volume and Critical Structure Constraints with Compliance Criteria 
Structure  
Dose Constraint 
Acceptable 
Variation 
Unacceptable Deviation 
PTV 
30Gy >= 95% 
30Gy > =90% 
30Gy < 90% 
  
Min (0.03cc)  > 
=28.5Gy 
Min (0.03cc) > 
=27.9Gy 
Min (0.03cc) < 27.9Gy 
  
Max (0.03cc) <= 
36Gy 
Max (0.03) <= 
37.5Gy 
Max (0.03) > 37.5Gy 
Lungs  
V20Gy <= 20%  
V20Gy <= 35% 
V20Gy > 35% 
Mean < =15Gy  
Mean < =20Gy 
MLD > 20Gy 
Liver  
> 700 cc <= 10 Gy  
> 700 cc < =18 Gy  
< 700 cc <= 18 Gy  
Spinal cord  
Max (0.03cc) < 
=36Gy  
NA 
Max (0.03cc) > 36Gy  
Heart  
Max (0.03cc) < 
=36Gy 
Max (0.03cc) > 36Gy 
NA 
V30Gy < =30%  
V30Gy > 30% 
Min (0.03) > 30Gy 
Esophagus  
Max (0.03cc) <= 
36Gy 
Max (0.03cc) > 36Gy 
NA 
Note: All required structures must be labeled as listed in the table below for digital RT data submission. 
Resubmission of data may be required if labeling of structures does not conform to the DICOM standard name 
listed. 
 
 
 
 
 


38 
 
Table 5.6-2 outlines the naming of the various normal and critical structures for radiation treatment plan 
submission. 
Table 5.6-2. Uniform Tissue Naming Scheme and Descriptions 
DICOM Standard Name  
Description  
GTV  
Gross Tumor Volume  
Required for lesions that have not had CR to chemotherapy  
unless using GITV  
GITV  
Gross Internal Tumor Volume (*if using ITV approach)  
Optional  
CTV  
Clinical Target Volume  
Required - unless using CITV 
CITV  
Clinical Internal Target Volume (*if using ITV approach)  
Optional  
PTV  
Planning Target Volume  
Required  
Lungs  
Right Lung + Left Lung minus GTV  
Required  
Heart  
Heart/Pericardium  
Required  
Esophagus  
Esophagus  
Required  
Spinal Cord  
Spinal Cord  
Required  
Non-PTV  
External minus PTV   
Required 
Liver  
Liver (*if in path of beam)  
Optional  
 Documentation Requirements 
5.7
Portal images of each field must be obtained on or before the first day of therapy but will not be submitted.  
If IMRT is used, portal images will not be obtained, but patient specific QA will be performed prior to the first 
fraction. 
Verification films of each site will be done weekly, but not submitted.  
Cone beam CT, kV imaging, or other in-room imaging for set-up is allowed. 


39 
 
Isodose plans for 3D radiotherapy or IMRT planning with DVHs of GTV, CTV, PTV, and critical structures are 
required. 
Acceptable variations are allowed only when the geometrical arrangement of the target and critical structures is 
challenging.  Unacceptable deviations should be avoided whenever possible and plan modifications should be 
attempted to improve results.  Ultimately, the decision to deliver the proposed radiation treatment plan falls to 
the treating radiation oncologist.  The details of each radiation treatment plan are to be collected by the study 
sponsor and all acceptable variations and unacceptable deviations will be appropriately documented in the study 
record.    
 
 Radiation Therapy Quality Assurance Reviews  
5.8
The Radiation Oncology Principal Investigator, Bradford Perez, MD, or designee, will perform an RT Quality 
Assurance review for the first case from each study site prior to initiation of radiation therapy.  At least 3 
business days should be allowed for case review.  Once the initial case from each institution has been carefully 
reviewed and deemed acceptable, all other patients will be treated according to the protocol guidelines by the 
treating radiation oncologist.  All cases will be reviewed within 3 months after the study has reached the target 
accrual or as soon as complete data for all cases enrolled have been received at Moffitt Cancer Center. 
 
 Radiation Therapy Adverse Events 
5.9
Side effects of treatment will vary depending on the location of disease and volume of normal tissues in or near 
the radiation planning target volume. All attempts should be made to minimize adverse effects by limiting the 
normal tissue radiation dose (especially to the lung) as much as possible and adhering to the normal tissue dose 
constraints of this study. 
5.9.1 Acute Reactions 
It is likely that all patients treated on study will develop some level of fatigue.  Alopecia, skin 
hyperpigmentation, and erythema are possible acute side effects that are generally well tolerated.  Cough and 
esophagitis (if the esophagus is within or near the planning target volume) are likely. Severe esophagitis 
requiring intravenous hydration, therapy interruption, or feeding tube, severe cough, shortness of breath, and 
hemoptysis are possible but less likely.  
5.9.2 Late Reactions 
Asymptomatic fibrotic changes in the lung seen on chest imaging are likely. Severe fibrosis of lung resulting in 
severe respiratory compromise, symptomatic esophageal stricture, radiation pericarditis, and myocardial injury, 
spinal cord injury, and brachioplexopathy are possible but unlikely adverse effects of radiation. 
 


40 
 
5.9.3 Treatment of Radiation Adverse Events 
All attempts should be made to limit the symptoms and the overall impact of acute and late effects of radiation.  
Esophagitis should be treated empirically for candidiasis with fluconazole or nystatin, and managed with topical 
anesthetic, H2 blocker or proton pump inhibitor, NSAIDs, or narcotic pain medications, if necessary. 
 
6 STUDY DRUGS 
Study drugs include both Investigational [Medicinal] Product (IP/IMP) and Non-investigational [Medicinal] 
Product (Non-IP/Non-IMP), including the following (Table 6-1): 
 
Table 6-1. Study Drugs for MCC 18914 
Product Description/Class 
and Dosage Form 
IP/Non-IMP 
Potency 
Packaging/ 
Appearance 
Storage Conditions 
(per label) 
Nivolumab Solution for 
Injection 
IP 
100 mg (10 
mg/mL) 
10 mL/vial (5 or 
10 vials/carton) 
Store at 2-8°C; 
protect from light 
and freezing 
Ipilimumab Solution for 
Injection 
IP 
200 mg (5 
mg/mL) 
40 mL/vial (4 
vials/carton) 
Store at 2-8°C; 
protect from light 
and freezing 
 
Premedications or medications used to treat infusion-related reactions should be sourced by the investigative 
sites if available and permitted by local regulations. Solutions used as diluent or placebo (ie, 0.9% sodium 
chloride injection or 5% dextrose injection) should also be sourced by investigative sites if available and 
permitted by local regulations. 
 
 Investigational Product 
6.1
An investigational product, also known as investigational medicinal product in some regions, is defined a 
pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical study, 
including products already with a marketing authorization but used or assembled (formulated or packaged) 
differently than the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. 
The investigational product should be stored in a secure area according to local regulations. It is the 
responsibility of the investigator to ensure that investigational product is only dispensed to study participants. 
The investigational product must be dispensed only from official study sites by authorized personnel according 
to local regulations. In this protocol, the investigational medicinal products are: 


41 
 
• Nivolumab 
• Ipilimumab 
 
 Non-investigational Product 
6.2
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic reasons, as 
components of the standard of care for a given diagnosis, may be considered as non-investigational products. 
Non-investigational products should be sourced by the investigator sites if available and permitted by local 
regulations. 
 
 Storage of Study Drug 
6.3
The product storage manager should ensure that the study drug is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as outlined in the investigator’s brochure.  If concerns regarding 
the quality or appearance of the study drug arise, the study drug should not be dispensed and contact the 
principal investigator and BMS immediately. Study drug not supplied by BMS will be stored in accordance 
with the package insert. Please refer to Section 10.2.2 for guidance on IP records and documentation. Infusion-
related supplies (eg, IV bags, in-line filters, 0.9% sodium chloride injection, 5% dextrose injection) will not be 
supplied by the sponsor and should be purchased locally if permitted by local regulations. Please refer to the 
current version of the Investigator Brochure (IB) and/or pharmacy reference sheets for complete storage, 
handling, dispensing, and infusion information for nivolumab and ipilimumab. The infusion duration of 
nivolumab is 30 minutes and for ipilimumab is 90 minutes. 
 
 Method of Assigning Participant Identification 
6.4
Every participant that signs the informed consent form must be assigned a participant number. The investigator 
or designee will register the participant for enrollment by following the enrollment procedures established by 
principle investigator.  
All participants must be registered with the MCRN Coordinating Center to be able to participate in a trial. 
The participating site must fax or email the completed study specific eligibility checklist and registration 
forms, supporting documents and signed informed consent to the Coordinating Center. Unsigned or 
incomplete forms will be returned to the site. Once documents are received, the MCRN Research 
Coordinator will review them to confirm eligibility and to complete the registration process. If eligibility 
cannot be confirmed, the research coordinator will query the site for clarification or additional documents 
as needed. Participants failing to meet all study eligibility requirements will not be registered and will be 
unable to participate in the trial. 


42 
 
Upon completion of registration, the MCRN Research Coordinator will provide the participating site with the 
study sequence number, if indicated. Within 24-48 hours after registration, it is the site’s 
responsibility to: 
• Enter the demographic and on-study patient information into the Oncore database 
• Order investigational agent(s) if indicated per protocol 
It is the responsibility of the participating Investigator or designee to inform the participant of the research 
treatment plan and to conduct the study in compliance with the protocol as agreed upon with Moffitt Cancer 
Center and approved by the site’s IRB. 
To register a patient, the completed and signed eligibility checklist along with supporting documentation must 
be sent to the MCRN via email at affiliate.research@moffitt.org or via fax at 813-745-5666, Monday through 
Friday between 8:00AM and 5:00PM (EST). 
 Selection and Timing of Dose for Each Participant 
6.5
The dosing schedules are detailed in Table 6.5-1. 
Table 6.5-1. Dosing Schedule (Cycles 1-3) 
Cycles 1 and 2 
(42-day [6 week] cycles) 
Cycle 3 
(28-day [4 week] cycles) 
Day 1 
Day 22 
Day 1 
1 mg/kg Nivolumab 
(diluted to 100 mL) 
1 mg/kg Nivolumab 
(diluted to 100 mL) 
480 mg Nivolumab (48 
mL diluted 100 mL) 
3 mg/kg Ipilimumab 
(diluted to 100 mL) 
3 mg/kg Ipilimumab 
(diluted to 100 mL) 
For participants weighing < 35 kg, nivolumab and ipilimumab must be diluted to 50 mL in 0.9% sodium 
chloride or 5% dextrose solution.  
All participants will be monitored continuously for adverse events (AEs) while on study treatment. Treatment 
modifications (eg, dose delay or discontinuation) will be based on specific laboratory and AE criteria, as 
described in Sections 6.5.3. 
When study drugs (ipilimumab or nivolumab) are to be administered on the same day, separate infusion bags 
and filters must be used for each infusion. Nivolumab is to be administered first. The second infusion will 
always be the ipilimumab study drug and will start no sooner than 30 minutes after completion of the nivolumab 
infusion.  


43 
 
Ipilimumab must be diluted to 100 mL in 0.9% sodium chloride solution or 5% dextrose solution. Nivolumab 
must be diluted to 100 mL 0.9% sodium chloride solution or 5% dextrose solution. For weight-based dosing, if 
the participants weight on the day of dosing differs by > 10% from the weight used to calculate the dose, the 
dose must be recalculated. All doses should be rounded up or to the nearest milligram per institutional standard. 
There will be no dose modifications allowed. 
 
6.5.1 Dosing Windows 
During Cycles 1 and 2: 
• Participants may be dosed with ipilimumab 3 mg/kg and nivolumab 1 mg/kg with no less than 19 days 
between 
− C1D1 and C1D21 
− C1D21 and C2D1 
− C2D1 and C2D21 
− C2D21 and C3D1 
During Cycle 3 and beyond: 
• Participants may be dosed no less than 27 days from the previous dose of drug 
Participants may be dosed up to 3 business days after the scheduled date if necessary, or longer in the event of a 
toxicity requiring dose delay. Subsequent dosing should be based on the actual date of administration of the 
previous dose of drug. Treatment compliance will be monitored by drug accountability as well as the 
participant’s medical record and eCRF. 
6.5.2 Study Medications 
Nivolumab 1 mg/kg (30 min IV infusion) and ipilimumab 3 mg/kg (90 minute IV infusion) will be administered 
every 3 weeks for 4 doses, followed by nivolumab 480 mg every 4 weeks. The rationale for this dose schedule 
is provided in Section 1.1.7. The schedule of investigational treatments is divided into two 42-day cycles at the 
start of therapy, followed by ongoing 4-week cycles. This dosing schedule is described in detail in Table 6.5-1.  
Refer to the Pharmacy Information sheets for more detail. There are no pre-medications recommended on the 
first cycle. If an acute infusion reaction is noted, participants should be managed according to Section 6.5.6. See 
Section 6.5.4 for information on Management Algorithms for Immuno-Oncology Agents. 
6.5.3 Dose Modifications and Delays 
6.5.3.1 
Dose Modifications 
Dose reductions and discontinuation of ipilimumab or nivolumab for the management of toxicities of individual 
participants are permitted at the discretion of the treating physician Dose escalations are not permitted. 


44 
 
6.5.3.2 
Dose Delays 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the event is attributed 
to nivolumab, ipilimumab, or both).  
Study therapy administration should be delayed for the following: 
• Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions: 
− Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay 
• Any Grade 3 skin, drug-related adverse event 
• Any Grade 3, drug-related laboratory abnormality, with the following exceptions for asymptomatic 
amylase or lipase, AST, ALT, or total bilirubin: 
− Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose delay 
− If a participant has a baseline AST, ALT, or total bilirubin that is within normal limits, delay dosing 
for drug-related Grade ≥ 2 toxicity 
− If a participant 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 that, in the judgment of the 
investigator, warrants delaying the dose of study medication 
6.5.3.3 
Criteria to Resume Treatment 
Participants may resume treatment with study therapy when the drug-related AE(s) resolve to Grade ≤ 1 or 
baseline value, with the following exceptions: 
• Participants may resume treatment in the presence of Grade 2 fatigue 
• Participants 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 
• Drug-related pulmonary toxicity 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 participant should restart treatment at the next scheduled 
timepoint per protocol. Doses should not be skipped.  
If treatment is delayed > 6 weeks (42 days) from the last dose due to drug-related toxicity, the participant must 
be permanently discontinued from study therapy, except as specified in Section 6.5.3.4. In the event treatment is 


45 
 
delayed > 6 weeks due to reasons other than study drug-related toxicity, the case should be discussed with the 
Principal Investigator before proceeding. 
6.5.3.4 
Discontinuation Criteria 
Treatment with study therapy 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 AE lasting > 7 days, with the following exceptions:  
− Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
− Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except: 
♦ Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
♦ Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
o AST or ALT > 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 AE or laboratory abnormality, except for the following events which do not 
require discontinuation: 
− Grade 4 neutropenia ≤ 7 days 
− Grade 4 lymphopenia or leukopenia 
− Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours of 
their onset 
− Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations, or radiographic signs of pancreatitis. It is recommended to consult with the 
Principal Investigator for Grade 4 amylase or lipase abnormalities  
− For Grade 4 endocrinopathy AEs such as adrenal insufficiency, ACTH deficiency, hyper or 
hypothyroidosis, or glucose intolerance, which resolve or are adequately controlled with 
physiologic hormone replacement (steroids, thyroid hormones) or glucose controlling agents, 
respectively, retreatment can be considered after discussion with the Principal Investigator 
• Any dosing interruption lasting > 6 weeks from the last dose with the following exceptions: 


46 
 
− Dosing interruptions to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a participant with a dosing interruption lasting > 6 
weeks from the last dose, the Principal Investigator must be consulted  
− Dosing interruptions > 6 weeks from the last dose that occur for non-drug-related reasons may 
be allowed if approved by the Principal Investigator 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, 
presents a substantial clinical risk to the participant with continued study therapy dosing 
Tumor assessments for all participants should continue as per protocol even if study therapy dosing is 
interrupted. 
 
6.5.4 Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from AEs caused by 
other therapeutic classes. Nivolumab and ipilimumab are considered immuno-oncology agents in this protocol. 
Early recognition and management of AEs associated with immuno-oncology agents may mitigate severe 
toxicity. Management algorithms have been developed to assist investigators in assessing and managing the 
following groups of AEs: 
• Gastrointestinal 
• Renal 
• Pulmonary 
• Hepatic 
• Endocrinopathies 
• Skin 
• Neurological 
The recommendation is to follow the nivolumab algorithms for immune-oncology agents (I-O) in order to 
standardize the safety management across the study. 
The algorithms are found in the Nivolumab Investigator Brochure and Appendix 2 of this protocol. 
 
6.5.5 Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may derive clinical 
benefit despite initial evidence of progressive disease (PD)[48]. The assessment of clinical benefit should be 
balanced by clinical judgment as to whether the participant is clinically deteriorating and unlikely to receive any 


47 
 
benefit from continued study therapy. Participants will be permitted to continue treatment beyond initial 
progressive disease as long as all of the following criteria are met and clearly documented:  
• Investigator-assessed clinical benefit and no rapid disease progression; 
• Tolerating study drug(s); 
• Stable performance status; 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression 
• Participant provides written informed consent prior to receiving additional study therapy, using an ICF 
describing any reasonably foreseeable risks or discomforts, or other alternative treatment options  
Additionally, patients who have progressed between screening imaging and baseline imaging (See Table 7.4-1) 
but prior to initiation of ipilimumab/nivolumab may be allowed to proceed with ipilimumab/nivolumab beyond 
progression at the investigator's discretion.  All decisions to continue treatment beyond initial progression must 
be discussed with the Principal Investigator and documented in the study records. The participant will continue 
to receive monitoring according to the Time and Events Schedules in Table 7.1-2 and Table 7.1-3. A 
radiographic assessment should be performed within 6 weeks of original PD to determine whether there has 
been a decrease in the tumor size, or continued PD. For the participants who continue study therapy beyond PD, 
further progression is defined as an additional 10% increase in tumor burden from time of initial PD. This 
includes an increase in the sum of all target lesions and/or the development of new measurable lesions.  For 
patients with evaluable disease only, further progression is defined as unequivocal disease progression of non-
target lesions or the development of new lesions from time of initial PD. Treatment should be discontinued 
permanently upon documentation of further disease progression. New lesions are considered measurable at the 
time of initial progression if the longest diameter is at least 10 mm (except for pathological lymph nodes, which 
must have a short axis of at least 15 mm). Any new lesion considered non-measurable at the time of initial 
progression may become measurable and therefore included in the tumor burden measurement if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes, which must have an increase in 
short axis to at least 15 mm). 
For statistical analyses that include the investigator-assessed progression date, participants who continue 
treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be considered to have 
investigator-assessed progressive disease at the time of the initial progression event. For participants in all 
treatment arms, global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as ‘symptomatic deterioration’. Every effort 
should be made to document objective progression (i.e., radiographic confirmation) even after discontinuation 
of treatment. 
 
6.5.6 Treatment of Nivolumab- or Ipilimumab-Related Infusion Reactions 
Because nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to occur, 


48 
 
it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo or hypertension, 
bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be reported within 24 hours to the 
Principal Investigator and reported as a serious adverse event (SAE) if criteria are met. Infusion reactions 
should be graded according to NCI CTCAE (version 4.0) guidelines. Treatment recommendations are provided 
below and may be modified based on local treatment standards and guidelines as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not indicated) 
• Remain at bedside and monitor participant until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional study therapy 
administrations 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds promptly to 
symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, narcotics, corticosteroids, 
bronchodilators, IV fluids]; prophylactic medications indicated for ≤ 24 hours). 
• Stop the study therapy infusion, begin an IV infusion of normal saline, and treat the participant with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); remain at 
bedside and monitor the participant until resolution of symptoms. Corticosteroid or bronchodilator therapy may 
also be administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms recur then no further 
study therapy will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside 
and monitor the participant until resolution of symptoms. The amount of study drug infused must be recorded 
on the case report form (CRF). 
• 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 study therapy administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, pulmonary infiltrates]). 
Grade 4: (life threatening; pressor or ventilator support indicated). 
Immediately discontinue infusion of study therapy. Begin an IV infusion of normal saline and treat the 
participant as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, 
and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. Participants 
should be monitored until the investigator is comfortable that the symptoms will not recur. Study therapy will 


49 
 
be permanently discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor participant until recovery from symptoms.  
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritus 
within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids) 
 
 Treatment Compliance 
6.6
Treatment compliance will be monitored by drug accountability as well as the participant’s medical record and 
CRF. 
 
 Destruction or Return of Investigational Product 
6.7
For this study, IP (those supplied by BMS, a vendor or sourced by the investigator) such as partially used study 
drug containers, vials and syringes may be destroyed on site.  
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures for proper 
disposal have been established according to applicable federal, state, local and institutional guidelines and 
procedures and provided that appropriate records of disposal are kept. The following minimal standards must be 
met: 
• On-site disposal practices must not expose humans to risks from the drug 
• Written procedures for on-site disposal are available and followed. The procedures must be filed with 
the site’s SOPs and a copy provided to BMS upon request 
• Records are maintained that allow for traceability of each container, including the date disposed of, 
quantity disposed, and identification of the person disposing the containers. The method of disposal, ie, 
incinerator, licensed sanitary landfill, or licensed waste disposal vendor must be documented 
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to review 
throughout the clinical trial period 
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers. If conditions 
for destruction cannot be met the responsible Study Monitor will make arrangements for return of IP provided 
by BMS (or its vendors). Destruction of non-IP sourced by the site, not supplied by BMS, is solely the 
responsibility of the investigator or designee. 
Please refer to Section 10.2.2 for guidance on IP records and documentation. 
 
 
 


50 
 
 
7 STUDY ASSESSMENTS AND PROCEDURES 
 
 Flow Chart/Time and Event Schedule 
7.1
Table 7.1-1. Screening Procedural Outline (MCC 18914)A 
Procedure 
Screening 
Notes 
Informed Consent 
X 
Informed Consent may be obtained at any time, 
provided it is prior to conduct of any study-related 
procedures. Note that SAEs are collected from the date 
of consent. 
Inclusion/Exclusion Criteria 
X 
All inclusion/exclusion criteria should be assessed at 
screening and confirmed prior to study initiation. 
Medical History 
X 
  
Prior Systemic Therapy 
X 
  
Safety Assessments 
  
  
Physical Examination 
X 
  
Physical Measurements 
X 
Include Height, Weight, and ECOG performance Status. 
Within 28 days prior to thoracic RT. 
Vital Signs and Oxygen 
saturation 
X 
Temperature, BP, HR, and O2 saturation at rest by 
pulse oximetry. Obtain vital signs at the screening visit 
and within 72 hours prior to thoracic RT. 
Assessment of Signs and 
Symptoms 
X 
Within 28 days prior to initiation of thoracic RT. 
Concomitant Medication 
Collection 
X 
Within 28 days prior to initiation of Thoracic RT. 
Laboratory Tests 
X 
CBC with differential, chemistry panel including LDH, 
AST, ALT, ALP, T.Bili, BUN or serum urea level, uric 
acid, creatinine, Ca, Mg, Na, K, Cl, P, glucose, 
bicarbonates (optional), albumin, amylase, lipase, TSH 
(reflex to free T3, free T4 for abnormal TSH result), 
hepatitis B surface antigen (HBV sAg), and hepatitis C 
antibody (HCV Ab) within 28 days prior to initiation of 
thoracic RT. Screening labs done within 72 hours prior 
to first dose can also be used for on treatment lab 
purposes at Day 1 dosing. 
ECG 
X 
Within 28 days prior to initiation of thoracic RT. 


51 
 
 
Pregnancy Test 
X 
Performed within 24 hours prior to initiation of thoracic 
RT for WOCBP only (serum or urine - local/site). 
Efficacy/Biomarker Assessments  
  
Radiographic Tumor Assessment 
X 
Within 28 days prior to initiation of Thoracic RT.  
---CT/ Chest-With IV contrast preferred.   
---CT/MRI Abdomen-With oral and IV contrast 
preferred.   
---CT/MRI Pelvis-With oral and IV contrast preferred.  
Only required if patient has known pelvic visceral 
     metastases or bony metastases in the pelvis.  ---
MRI/CT Brain-with contrast if possible.  MRI 
preferred.  
Attempt collection of tumor tissue 
for pathologic confirmation and 
exploratory biomarker evaluation 
X 
Although it is not required, a serious attempt must be 
made to obtain diagnostic tumor tissue for confirmation 
of small cell pathologic diagnosis and for exploratory 
endpoints. (FFPE) tumor tissue block or minimum of 10 
slides, obtained from core biopsy, punch biopsy, 
excisional biopsy or surgical specimen). Fine needle 
aspiration is sufficient if that is the only available tissue. 
Archival tumor material must be made available. 
 
 
Moffitt Cancer Research 
Network/Clinical Drug Supplies 
  
  
Phone calls to MCRN 
  
Phone calls must be made to MCRN as follows: 
 
Screening phone call to IVRS: For participant number 
assignment at the time informed consent is obtained. 
A-Screening Procedure Visit cannot be more than 28 days before initiation of RT 
 
 
 
 
 


52 
 
Table 7.1-2. On-Treatment Assessments for All Participants, Thoracic Radiation TherapyA,B  
 
Procedure 
Radiation 
Treatments 1-5 
Radiation 
Treatments 6-10 
Notes 
Beginning of 
Week 1 
 
End of Week 2  
 
Targeted Physical 
Examination 
X 
X 
Within 72 hours prior to initiating 
(Week 1) and after ending (Week 2) 
thoracic radiation therapy. 
Vital Signs and 
Oxygen Saturation 
X 
X 
Temperature, BP, HR, O2 saturation at 
rest by pulse oximetry at rest (also 
monitor amount of supplemental 
oxygen if applicable) within 72 hours 
prior to initiating and after ending 
Thoracic Radiation Therapy and at any 
time a participant has any new or 
worsening respiratory symptoms.  
These can also be used for screening 
purposes if appropriate.  
Physical 
Measurements 
X 
X 
Includes Weight and ECOG 
performance status within 72 hours 
prior to dosing. These can also be used 
for screening purposes if appropriate. 
Adverse Events 
Assessment 
CONTINUOUS 
Assessed using NCI CTCAE v. 4.0. 
SAEs should be reported within 24 
hours through the MCRN protocol 
outlined in Section 8.1.   
Review of 
Concomitant 
Medications 
X 
X 
  
Extended 
Laboratory Tests 
X 
X 
Extended on-study local laboratory 
assessments should be done within 72 
hours prior to initiation of thoracic RT 
(Week 1) and within 72 hours of 
completing thoracic RT (Week 2).  
Labs to be collected include CBC with 
differential, uric acid, BUN or serum 
urea level, creatinine, Na, K, Ca, Mg, 
phosphorus, chloride, bicarbonate 
(optional), amylase, lipase, glucose, 
AST, ALT, total bilirubin, alkaline 
phosphatase, LDH. 


53 
 
Thyroid Function 
Testing 
X 
TSH (reflex to free T3 and free T4 if 
abnormal result) to be performed every 
6 weeks (+/-1 week) throughout the 
study.   
Pregnancy Test 
X 
Serum or urine within 24 hours prior to 
first dose and then at least once every 4 
weeks regardless of dosing schedule. 
Efficacy 
Assessments 
  
  
  
Radiographic 
Tumor Assessment 
NA 
See Table 7.4-1 and Table 7.4-2 for CT 
and MRI scan schedule. 
Additional Exploratory Biomarker Testing  
  
Serum, Whole 
Blood Collection 
X 
X 
See Table 7.5-1 for biomarker 
sampling schedule. 
A Thoracic RT start must be at least 3 weeks but not more than 8 weeks after completion of 
platinum based chemotherapy 
BPlease see section 5.2 for details of RT treatment schedule 
 
Table 7.1-3. On-Treatment Assessments for All Participants, Combined Nivolumab and Ipilimumab 
(Cycle 1 [cycle length = 42 days])A 
Procedure 
Cycles 1 and 2 
Notes 
Day 1  
Day 22  
Targeted Physical 
Examination 
X 
X 
Within 72 hours prior to dosing. 
Vital Signs and Oxygen 
Saturation 
X 
X 
Temperature, BP, HR, O2 saturation at rest by 
pulse oximetry at rest (also monitor amount of 
supplemental oxygen if applicable) within 72 
hours prior to dosing and at any time a 
participant has any new or worsening 
respiratory symptoms. 
Physical Measurements 
X 
X 
Includes Weight and ECOG performance status 
within 72 hours prior to dosing. 
Adverse Events Assessment 
CONTINUOUS 
Assessed using NCI CTCAE v. 4.0. SAEs 
should be reported within 24 hours through the 
MCRN protocol outlined in Section 8.1.   


54 
 
Review of Concomitant 
Medications 
X 
X 
  
Extended Laboratory Tests 
X 
X 
Extended on-study local laboratory 
assessments should be done within 72 hours 
prior to dosing on Days 1, 22 and include: CBC 
with differential, uric acid, BUN or serum urea 
level, creatinine, Na, K, Ca, Mg, phosphorus, 
chloride, bicarbonate (optional), amylase, 
lipase, glucose, AST, ALT, total bilirubin, 
alkaline phosphatase, LDH. 
Thyroid Function Testing 
X 
TSH (reflex to free T3 and free T4 if abnormal 
result) to be performed every 6 weeks (+/- 1 
week). (Day 1 of each Cycle). 
Pregnancy Test 
X 
X 
Serum or urine within 24 hours prior to first 
dose and then at least once every 4 weeks 
regardless of dosing schedule. 
Efficacy Assessments 
  
Radiographic Tumor 
Assessment 
See Note 
CT chest, CT/MRI abdomen, and any other 
known or suspected sites of disease. Repeat 
CT/MRI of pelvis is required for participants 
with pelvic metastases at baseline, or if 
clinically indicated. Participants should have 
surveillance MRI/CT scans of the brain every 
12 weeks or sooner if clinically indicated. 
 
See Table 7.4-1 and Table 7.4-2 for CT and 
MRI scan schedule. 
Additional Exploratory 
Biomarker Testing 
  
Serum, Whole Blood, 
Tumor Biopsy 
X 
X 
See Table 7.5-1 for biomarker sampling 
schedule. 
Clinical Drug Supplies 
  
Administer Ipi-3/Nivo-1 
X 
X 
  
ACycle 1 must start at least 14 days but not more than 21 days after completion of RT 
B Please see section 6.5.1 for Dosing Windows 
 
 
 


55 
 
 
Table 7.1-4. On-Treatment Assessments for All Participants, Cycle 3 and Subsequent cycles (cycle 3+ length = 28 
days)A,B 
 
Procedure 
Cycle 3+ 
Notes 
Day 1 
Targeted 
Physical 
Examination 
X 
Within 72 hours prior to dosing. 
Vital Signs and 
Oxygen 
Saturation 
X 
Temperature, BP, HR, O2 saturation at rest by pulse oximetry at rest (also monitor 
amount of supplemental oxygen if applicable) within 72 hours prior to dosing and at 
any time a participant has any new or worsening respiratory symptoms. 
Physical 
Measurements 
X 
Includes Weight and ECOG performance status within 72 hours prior to dosing. 
Adverse 
Events 
Assessment 
CONTINUOUS 
Assessed using NCI CTCAE v. 4.0. SAEs should be reported within 24 hours 
through the MCRN protocol outlined in Section 8.1.   
Review of 
Concomitant 
Medications 
X 
  
Extended 
Laboratory 
Tests 
X 
Extended on-study local laboratory assessments should be done within 72 hours prior 
to dosing for Cycle 3 and every cycle thereafter and include: CBC with differential, 
uric acid, BUN or serum urea level, creatinine, Na, K, Ca, Mg, phosphorus, chloride, 
bicarbonate (optional), amylase, lipase, glucose, AST, ALT, total bilirubin, alkaline 
phosphatase, LDH. 
Thyroid 
Function 
Testing 
X (every 2 
cycles) 
TSH (reflex to free T3 and free T4 if abnormal result) to be performed every 6 weeks 
(+/- 1 week) 
Pregnancy Test 
X (every 2 
cycles) 
Serum or urine within 24 hours prior to first dose and then at least once every 4 
weeks regardless of dosing schedule. 
Efficacy 
Assessments 
  
Radiographic 
Tumor 
Assessment 
See Note 
CT chest, CT/MRI abdomen, and any other known or suspected sites of disease. 
Repeat CT/MRI of pelvis is required for participants with pelvic metastases at 
baseline, or if clinically indicated. See Table 7.4-1 and Table 7.4-2 for CT and MRI 
scan schedule. 
Additional 
Exploratory 
  


56 
 
Biomarker 
Testing 
Serum, Whole 
Blood, Tumor 
Biopsy 
See Note 
See Table 7.5-1 for biomarker sampling schedule. 
Clinical Drug 
Supplies 
  
Administer 
Nivo 480mg 
X 
  
ACycle 3 must start at least 42 days but not more than 56 days after completion of Cycle 1 and 2 
B Please see section 6.5.1 for Dosing Windows 
 
Table 7.1-5. Follow-Up Assessments for All Participants (MCC 18914) 
Procedure 
Follow-Up 
Visits 1 and 2A 
Survival 
Follow-Up 
VisitsB 
Notes 
Safety Assessments 
  
  
  
Targeted Physical Examination 
X 
  
To assess for potential late emergent study 
drug-related issues. 
Adverse Events Assessment 
X 
X 
NSAEs and SAEs must be collected up to 30 
days after study drug discontinuation. SAEs 
that relate to any later protocol specified 
procedure must be collected. SAEs should be 
reported through the MCRN protocol outlined 
in Section 8.1.   
Review of Concomitant 
Medications 
X 
X 
  
Extended Laboratory Tests 
X  
  
CBC with differential, uric acid, BUN or 
serum urea level, creatinine, Na, K, Ca, Mg, 
phosphorus, chloride, bicarbonate (optional), 
amylase, lipase, glucose, AST, ALT, total 
bilirubin, alkaline phosphatase, LDH. 
Thyroid Function Testing 
X  
  
TSH (reflex to free T3 and free T4 if abnormal 
result). 
Pregnancy Test 
X 
  
Serum or urine. 
 


57 
 
Efficacy Assessments 
  
  
  
Radiographic Tumor 
Assessment 
See Note 
See Note 
See Table 7.4-1 and Table 7.4-2 for CT and 
MRI scan schedule. 
Exploratory Biomarker 
Testing 
  
  
  
Serum, Whole Blood, Tumor 
Biopsy 
See Note 
  
See Table 7.5-1 for biomarker sampling 
schedule. 
Participant Status 
  
  
  
Survival Status 
X 
X 
Every 3 months after follow-up visit 2; may be 
accomplished by visit or phone contact, to 
update survival information and assess 
subsequent anti-cancer therapy. 
  
  
A-Follow-up visits occur as follows: X01 = 35 days ± 7 days from last dose, X02 = 80 days ± 7 days from X01 
B-Survival visits continue every 3 months ± 14 days after Follow-up Visit 2 until death, lost to follow-up, or withdrawal of 
study consent 
7.1.1 Retesting During Screening 
Retesting of laboratory parameters and/or other assessments within the screening period will be permitted (in 
addition to any parameters that require a confirmatory value). Any new result will override the previous result 
(i.e., the most current result prior to initiation of thoracic radiation therapy) and is the value by which study 
inclusion will be assessed, as it represents the participant’s most current, clinical state. Laboratory parameters 
and/or assessments that are included in Table 7.1-1, Screening Procedural Outline may be repeated in an effort 
to find all possible well-qualified participants. Consultation with the Principal Investigator may be needed to 
identify whether repeat testing of any particular parameter is clinically relevant. 
 Study Materials 
7.2
The following materials will be provided to the site. 
• Nivolumab Investigator Brochure 
• Ipilimumab Investigator Brochure 
• Pharmacy Binder 
• Laboratory manuals for collection and handling of blood (including biomarker and immunogenicity) 
and tissue specimens 
• Imaging and Radiation Planning Manual for image acquisition and submission to central vendor 
• Pregnancy Surveillance Forms 


58 
 
 
 Safety Assessments 
7.3
Safety assessments include AEs, physical examinations, vital signs, ECOG performance status, assessment of 
signs and symptoms, laboratory tests, pregnancy tests as outlined in Section 7.1. 
Some of the previously referred to assessments may not be captured as data in the eCRF. They are intended to 
be used as safety monitoring by the treating physician. Additional testing or assessments may be performed as 
clinically necessary or where required by institutional or local regulations. 
 
7.3.1 Imaging Assessment for the Study 
Any incidental findings of potential clinical relevance that are not directly associated with the objectives of the 
protocol should be evaluated and handled by the investigator as per standard medical/clinical judgment. 
 
 Efficacy Assessments 
7.4
Study evaluations will take place in accordance with the flow charts in Section 7.1. Contrast-enhanced 
computed tomography (CT) of the chest and CT or magnetic resonance imaging (MRI) of abdomen and any 
other known or suspected sites of disease are the preferred methods of radiographic assessment of tumors. 
Repeat CT/MRI of pelvis is required for participants with pelvic metastases at baseline, or if clinically 
indicated. Brain MRI scan is the preferred imaging method for evaluating CNS metastasis, and assessment is 
required at screening and every 12 weeks while on study; however, CT of the brain is acceptable if MRI is 
contraindicated. Patients with incidental asymptomatic brain metastases findings at screening will need to 
undergo radiation treatment in order to be eligible. Patients are only eligible if according to the clinical 
judgment of the investigator the finding of an incidental brain metastasis is unlikely to represent progression of 
disease. The investigator should take results from brain scans at the initial diagnosis into consideration. If a 
patient has a known allergy to contrast material, please use local prophylaxis standards to obtain the assessment 
with contrast if at all possible, or use the alternate modality. In cases where contrast is strictly contraindicated, a 
non-contrast scan will suffice. 
All known or suspected sites of disease (including CNS) should be assessed at screening and at subsequent 
assessments using the same imaging method and technique. If more than one method is used at screening, then 
the most accurate method according to RECIST 1.1 should be used when recording data and should again be 
used for all subsequent assessments. Bone scan, PET scan, and ultrasound are not adequate for assessment of 
RECIST 1.1 response. In selected circumstances where such modalities are the sole modality used to assess 
certain non-target organs, those non-target organs may be evaluated less frequently. For example, bone scans 
may need to be repeated only when complete response is identified in target disease or when progression in 
bone is suspected. Previously treated CNS metastases are not considered measurable lesions for purposes of 
RECIST 1.1 response.  Screening  assessments should be performed within 28 days of initiation of radiation 
therapy . Participants will be evaluated for tumor response outlined in Table 7.4-1 and Table 7.4-2 or more 
frequently as clinically indicated or per local Standard of Care, until disease progression (or until 


59 
 
discontinuation of study drug in participants receiving study therapy beyond progression), lost to follow-up, 
withdrawal of study consent, or the study ends. Tumor assessments for all participants should continue as per 
protocol even if dosing is delayed. Tumor measurements should be made by the same investigator or radiologist 
for each assessment whenever possible. 
As outlined in section 9.4.1, progression free survival will be calculated from the date of patient registration.  
The baseline scan for RECIST 1.1 response evaluation will be the imaging assessment performed 2 weeks after 
completion of thoracic radiation and prior to C1D1 of combined ipilimumab/nivolumab.  If the patient 
progresses between pre-treatment imaging and the baseline scan prior to initiation of ipilimumab/nivolumab, 
this will be considered disease progression according to the defined primary endpoint.  In this circumstance, at 
the investigator's discretion, the patient may elect to receive study drugs beyond progression according to 
section 6.5.5. Tumor imaging assessments for ongoing study treatment decisions will be completed by the 
investigator using RECIST 1.1 criteria. 
Table 7.4-1. Schedule of CT/MRI Tumor Assessments A 
Time On Study 
Assessment Frequency 
Assessment Week 
(Day 1 of Week 
Shown) 
Assessment 
Window 
Screening 
  
Week 0 
± 28 days 
Baseline (RECIST 1.1) 
  
Week 4 (prior to 
initiation of 
ipilimumab/ 
nivolumab) 
 +/- 5 days 
Between Week 10 and Week 
35 
Every 8-9 weeks after initiation 
of Nivolumab/Ipilimumab 
10,19,27,35,  
± 5 days 
Beyond Week 35 
Every 12 weeks 
47,59,71+, 
± 5 days 
A-Acceptable Radiographic Tumor Assessments: 
---CT/ Chest-With IV contrast preferred.   
---CT/MRI Abdomen-With oral and IV contrast preferred.   
---CT/MRI Pelvis-With oral and IV contrast preferred.  Only required if patient has known pelvic visceral 
metastases or bony metastases in the pelvis.   
 
Table 7.4-2. Schedule of MRI/CT Brain Surveillance Assessments A 
Time On Study 
Assessment 
Frequency 
Assessment Week (Day 1 
of Week Shown) 
Assessment Window 
Screening/Baseline 
  
Week 0 
Within 28 days 
Week 10 
Every 12-13 
Weeks 10, 23, 35, 47,59+   
±5 days 


60 
 
weeks 
A-MRI/CT Brain-with contrast if possible.  MRI preferred.  
7.4.1 Primary and Secondary Efficacy Assessments 
The primary endpoint is progression-free survival at 6 months in all participants. The secondary endpoint is 
overall survival at 1 year. 
See Section 9.4 for the definitions of unacceptable toxicity, OS and PFS. Every effort will be made to collect 
toxicity, survival and imaging data on all participants, including those withdrawn from treatment for any reason, 
who are eligible to participate in the study and who have not withdrawn consent for additional data collection. If 
the death of a participant is not reported, all dates in this study representing a date of participant contact will be 
used in determination of last known date alive. 
 
 Biomarker Assessments 
7.5
A variety of factors that could potentially predict clinical response to nivolumab and ipilimumab will be 
investigated in tumor specimens obtained at screening and in peripheral blood taken both at screening (prior to 
initiation of thoracic radiation therapy) and during the study, from all participants as outlined in Table 7.5-1. 
The de-identified samples will be sent to DiaCarta which is a company that will be performing DNA and RNA 
sequencing analysis of the peripheral blood specimens we collected for the trial. The de-identified samples will 
also be sent to Circulogene which is a company that will be performing DNA and RNA sequencing analysis of 
the peripheral blood specimens we collected for the trial. 
Table 7.5-1. Biomarker Sampling Schedule for all Participants (MCC 18914) 
Collection TimingA 
Serum 
PBMC 
Tumor 
Whole 
Blood 
Study Day 
Soluble 
Biomarkers 
Immunopheno-
typing 
Tumor 
Biopsy 
SNP 
Screening 
XB 
Prior to First Fraction of Thoracic 
Radiation (0-3 days prior) 
X 
X 
X 
After Last Fraction of Thoracic Radiation 
(0-3 days after) 
X 
X 
Prior to each dose of 
ipilimumab/nivolumab or nivolumab 
therapy 
X 
X 
 
 


61 
 
Upon Progression 
X 
X 
At first Follow-Up after study 
discontinuation 
X 
X 
ABiomarker sampling occurs prior to dosing and can occur up to 4 days prior to dosing. 
However, if a sample is collected and the dose is subsequently delayed an additional sample 
should not be collected. 
BSubmission of a tumor sample prior to study initiation is optional. 
 
7.5.1 Tumor Tissue Specimens 
Archival or recently collected FFPE tumor tissue (in the form of paraffin embedded block of a minimum of 10 
unstained slides) will be collected if possible prior to enrollment.  Available specimens must be sent at 
screening to Moffitt Cancer Center  for retrospective determination of PD-L1 status using an analytically 
verified IHC assay. A biopsy sample from participants who experience progression at any time while on 
treatment is optional but strongly encouraged for the purposes of understanding mechanisms of resistance to 
therapy. Biopsy samples may be used for the assessments listed below. Tumor tissue collection details are 
provided in Section 7.5.4. 
 
7.5.2  Characterization of Tumor Infiltrating Lymphocytes (TILS) and Tumor Antigens 
Immunohistochemistry may be used to assess the number and composition of immune infiltrates in order to 
define the immune cell subsets present within FFPE tumor tissue before and after exposure to therapy. These 
immunohistochemistry analyses will include, but not necessarily be limited to, the following markers: CD3, 
CD4, CD8, CD45RO, FOXp3, PD-1, PD-L1 and PD-L2. 
 
7.5.3 DNA and RNA Genomic Assessment 
DNA or RNA extracted from tumor provided may be participant to whole genome or exome sequencing using 
next-generation sequencing to identify mutational load and transcriptional expression. 
 
7.5.4 Tumor Sample Collection Details 
Archival tumor specimens are expected. Pathology report should be provided with tumor samples. For 
participants without available archival tissue, a new biopsy is not required as long as a pathologic diagnosis of 
small cell lung cancer has been established. Formalin-fixed paraffin embedded tissue may be evaluated also by 
fluorescence in situ hybridization (FISH), genetic mutation detection methods, and/or by quantitative 
polymerase chain reaction (QPCR) for exploratory analyses of prognostic or predictive molecular markers 


62 
 
associated with SCLC (eg, gene mutation, amplification or overexpression), to determine if these factors 
influence response to ipilimumab and nivolumab. Such analyses will be completed retrospectively and within 
the scope of informed consent. 
If feasible, tumor biopsies or surgical specimens obtained throughout the participant’s standard of care 
treatment course may be obtained. Where appropriate, changes in expression of immunoregulatory proteins may 
be assessed in these specimens with the consent of the participant.  
 
7.5.5 Peripheral Blood Markers 
A variety of factors that may affect the immunomodulatory properties and efficacy of nivolumab will be 
investigated in peripheral blood specimens taken from all participants prior to or during treatment. Data from 
these investigations will be evaluated for associations with response, survival, and/or safety (adverse event) 
data. Several analyses may be completed and are described briefly below. 
 
7.5.6 Single Nucleotide Polymorphisms (SNPs) 
Whole blood will be collected from all participants prior to treatment to generate genomic DNA for Single 
Nucleotide Polymorphism (SNP) analyses and serve as a reference for tumor mutational profiling, unless 
restricted by local regulations. These analyses will focus on SNPs within genes associated with PD-1 and other 
immunoregulatory signaling pathways to determine if natural variation within those genes is associated with 
response to ipilimumab/nivolumab and/or with AEs during treatment. 
 
7.5.7 Serum Soluble Factors 
To understand the prevalence of circulating proteins and the impact they may have on the clinical activity of 
ipilimumab/nivolumab, the protein concentrations of a panel of cytokines, chemokines, and other relevant 
immunomodulatory, serum-soluble factors (eg, soluble PD-L1) may be investigated at baseline and during 
treatment. 
7.5.8 Peripheral Blood Mononuclear Cells 
Peripheral blood mononuclear cells in whole blood taken from participants at baseline and on treatment and will 
be analyzed by flow cytometry or other methods (e.g., ELIspot) to assess immune cell activity. 
7.5.9 Peripheral Blood DNA and RNA Genomic Assessment 
DNA or RNA extracted from peripheral blood samples collected throughout the study may be participant to 
whole genome or exome sequencing using next-generation sequencing to identify mutational load and 
transcriptional expression. 
 


63 
 
8 ADVERSE EVENTS 
NCI CTCAE Version 4.0 will be utilized for identification and grading of all adverse events.   
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation participant administered study drug and that does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, 
whether or not considered related to the study drug. The causal relationship to study drug is determined by a 
physician and should be used to assess all adverse events. The causal relationship can be one of the following: 
• Unrelated: The Adverse Event is clearly not related to the investigational agent(s) 
• Unlikely: The Adverse Event is doubtfully related to the investigational agent(s) 
• Possible: The Adverse Event may be related to the investigational agent(s) 
• Probable: The Adverse Event is likely related to the investigational agent(s) 
• Definite: The Adverse Event is clearly related to the investigational agent(s) 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. (In order to prevent reporting bias, participants should not be questioned regarding 
the specific occurrence of one or more AEs.) 
The study sponsor, Moffitt Cancer Center ,will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including FDA Code of Federal Regulations 21 CFR Parts 312 
and 320. In addition, K08 CA231454-01A1 Grant support will be provided through Moffitt Cancer Center. 
 
Serious Adverse Events 
8.1
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
Results in death 
Is life-threatening (defined as an event in which the participant was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more severe) 
Requires in-patient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the participant or may require intervention [eg, medical, surgical] to prevent 
one of the other serious outcomes listed in the definition above.) Examples of such events include, but 


64 
 
are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias, or convulsions that do not result in hospitalization.  
Potential drug-induced liver injury (DILI) is also considered an important medical event. (See Section 
8.6 for the definition of potential DILI.) 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via study drug is an 
SAE. 
Although pregnancy, overdose, cancer, and potential drug-induced liver injury (DILI) are not always 
serious by regulatory definition, these events must be handled as SAEs. (See Section 8.4 for reporting 
pregnancies.) 
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported as 
SAE (see Section 8.1.1 for reporting details). 
NOTE: 
The following hospitalizations are not considered SAEs: 
a visit to the emergency room or other hospital department < 24 hours that does not result in admission 
(unless considered an important medical or life-threatening event) 
elective surgery, planned prior to signing consent 
admissions as per protocol for a planned medical/surgical procedure 
routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 
medical/surgical admission other than to remedy ill health and planned prior to entry into the study. 
Appropriate documentation is required in these cases 
admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver respite, 
family circumstances, administrative reason). 
 
8.1.1  Serious Adverse Event Collection and Reporting 
The Investigator Brochure (IB) contains Reference Safety Information to determine expectedness of serious 
adverse events for expedited reporting. Following the participant’s written consent to participate in the study, all 
SAEs, whether related or not related to the study, must be collected, including those thought to be associated 
with protocol-specified procedures.  
All SAEs must be collected that occur during the screening period and within 100 days of discontinuation of 
dosing. If applicable, SAEs must be collected that relate to any later protocol-specified procedure. The 
investigator must report any SAE that occurs after these time periods and that is believed to be related to the 


65 
 
study or protocol-specified procedure. An SAE report must be completed for any event where doubt exists 
regarding its seriousness.  All SAEs must be reported to BMS Worldwide Safety.  The BMS SAE form should 
be used to report SAEs.   
If the investigator believes that an SAE is not related to the study, but is potentially related to the conditions of 
the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship must 
be specified in the narrative section of the SAE Report Form.  
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (as below) and to  
the study sponsor, Moffitt Cancer Center, through the MCRN coordinating center within 24 hours of awareness 
of the event. SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy Surveillance Form 
(electronic or paper forms).  
To ensure patient safety, each serious adverse event must be reported to the BMS, the PI and to the MCRN 
coordinating center within 24 hours of the investigational staff’s knowledge. All participating sites will report 
SAEs by completing an SAE report in OnCore, the electronic data capture system. The SAE must be reported 
by email (affiliate.research@moffitt.org) to the MCRN within 24 hours of discovery. 
The preferred method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning. In this case, 
the paper forms are to be transmitted via email or confirmed facsimile (fax) transmission to both : 
SAE Email Addresses: affiliate.research@moffitt.org , Worldwide.Safety@BMS.com 
SAE Facsimile Numbers: MCRN 813-745-5666, BMS 609-818-3804 
SAE Telephone Contacts: 813-745-6993 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports 
should include the same investigator term(s) initially reported.)  
 If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, the SAE report must be updated and submitted within 24 hours to Sponsor or designee using the same 
procedure used for transmitting the initial SAE report.  
All SAEs must be followed to resolution or stabilization. 
The Sponsor/Investigator will ensure that all SAEs in the clinical database are reported to BMS and any 
applicable health authority during the conduct of the study. This reconciliation will occur at least quarterly and 
be initiated by the sponsor/investigator. Sponsor/investigator will request a reconciliation report from: 
aepbusinessprocess@bms.com. During reconciliation, any events found to not be reported previously to BMS 
must be sent to Worldwide.Safety@BMS.com.  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a subset of SAEs and will be reported to the 
appropriate regulatory authorities and investigators following local and global guidelines and requirements. 


66 
 
 Nonserious Adverse Events 
8.2
A nonserious adverse event is an AE not classified as serious. 
8.2.1 Nonserious Adverse Event Collection and Reporting 
NCI CTCAE Version 4.0 will be utilized for grading of all nonserious adverse events. 
The collection of nonserious AE information should begin at initiation of the study.  Data will be captured in 
OnCore, Moffitt’s Clinical Trials Database. To obtain access to OnCore, the site research staff must complete 
forms provided by the MCRN Regulatory Coordinator. Once the completed forms are received, the site 
coordinator will receive DUO access, logon/password, and information on how to access OnCore. The 
MCRN Coordinating Center will provide OnCore training to the site once initial access is granted and on an 
ongoing basis, as needed.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious 
(see Section 8.1.1). Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study drug and for those present at the end of study treatment as appropriate. All identified nonserious AEs 
must be recorded and described on the nonserious AE page of the OnCore CRF. All nonserious AEs (not only 
those deemed to be treatment-related) should be collected continuously during the treatment period and for a 
minimum of 100 days following the last dose of study treatment. Completion of supplemental CRFs may be 
requested for AEs and/or laboratory abnormalities that are reported/identified during the course of the study. 
 
 Laboratory Test Result Abnormalities 
8.3
The following laboratory test result abnormalities should be captured on the nonserious AE CRF page or SAE 
Report Form (paper or electronic using OnCore) as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory test result abnormality that required the participant to have study drug discontinued or 
interrupted 
• Any laboratory test result abnormality that required the participant to receive specific corrective 
therapy 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the reporting 
investigator (eg, anemia versus low hemoglobin value). 
 
 Pregnancy 
8.4
If, following initiation of the study, it is subsequently discovered that a study participant is pregnant or may 
have been pregnant at the time of study exposure, including during at least 6 half lives after product 


67 
 
administration, the investigator must immediately notify the BMS Worldwide Safety and the Principal 
Investigator/designee of this event and complete and forward a Pregnancy Surveillance Form within 24 hours of 
awareness of the event and in accordance with SAE reporting procedures described in Section 8.1.1. An SAE 
must also be entered into the OnCore system and an email sent to the MCRN (affiliate.research@moffitt.org) 
and to BMS (Worldwide.Safety@BMS.com) within 24 hours of discovery. 
In most cases, the study drugs will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Please call the Principal Investigator within 24 hours of awareness of the 
pregnancy. 
In the rare event that the benefit continuing the study drug is thought to outweigh the risk, after consultation 
with the study sponsor, the pregnant participant may continue study drug after a thorough discussion of benefits 
and risk with the participant.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the participant 
unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy follow-up procedures 
must be performed on the participant.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, 
where applicable, offspring information must be reported on the Pregnancy Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS and the 
MCRN Coordinating Center. In order for the study to collect any pregnancy surveillance information from the 
female partner, the female partner must sign an informed consent form for disclosure of this information. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
 Overdose 
8.5
An overdose is defined as the accidental or intentional administration of any dose of a product that is considered 
both excessive and medically important. All occurrences of overdose must be reported as an SAE (see Section 
8.1.1 for reporting details). 
 
 Potential Drug-Induced Liver Injury (DILI) 
8.6
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the 
reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined criteria, must be 
reported as SAEs (see Section 8.1.1 for reporting details). 
Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 


68 
 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase), 
AND 
3.No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, including, but not 
limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) 
known to be hepatotoxic. 
 
 Other Safety Considerations 
8.7
Any significant worsening noted during interim or final physical examinations, electrocardiogram, x-ray 
filming, any other potential safety assessment required or not required by protocol should also be recorded as a 
nonserious or serious AE, as appropriate, and reported accordingly. 
 
 Protocol Monitoring Committee 
8.8
A Protocol Monitoring Committee (PMC) will be established to provide oversight of safety and 
efficacy considerations in the protocol. The PMC meets monthly and reviews accrual, patterns and 
frequencies of all adverse events, protocol violations and when applicable, internal audit results. 
 
9 STATISTICAL CONSIDERATIONS 
 
 Lead in Safety Observation  
9.1
We will utilize 6-9 patient safety lead in as described in the Section 4.1 with a dose-limiting toxicity period of 
13 weeks.  We will initially enroll 6 patients. If 0 or 1 of 6 patients develops unacceptable toxicity, then we will 
proceed with the study as outlined below (to accrue an additional 46 patients).  If 2 patients develop 
unacceptable toxicity, we will enroll an additional 3 patients to determine the rate of unacceptable toxicity with 
9 patients.  If 3 or more patients develop unacceptable toxicity during any portion of the safety lead in phase, we 
will discontinue the study. 
Additionally, we will be continually assessing toxicity throughout the study and if at any time 3 of the first 9 
patients or greater than 33% of patients experience unacceptable toxicity within the 13 week safety observation 
period, we will discontinue the study. Following the 13-week safety observation period, toxicity will be 
assessed on an ongoing basis for all patients prior to each dose of ipilimumab/nivolumab or nivolumab alone 
until study completion.   


69 
 
 
 Phase I/II Sample Size Determination 
9.2
We propose a single arm, non-randomized phase I/II study, with the goal to evaluate efficacy compared to 
historical controls. Slotman et al. [5] reported a 6-month progression-free survival (PFS) of 24% with platinum-
based chemotherapy and thoracic radiation therapy. We would propose to pursue a phase III randomized 
controlled study if there is a 20% improvement in 6-month PFS with the addition of combined immune 
checkpoint blockade as part of the proposed clinical study. Therefore, this regimen would be considered not 
worthwhile to pursue if the true 6-month PFS is 24% or less and worth pursing if the true 6-month PFS is 44% 
or greater. The trial will use a Simon’s 2-stage design[49] with 1-sided 0.05 level type I error and 90% power. 
The total target sample size is 52 patients.  During the 1st stage, 18 patients will be accrued. If 4 or fewer 
patients have not progressed at 6 months, the study will be closed for futility.  However, if at least 5 patients 
have not progressed at 6 months, then the study will continue to accrue an additional 34 patients. Once the total 
number of patients has accrued (n=52), then the null hypothesis will be rejected if at least 18 patients have not 
progressed at 6 months.   In order to accommodate censoring, we may increase the total sample size by up to 
10% (n=57).   
• The final PFS analysis is targeted to occur 6 months after the last participant is enrolled 
• The final OS analysis is targeted to occur 1 year after the last participant is enrolled.  
 
9.2.1 Accrual Justification 
Fifty patients will be included at phase I/II study completion inclusive of those patients treated as part of the 
safety lead in.  Moffitt Cancer Center in Tampa, FL, will be the primary and lead institution for this phase I/II 
single arm study.  Moffitt sees about 40 patients with ED-SCLC each year, and we estimate that approximately 
25% of patients will be eligible for study enrollment.  Additionally, we have support to enroll patients at up to 5 
additional US academic institutions that see a similar number or more patients with ED-SCLC annually.  
Accounting for delays in study opening at the onset and for delays due to interim safety and efficacy stopping 
points as described above, we anticipate completing accrual to our 50-patient study in about 18 months.  We 
expect to accrue approximately 1 or 2 patients per month for the first 6 months, then approximately 4 patients 
per month for the remaining 12 months.   
 
 Populations for Analyses - Data Set Descriptions 
9.3
• All Treated Participants: All participants who received at least one dose of any study medication 
• Biomarker Participants: All participants with available biomarker data 
 


70 
 
 Endpoints 
9.4
9.4.1 Primary Endpoints 
Part I: Safety Run In Phase I: Unacceptable toxicity status at the end of 13-week safety observation period 
with unacceptable toxicity defined as: 
• Any grade 4 immune related adverse event (irAE), 
• Any ≥ grade 3 noninfectious pneumonitis,  
•  
• Any grade 3 irAE, excluding pneumonitis, that does not downgrade to grade 2 within 7 days 
after onset of the event despite optimal medical management including systemic corticosteroids 
or does not downgrade to ≤ grade 1 or baseline within 14 days,  
• Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN,  
• Any ≥ grade 3 non-irAE, except for the following exclusions:  
 grade 3 fatigue lasting ≤ 7 days 
 grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the participant is asymptomatic 
 grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
 grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days.  
Part II: Phase II: The primary endpoint is 6-month PFS status. PFS is defined as the duration from date of 
registration to date of first documentation of progression assessed by local investigator or symptomatic 
deterioration (as defined above) or death due to any cause. Patients last known to be alive without report of 
progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive 
missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as 
defined by the disease assessment schedule) will be used as the date of progression.  
 
9.4.2 Secondary Endpoint 
1 year overall survival status: Overall survival (OS) is defined as the duration from date of registration to date 
of death due to any cause. Patients last known to be alive are censored at date of last contact. 
 


71 
 
9.4.3 Exploratory Endpoints 
1. Patterns of radiographic response and progression in the thorax, brain, and other sites from the time of small 
cell lung cancer diagnosis until study conclusion.  
2. Patterns of radiographic response and progression within and outside the radiation treatment field from the 
time of small cell lung cancer diagnosis until study conclusion. 
 
 Analyses 
9.5
 
9.5.1 Demographics and Baseline Characteristics 
Demographics and baseline laboratory results will be summarized using descriptive statistics for all participants. 
 
9.5.2 Efficacy Analyses 
At the PFS analysis time point, primary PFS analyses will be conducted.  The PFS curve, PFS median with 95% 
CIs, and PFS rates at 6 and 12 months with 95% CIs will be estimated using Kaplan-Meier methodology. 
At the OS analysis time point, the OS analyses will be conducted. OS curves, OS medians with 95% CIs, and 
OS rates at 12 and 24 months with 95% CIs will be estimated using Kaplan-Meier methodology. 
Additionally, at the same time point as the primary OS analysis, PFS curves, PFS medians with 95% CIs, and 
PFS rates at 6 and 12 months with 95% CIs will be estimated using Kaplan-Meier methodology.  
  
9.5.3 Safety Analyses 
Safety analyses will be performed for all treated participants. Descriptive statistics of safety will be presented 
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
All on-study AEs, drug-related AEs, SAEs and drug-related SAEs will be tabulated using worst grade per NCI 
CTCAE v4.0 criteria by system organ class and MedDRA preferred term. The listings by participant will be 
produced for all deaths, all SAEs, and all AEs leading to discontinuation of study drug. On-study laboratory 
parameters including hematology, chemistry, liver function, thyroid function, and renal function will be 
summarized using worst grade per NCI CTCAE v4.0 criteria.  
 
 


72 
 
10 STUDY MANAGEMENT 
 Compliance 
10.1
10.1.1 Compliance with the Protocol and Protocol Revisions 
The investigator should not implement any deviation or change to the protocol without prior review and 
documented approval/favorable opinion of an amendment from the IRB/IEC (and if applicable, also by local 
health authority) except where necessary to eliminate an immediate hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to obtaining 
relevant approval/favorable opinion(s), the deviation or change will be submitted as soon as possible to: 
• IRB/IEC 
• Regulatory Authority(ies), if applicable by local regulations per national requirements  
Documentation of approval/favorable opinion signed by the chairperson or designee of the IRB(s)/IEC(s) and if 
applicable, also by local health authority, must be sent tothe Study Sponsor, Moffitt Cancer Center through the 
MCRN Coordinating Center. 
If an amendment substantially alters the study design or increases the potential risk to the participant: (1) the 
consent form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable opinion; (2) 
the revised form must be used to obtain consent from participants currently enrolled in the study if they are 
affected by the amendment; and (3) the new form must be used to obtain consent from new participants prior to 
enrollment. 
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
10.1.2 Monitoring 
Regulatory documents and case report forms will be monitored internally according to Moffitt Cancer Center 
Monitoring Policies.  Monitoring will be performed regularly to verify data is accurate, complete, and verifiable 
from source documents; and the conduct of the trial is in compliance with the currently approved protocol/ 
amendments, Good Clinical Practice (GCP), and applicable regulatory requirements. 
 
10.1.3 Source Documentation 
The Investigator is responsible for ensuring that the source data are accurate, legible, contemporaneous, original 
and attributable, whether the data are hand-written on paper or entered electronically. If source data are created 
(first entered), modified, maintained, archived, retrieved, or transmitted electronically via computerized systems 
(and/or any other kind of electronic devices) as part of regulated clinical trial activities, such systems must be 
compliant with all applicable laws and regulations governing use of electronic records and/or electronic 


73 
 
signatures. Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability records). 
When paper records from such systems are used in place of electronic format to perform regulated activities, 
such paper records should be certified copies. A certified copy consists of a copy of original information that 
has been verified, as indicated by a dated signature, as an exact copy having all of the same attributes and 
information as the original. 
 
 Records 
10.2
10.2.1 Records Retention 
The Investigator must ensure that the records and documents pertaining to the conduct of the study and the 
distribution of the study drug, that is copies of CRFs and source documents (original documents, data, and 
records [e.g., hospital records; clinical and office charts; laboratory notes; memoranda; participant’s diaries or 
evaluation checklists; SAE reports, pharmacy dispensing records; recorded data from automated instruments; 
copies or transcriptions certified after verification as being accurate copies; microfiches; photographic 
negatives, microfilm, or magnetic media; x-rays; participant files; and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical study; documents regarding patient 
treatment and study drug accountability; original signed informed consents, etc.]) be retained by the Investigator 
for as long as needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). The Investigator agrees to adhere to 
the document/records retention procedures by signing the protocol. 
10.2.2 Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP integrity and traceability 
from receipt, preparation, administration, and through destruction or return. Records must be made available for 
review at the request of BMS/designee or a Health Authority. Moffitt will provide forms to facilitate inventory 
control if the investigational site does not have an established system that meets these requirements.  
10.2.3 Case Report Forms 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database.  
An investigator is required to prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the investigation on each individual treated in the investigation. Data 
that are derived from source documents and reported on the CRF must be consistent with the source documents 
or the discrepancies must be explained. Additional clinical information may be collected and analyzed in an 
effort to enhance understanding of product safety. CRFs may be requested for AEs and/or laboratory 
abnormalities that are reported or identified during the course of the study.  
The confidentiality of records that could identify participants must be protected, respecting the privacy and 
confidentiality rules in accordance with the applicable regulatory requirements.  


74 
 
 
 Clinical Study Report and Publications 
10.3
The study of these patients and results of all laboratory studies are considered private and confidential. The 
progress and results of this study will not be presented without approval by the principal investigator.  
Any publications or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA) governing participation in the study. These requirements include, but are not 
limited to, submitting proposed publications to BMS at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTA. 
11 LIST OF ABBREVIATIONS 
Term 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AIDS 
Acquired immunodeficiency syndrome 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AT 
Amino transaminases 
-HCG 
beta-human chorionic gonadotrophin 
BID,bid 
Bis in die, twice daily 
BMS 
Bristol-Myers Squibb 
BP 
Blood pressure 


75 
 
BUN 
Blood urea nitrogen 
C 
Celsius 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
C1- 
Chloride 
CLcr 
Creatinine clearance 
Cm 
Centimeter 
CNS 
Central nervous system 
CRF 
Case Report Form, paper or electronic 
CTLA-4 
Cytotoxic t lymphocyte-associated antigen 4 
dL 
Deciliter 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ED-SCLC 
Extensive disease-small cell lung cancer 
Eg 
Exempli gratia(for example) 


76 
 
FDA 
Food and Drug Administration 
FISH 
Fluorescent in situ hybridization 
FSH 
Follicle stimulating hormone 
G 
Gram 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GFR 
Glomerular filtration rate 
H 
hour 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HCO3- 
bicarbonate 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
ICD 
Immunogenic Cell Death 
ICH 
International Conference on Harmonization 
Ie id 
Est (that is) 


77 
 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal products 
IND 
Investigational New Drug Exemption 
IRB 
Institutional Review Board 
IU 
International Unit 
IU/L 
International unit per liter 
IU/mL 
International unit per milliliter 
IVRS 
Interactive voice response system 
IV 
intravenous 
K+ 
potassium 
Kg 
Kilogram 
KM 
Kaplan-meier 
L 
Liter 
LAM 
Lactation amenorrhea method 
LDH 
Lactate dehydrogenase 
mAB 
Monoclonal antibody 
Mg 
Milligram 
Mg++ 
magnesium 


78 
 
Min 
Minute 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
g 
Microgram 
N 
Number of subjects or observations 
Na+ 
Sodium 
N/A 
Not applicable 
NE 
Not evaluable 
Ng 
Nanogram 
NCCN 
National Comprehensive Cancer Network 
NIMP 
non-investigational medicinal products 
NSCLC 
Non small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD 
Pharmacodynamics 
PD-1 
ProgrammedDeath-1 
PD-L1 
Programmeddeath-ligand1 


79 
 
PD-L2 
Programmeddeath-ligand2 
PFS 
progression-free survival 
PR 
Partial response 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
RCC 
Renal cell carcinoma 
RECIST1.1 
Response evaluation criteria in solid tumors version 1.1 
RBC 
Red blood cell 
RT 
Radiation Therapy 
SAE 
Serious adverse event 
SCLC 
Small cell lung cancer 
SD 
Standard deviation 
SD 
Stable disease 
SOP 
Standard Operating Procedures 
T 
Temperature 
T 
Time 
TILs 
Tumor infiltrating lymphocytes 
TTR 
Thoracic radiation therapy 


80 
 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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3. 
Janne, P.A., et al., Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma 
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4. 
Chute, J.P., et al., Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: 
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5. 
Slotman, B.J., et al., Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 
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6. 
Jeremic, B., et al., Role of radiation therapy in the combined-modality treatment of patients with extensive 
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7. 
Ready, N.E., et al., Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-
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Oncol, 2015. 33(15): p. 1660-5. 
8. 
Schiller, J.H., et al., Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung 
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9. 
van Oosterhout, A.G., et al., Neurologic disorders in 203 consecutive patients with small cell lung cancer. Results 
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10. 
Graus, F., et al., Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain, 2001. 
124(Pt 6): p. 1138-48. 
11. 
Maddison, P., et al., Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. 
Lancet, 1999. 353(9147): p. 117-8. 
12. 
Graus, F., et al., Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to 
therapy and improved survival. J Clin Oncol, 1997. 15(8): p. 2866-72. 


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13. 
Wang, W., et al., Histologic assessment of tumor-associated CD45(+) cell numbers is an independent predictor of 
prognosis in small cell lung cancer. Chest, 2013. 143(1): p. 146-51. 
14. 
Berghoff, A.S., et al., Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung 
cancer (SCLC). J Neurooncol, 2016. 130(1): p. 19-29. 
15. 
Koyama, K., et al., Reciprocal CD4+ T-cell balance of effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ 
regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res, 2008. 14(21): p. 6770-9. 
16. 
Alexandrov, L.B., et al., Signatures of mutational processes in human cancer. Nature, 2013. 500(7463): p. 415-21. 
17. 
George, J., et al., Comprehensive genomic profiles of small cell lung cancer. Nature, 2015. 524(7563): p. 47-53. 
18. 
Hanel, W. and U.M. Moll, Links between mutant p53 and genomic instability. J Cell Biochem, 2012. 113(2): p. 
433-9. 
19. 
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small 
cell lung cancer. Science, 2015. 348(6230): p. 124-8. 
20. 
Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med, 2014. 
371(23): p. 2189-99. 
21. 
Tanio, Y., et al., High sensitivity to peripheral blood lymphocytes and low HLA-class I antigen expression of small 
cell lung cancer cell lines with diverse chemo-radiosensitivity. Jpn J Cancer Res, 1992. 83(7): p. 736-45. 
22. 
Yazawa, T., et al., Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung 
cancer. J Pathol, 1999. 187(2): p. 191-9. 
23. 
Antonia, S.J., et al., Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer 
(CheckMate 032): a multicentre, open-label, phase 1/2 trial. The Lancet Oncology, 2016. 17(7): p. 883-895. 
24. 
Slotman, B., et al., Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med, 2007. 357(7): 
p. 664-72. 
25. 
Seto, T., et al., Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of 
patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III 
trial. ASCO Meeting Abstracts, 2014. 32(15_suppl): p. 7503. 
26. 
Goldberg, S.B., et al., Activity and safety of pembrolizumab in patients with metastatic non-small cell lung cancer 
with untreated brain metastases. ASCO Meeting Abstracts, 2015. 33(15_suppl): p. 8035. 
27. 
Demaria, S., E.B. Golden, and S.C. Formenti, Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA 
Oncol, 2015. 1(9): p. 1325-32. 
28. 
Eriksson, D. and T. Stigbrand, Radiation-induced cell death mechanisms. Tumour Biol, 2010. 31(4): p. 363-72. 
29. 
Kroemer, G., et al., Immunogenic cell death in cancer therapy. Annu Rev Immunol, 2013. 31: p. 51-72. 
30. 
Garg, A.D., A.M. Dudek, and P. Agostinis, Cancer immunogenicity, danger signals, and DAMPs: what, when, and 
how? Biofactors, 2013. 39(4): p. 355-67. 
31. 
Obeid, M., et al., Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-
induced apoptosis. Cell Death Differ, 2007. 14(10): p. 1848-50. 


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32. 
Reits, E.A., et al., Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces 
successful antitumor immunotherapy. J Exp Med, 2006. 203(5): p. 1259-71. 
33. 
Sridharan, V. and J.D. Schoenfeld, Immune effects of targeted radiation therapy for cancer. Discov Med, 2015. 
19(104): p. 219-28. 
34. 
Grass, G.D., N. Krishna, and S. Kim, The immune mechanisms of abscopal effect in radiation therapy. Curr Probl 
Cancer, 2016. 40(1): p. 10-24. 
35. 
Chakravarty, P.K., et al., Flt3-ligand administration after radiation therapy prolongs survival in a murine model of 
metastatic lung cancer. Cancer Res, 1999. 59(24): p. 6028-32. 
36. 
Camphausen, K., et al., Radiation abscopal antitumor effect is mediated through p53. Cancer Res, 2003. 63(8): p. 
1990-3. 
37. 
Demaria, S., et al., Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune 
mediated. Int J Radiat Oncol Biol Phys, 2004. 58(3): p. 862-70. 
38. 
Reynders, K., et al., The abscopal effect of local radiotherapy: using immunotherapy to make a rare event 
clinically relevant. Cancer Treat Rev, 2015. 41(6): p. 503-10. 
39. 
Demaria, S., et al., Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 
blockade in a mouse model of breast cancer. Clin Cancer Res, 2005. 11(2 Pt 1): p. 728-34. 
40. 
Park, S.S., et al., PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer Immunol Res, 2015. 3(6): p. 610-9. 
41. 
Postow, M.A., et al., Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med, 
2012. 366(10): p. 925-31. 
42. 
Golden, E.B., et al., An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell 
lung cancer. Cancer Immunol Res, 2013. 1(6): p. 365-72. 
43. 
Theurich, S., et al., Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs 
Overall Survival in Patients with Advanced Malignant Melanoma. Cancer Immunol Res, 2016. 4(9): p. 744-54. 
44. 
Calveley, V.L., et al., Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA 
damage and inflammatory cytokines following irradiation. Int J Radiat Biol, 2005. 81(12): p. 887-99. 
45. 
Boyer, M.J., et al., Toxicity of definitive and post-operative radiation following ipilimumab in non-small cell lung 
cancer. Lung Cancer, 2016. 98: p. 76-8. 
46. 
Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J 
Med, 2015. 373(17): p. 1627-39. 
47. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. New England 
Journal of Medicine, 2012. 366(26): p. 2443-2454. 
48. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med, 2013. 369(2): p. 122-33. 
49. 
Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials, 1989. 10(1): p. 1-10. 


83 
 
13 APPENDIX 1: STUDY CALENDAR 
Scree
n-ingA 
W
-3 
W
-2 
W
-1 
W1B 
W2C 
W
3 
W4
D 
W
5 
W
6 
W
7 
W
8 
W
9 
W1
0 
W1
1 
W1
2 
W1
3 
W1
4 
W1
5 
W1
6 
W1
7 
W1
8 
W19
E 
W2
0 
W2
1 
W2
2 
W2
3 
W2
4 
W2
5 
W2
6 
W27
+F 
Follo
w 
UpG 
Surviv
al 
Follow 
upH 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclus
ion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Adverse Events 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of 
Concomitant 
Medications 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Screening 
Laboratory Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extended 
Laboratory Tests 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Thyroid 
Function Testing 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Simulation for 
Thoracic 
Radiation 
Therapy 
 
XO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Chest w/ IV 
contrastI 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
CT Abdomen w/ 
IV and oral 
contrastJ 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
CT Pelvis w/ IV 
and oral 
contrastK 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
MRI Brain w/ IV 
contrastL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Attempt 
collection of 
diagnostic FFPE 
tumor tissueM 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood 
for BiomarkersN 
X 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Administer 
Thoracic 
Radiation 
Therapy  
 
 
 
 
XXXX
X 
XXXX
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer 
Ipilimumab 
3mg/kg  
 
 
 
 
 
 
 
XP 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer 
Nivolumab 
1mg/kg 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer 
Nivolumab 
480mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 


84 
 
 
 
A Not more than 28 days before initiation of RT. See Table 7.1-1 for details of screening procedures. 
B Within 72 hours prior to initiation of RT.  See Table 7.1-2 for details of thoracic RT schedule. 
C Within 72 hours after completing RT.  See Table 7.1-2 for details of thoracic RT schedule. 
D See Table 7.1-3 for details of combined ipilumumab and nivolumab treatment schedule. 
E See Table 7.1-4 for details of nivolumab alone treatment schedule. 
F See Table 7.1-4 for detailed instructions related to ongoing assessments with nivolumab maintenance therapy 
G See Table 7.1-5 for details of follow up after discontinuation of study therapy.   
H See Table 7.1-5 for details of survival follow up visits. 
K Required only if patient has known history of pelvic metastases 
L CT brain w/ contrast acceptable 
M For exploratory biomarker evaluation (prefer surgical specimen or core biopsy tissue, FNA also acceptable) 
N See Table 7.5-1 for details of peripheral blood collection for biomarkers 
O Anytime within 28 days before initiation of RT 
P Must start more than 14 days but less than 28 days after completion of RT 
 


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14 APPENDIX 2: MANAGEMENT ALGORITHMS FOR IMMUNE ADVERSE EVENTS 
These general guidelines constitute guidance to the Investigator and may be supplemented by discussions with the Principal Investigator.. The 
guidance applies to all immuno-oncology (I-O) agents and regimens. A general principle is that differential diagnoses should be diligently evaluated 
according to standard medical practice. Non-inflammatory etiologies should be considered and appropriately treated. Corticosteroids are a primary 
therapy for immuno-oncology drug-related adverse events. The oral equivalent of the recommended IV doses may be considered for ambulatory 
patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose 
of oral corticosteroids. Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure, is 
recommended.  The frequency and severity of the related adverse events covered by these algorithms will depend on the immuno-oncology agent or 
regimen being used.  
 


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