Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer
Phase: PHASE1
Conditions: Non Small Cell Lung Cancer, Lung Cancer, Nonsmall Cell, Non Small Cell Lung Cancer Metastatic
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Clinical Study Protocol 
Drug Substance: Nivolumab, Ipilimumab and Nintedanib MCC #: 19406 
Version: 8 
Date: 12 January 2024 
 
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PHASE I/II STUDY OF NIVOLUMAB/IPILIMUMAB COMBINED WITH NINTEDANIB IN 
ADVANCED NSCLC 
 
 
 
 
 Phase: 
 
 
       I/II 
 
 
Sponsor: 
Moffitt Cancer Center 
 
 
Principal Investigator: 
Jhanelle E. Gray, MD 
H. Lee Moffitt Cancer Center and Research 
Institute 12902 Magnolia Drive, FOB1 
Tampa, FL 33612 
Telephone: (813) 745-6895 
Fax: (813) 745-3027 
E-mail: jhanelle.gray@moffitt.org 
 
 
 
 
 
Version #: 
Version Date: 
8 
January 12, 2024  
MCC Number: 
19406 
IND Number: 
137424 
IRB Number: 
Pro00023475 
BMS: 
CA209-9P8 
BI:                                    
1199.316 
 

Clinical Study Protocol 
Drug Substance: Nivolumab, Ipilimumab and Nintedanib MCC #: 19406 
Version: 8 
Date: 12 January 2024 
 
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Table of Contents 
SCHEMA / Flow Chart ....................................................................................................................... 6 
PROTOCOL SYNOPSIS ................................................................................................................... 7 
1 
BACKGROUND ................................................................................................................... 9 
1.1 
Introduction - Medical Background........................................................................................ 9 
1.2 
Immunotherapy in NSCLC .................................................................................................... 9 
1.3 
Nivolumab .......................................................................................................................... 10 
1.3.1 
Preclinical development and pharmacokinetics ................................................................... 10 
1.3.2 
Clinical development of Nivolumab ..................................................................................... 10 
1.3.3 
Clinical experience with Nivolumab in NSCLC .................................................................... 11 
1.4 
Ipilimumab .......................................................................................................................... 12 
1.4.1 
Preclinical development and pharmacokinetics ................................................................... 12 
1.4.2 
Clinical development of Ipilimumab ..................................................................................... 15 
1.4.3 
Clinical development with Ipilimumab in NSCLC. ................................................................ 16 
1.5 
Combined Immune Checkpoint Inhibition ............................................................................ 17 
1.6 
Nintedanib (BIBF1120) ....................................................................................................... 17 
1.6.1 
Preclinical development and pharmacokinetics ................................................................... 17 
1.6.2 
Clinical development of Nintedanib ..................................................................................... 19 
1.6.3 
Clinical Experience of Nintedanib in NSCLC ....................................................................... 20 
1.7 
Rationale for performing this trial ........................................................................................ 21 
1.7.1 
Preclinical Rationale for Combined Immunotherapy and PDGFR Inhibition ......................... 22 
1.7.2 
Preclinical Data from Dr. Antonia’s Lab at Moffitt Cancer Center and FGFR Inhibition ....... 22 
1.7.3 
Potential Biomarkers of FGFR Inhibition ............................................................................. 28 
1.8 
Proposed Clinical Rationale ................................................................................................ 29 
1.9 
Benefit – Risk Assessment ................................................................................................. 29 
2. 
OBJECTIVES ..................................................................................................................... 30 
2.2 
Secondary Objectives......................................................................................................... 31 
3. 
PATIENT SELECTION ....................................................................................................... 31 
3.1 
Core Inclusion criteria ......................................................................................................... 31 
3.2 
Core Exclusion criteria: ....................................................................................................... 33 
3.3 
Contraception in patients with preserved reproductive capacity .......................................... 35 
3.4 
Withdrawal of consent for study .......................................................................................... 35 
4. 
TREATMENT PLAN ........................................................................................................... 35 
4.1 
Dose Preparation ................................................................................................................ 35 
4.2 
Agent Administration .......................................................................................................... 36 
4.2.1 
Nintedanib (BIBF1120) ....................................................................................................... 36 
4.2.2 
Nivolumab .......................................................................................................................... 36 
4.2.3 
Ipilimumab .......................................................................................................................... 38 
4.3 
Clinical Trial Design ............................................................................................................ 39 

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4.4 
Patient enrollment: ............................................................................................................. 40 
4.4.1 
Specific considerations ....................................................................................................... 41 
4.4.2 
Inclusion of Women and Minorities: .................................................................................... 41 
4.4.3 
Patient numbering .............................................................................................................. 41 
4.4.4 
Patients and Sites .............................................................................................................. 41 
4.4.5 
Efficacy .............................................................................................................................. 41 
4.4.6 
Safety ................................................................................................................................ 42 
4.6 
General Concomitant Medication and Supportive Care Guidelines ..................................... 42 
4.7 
Duration of Therapy ............................................................................................................ 42 
4.8 
Duration of Follow Up ......................................................................................................... 42 
4.9 
Criteria for Removal from Study Treatment ......................................................................... 43 
5. 
DOSING SELECTION/DELAYS/DOSE MODIFICATIONS .................................................. 44 
5.3 
Trial Treatments ................................................................................................................. 45 
5.4. 
Management of adverse events.......................................................................................... 47 
5.4.2 
Dose modification and toxicity management of Nivolumab and Ipilimumab specifically . 48 
5.4.3 
Dose modification and toxicity management of combination of Nintedanib and/or Nivolumab 
plus Ipilimumab ............................................................................................................................... 51 
5.4.4 
QT Prolongation ................................................................................................................. 51 
5.5. 
Dose limiting toxicity ........................................................................................................... 51 
5.6. 
Additional precautions for Nintedanib (BIBF1120) ............................................................... 52 
5.7 
Trial Blinding/Masking ........................................................................................................ 55 
5.8 
Randomization and Stratification ........................................................................................ 55 
5.9 
Acceptable Concomitant Medications ................................................................................. 55 
5.10 
Prohibited Concomitant Medications ................................................................................... 55 
5.11 
Rescue medication and additional treatments ..................................................................... 56 
5.12 
Restrictions ........................................................................................................................ 56 
6. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..................................... 56 
6.1 
Adverse Event Characteristics ............................................................................................ 56 
6.2 
Definition of Adverse Events of SPECIAL Interest (AESI) ................................................... 57 
6.2.1 
Pneumonitis ....................................................................................................................... 58 
6.2.2 
Hypersensitivity reactions ................................................................................................... 58 
6.2.3 
Hepatic function abnormalities (hepatotoxicity) ................................................................... 58 
6.2.4 
Gastrointestinal disorders ................................................................................................... 59 
6.2.5 
Endocrine disorders ........................................................................................................... 59 
6.2.6 
Pancreatic disorders ........................................................................................................... 59 
6.2.7 
Neurotoxicity ...................................................................................................................... 59 
6.2.8 
Nephritis ............................................................................................................................. 59 
6.2.9 
Immune-related adverse events ......................................................................................... 59 
6.3 
Recording of adverse events and serious adverse events .................................................. 61 
6.4 
SAE, AESI and non-serious AE Reporting to Boehringer Ingelheim (BI) and/or Bristol- 

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Myers Squibb (BMS) ....................................................................................................................... 62 
6.5 
Other Events Requiring Reporting ...................................................................................... 63 
6.5.1 
Reporting of deaths ............................................................................................................ 63 
6.5.2 
Overdose ........................................................................................................................... 64 
6.5.3 
Hepatic function abnormality .............................................................................................. 64 
6.5.4 
Pregnancy .......................................................................................................................... 64 
6.5.5 
Dose-Limiting Toxicity ........................................................................................................ 66 
6.6 
Sponsor Responsibility for Reporting Adverse Events ........................................................ 66 
7. 
CORRELATIVE/SPECIAL STUDIES .................................................................................. 66 
7.1 
Laboratory Correlative Studies ........................................................................................... 66 
7.2 
Special Studies: Medical History, Electrocardiogram, Weight, and Vital Signs .................... 73 
8 
STUDY CALENDAR ........................................................................................................... 76 
9. 
MEASUREMENT OF EFFECT ........................................................................................... 78 
9.1 
Antitumor Effect .................................................................................................................. 78 
9.1.1 
Definitions .......................................................................................................................... 78 
9.1.2 
Disease Parameters ........................................................................................................... 78 
9.1.3 
Methods for evaluation of measurable disease ................................................................... 79 
9.2 
Other Response Parameters .............................................................................................. 80 
9.2.1 
Evaluation of target lesions................................................................................................. 80 
9.2.2 
Evaluation of non-target lesions .......................................................................................... 80 
9.2.3 
Evaluation of best overall response .................................................................................... 81 
9.2.4 
Efficacy variables ............................................................................................................... 82 
10. 
DATA REPORTING / REGULATORY CONSIDERATIONS ................................................ 83 
10.1 
Data Reporting ................................................................................................................... 83 
10.1.1 Risks to patients ................................................................................................................. 83 
10.1.2 Adequacy of protection against risk .................................................................................... 84 
10.2 
Safety and Monitoring Plan ................................................................................................. 85 
10.2.1 Scientific Review Committee (SRC) .................................................................................... 85 
10.2.2 PI responsibility .................................................................................................................. 86 
10.2.3 Protocol Monitoring Committee (PMC) ................................................................................ 86 
10.2.4 Research Compliance Division (RCD) ................................................................................ 86 
10.2.5 Internal and external monitoring ......................................................................................... 87 
10.2.6 The Institutional Review Board (IRB) .................................................................................. 87 
10.2.7 Suspension/termination ...................................................................................................... 87 
10.2.8 Trial discontinuation............................................................................................................ 87 
10.2.9 Monitoring of the study and regulatory compliance ............................................................. 87 
10.2.10 Protocol modifications ........................................................................................................ 88 
10.2.11 Patient privacy.................................................................................................................... 88 
10.2.12 Institutional and individual conflicts of interest ..................................................................... 88 
10.2.13 Records retention ............................................................................................................... 89 

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11. 
STATISTICAL CONSIDERATIONS .................................................................................... 89 
11.1 
Description of Analysis Sets ............................................................................................... 89 
11.1.1 Safety analysis set ............................................................................................................. 89 
11.1.2 Efficacy analysis set ........................................................................................................... 89 
11.2 
Methods of Statistical analysis ............................................................................................ 89 
11.2.2 Efficacy Analyses ............................................................................................................... 89 
12 
ETHICAL AND REGULATORY REQUIREMENTS ............................................................. 94 
12.1 
Ethical Conduct of the Study .............................................................................................. 94 
12.2 
Regulatory and Ethical Compliance .................................................................................... 94 
12.3 
Responsibilities of the Investigator and IRB/IEC/REB ......................................................... 94 
12.4 
Informed Consent ............................................................................................................... 95 
12.5 
Optional Biopsy Consent Form ........................................................................................... 95 
12.6 
Amendments to the Protocol .............................................................................................. 95 
12.7 
Study Drug Supply and Resupply, Storage, and Tracking/Drug Accountability .................... 95 
12.8 
Protocol Adherence ............................................................................................................ 96 
12.9 
Disclosure and Confidentiality ............................................................................................. 96 
12.10 
Ethics and Good Clinical Practice ....................................................................................... 96 
12.11 
Data Sharing ...................................................................................................................... 96 
LIST OF ABBREVIATIONS ............................................................................................................. 98 
13.1 
APPENDIX I : Hy’s Law .................................................................................................... 102 
13.2 
APPENDIX II: Detailed statistical sensitivity analysis for the phase II trial ......................... 104 
13.3 
ECOG Performance Status .............................................................................................. 114 
13.5 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors ............................................................................................................ 114 
13.6 
See Events of Clinical Interest Guidance Document ......................................................... 114 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Date: 12 January 2024 
 
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SCHEMA / Flow Chart 
 
 
 
Phase 1 (dose escalation) 
Patients with locally advanced or 
metastatic NSCLC who are: 
• Newly diagnosed and 
treatment naïve or 
• previously treated 
Phase I 
Nintedanib 
+Nivolumab 
+Ipilimumab 
Phase 2 (Arm A) 
Patients with locally advanced or 
metastatic NSCLC who are: 
newly diagnosed and treatment 
naïve 
Phase 2 
Arm A 
Nintedanib 
+Nivolumab 
+Ipilimumab 
Phase 2 (Arm B) 
Patients with locally advanced or 
metastatic NSCLC who are 
refractory or relapsed to 
immunotherapy. 
 
Phase 2 
Arm B 
Nintedanib 
+Nivolumab 
+Ipilimumab 

Clinical Study Protocol 
Drug Substance: Nivolumab, Ipilimumab and Nintedanib MCC #: 19406 
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PROTOCOL SYNOPSIS 
 
Trial title 
Phase I/II 
Study of 
Nintedanib 
combined 
with 
Nivolumab and Ipilimumab in advanced-stage NSCLC. 
IND Number: 
TBD 
Protocol Number: 
MCC no. 19406 
Sponsor: 
H. Lee Moffitt Cancer Center and Research Institute 
Investigational Product: 
Nintedanib, Ipilimumab and Nivolumab 
Trial Phase 
I/II 
Trial Type 
Phase I/II investigational, non-randomized, parallel assignment 
trial 
Indication Under 
Investigation 
Locally advanced or metastatic NSCLC patients who are 
Immunotherapy naïve or with disease progression following 
immunotherapy prior to study enrollment. 
Study Endpoints 
Primary Objectives: 
 
Phase I (Dose Escalation) 
To determine the MTD and RP2D of concurrent administration of 
nivolumab, ipilimumab, and nintedanib. 
 
Phase II (Single Arm Cohorts) 
To confirm whether concurrent administration of nivolumab, 
ipilimumab, and nintedanib will be efficacious in NSCLC patients. 
   (1) Arm A: Newly diagnosed or treatment-naïve patients, with a  
        target ORR of 50%, or 
   (2) Arm B: Patients who have been previously exposed to  
           immunotherapy, such as anti-PD-1, anti-PD-L1 or anti-CTLA- 
        4, with a target ORR of 20%. 
 
Secondary Objectives: 
 
Phase II: 
Determine the overall survival (OS), response rate (RR), Disease 
Control Rate (DCR), Duration of response, and progression-free 
survival (PFS) of patients treated with nivolumab, ipilimumab, and 
nintedanib. 
 
Examine potential predictive and resistance mechanisms in the 
tumors of clinical non- responders. 
Treatment Groups 
• 
Patients must have histologically or cytologically confirmed 
locally advanced or metastatic NSCLC, with at least one 
measurable lesion, with adequate organ and marrow 
function, and with Eastern Cooperative Oncology Group 
(ECOG) performance status of 0-1. 

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• 
Subjects in this study will be male or female patients 18 
years of age or older. 
 
• 
Phase I dose-escalation trial of nivolumab plus Ipilimumab 
plus nintedanib in patients with locally advanced or 
metastatic NSCLC who are either: 
o Refractory to immunotherapy (i.e., Patients who 
were previously treated with immunotherapy and 
did not at least achieve stable disease on first 
imaging assessment on immunotherapy 
o Have relapsed disease (i.e. Patients that were 
treated with immunotherapy, achieved at least 
stable disease on first imaging assessment and 
then subsequently developed disease progression) 
o Are newly diagnosed and treatment naïve. 
• 
Phase II non-randomized, parallel assignment trial of 
nivolumab plus ipilimumab plus nintedanib at RP2D in 
patients with locally advanced or metastatic NSCLC. 
o Arm A (treatment naïve group) 
▪ 
Newly diagnosed and treatment naïve 
o Arm B (pre-treated group 
▪ 
Primary refractory to immunotherapy (i.e., 
Patients who were previously treated with 
immunotherapy and did not at least achieve 
stable disease on first imaging assessment 
on immunotherapy 
▪ 
Have relapsed disease (i.e. Patients that 
were treated with immunotherapy, achieved 
at least stable disease on first imaging 
assessment and subsequently developed 
disease progression or relapse) 
Planned sample size 
Phase I: up to 24 
Phase II (Non-randomized) Arm A (treatment naïve): 40 Arm B 
(pre-treated): 40 
Arm A (treatment naïve): 40  
Arm B (pre-treated): 40 
Estimated duration of 
trial 
18 months 
Duration of Participation 
2- 3 years 
Study Sites and 
Location 
H. Lee Moffitt Cancer Center and Research Institute 

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1 
BACKGROUND 
1.1 Introduction - Medical Background 
Lung cancer (LC) is the most common diagnosis of cancer annually and causes more death 
than colorectal, breast, and prostate cancer combined 1. Non-small cell lung cancer 
(NSCLC) represents approximately 85% of all LC cases, with most patients presenting with 
stage IIIB or IV. Small cell lung cancer (SCLC) accounts for 15% of lung cancer, with most 
patients presenting with extensive stage. Advanced-stage NSCLC and extensive-Stage 
(ES)-SCLC remain incurable diseases. These late-stage tumors are unresectable, and 
patients have only a 1–5% 5-year survival with chemoresistance playing a major role 2,3. 
Standard therapy for non-squamous cell lung cancer is carboplatin with either pemetrexed 
or paclitaxel in combination with bevacizumab, followed by maintenance bevacizumab or 
pemetrexed. This produces a survival benefit; however, median survival is only 12.3 months. 
Historical data indicate a median progression-free survival (PFS)/time to progression of only 
about 4 months for newly diagnosed, advanced-stage squamous cell lung cancer patients 
treated with platinum doublet chemotherapy 4-8. The results of a phase III randomized 
multicenter trial of nab-paclitaxel plus carboplatin versus paclitaxel and carboplatin in 
patients with advanced NSCLC revealed, by histological stratification, that the combination 
of nab-paclitaxel/carboplatin was superior to paclitaxel/carboplatin, with overall response 
rate (ORR) of 41% versus 24% (P = 0.001), respectively, in patients with squamous cell lung 
cancer, whereas patients with non-squamous histology had no differences in ORR, 26% 
versus 25% (P = 0.808), respectively 7. Unfortunately, despite this progress, there continues 
to be an unmet medical need for more effective and less toxic therapies, especially for 
patients with NSCLC. 
1.2 Immunotherapy in NSCLC 
Immune responses directed against tumors are one of the body’s natural defenses against 
the growth and proliferation of cancer cells. However, over time and under pressure from 
immune attack, cancers develop strategies to evade immune-mediated killing, allowing them 
to develop unchecked. One such mechanism involves upregulation of surface proteins that 
deliver inhibitory signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one 
such protein; this protein is upregulated in a broad range of cancers with a high frequency, 
with up to 88% expression in some tumor types. In a number of these cancers, including lung 
9, renal 10-12, pancreatic 13-15, and ovarian cancer 16, tumor cell expression of PD- L1 is 
associated with reduced survival and an unfavorable prognosis 9-16. 
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that 
are involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help 
regulate normal immune responses and is utilized by tumors to help evade detection and 
elimination by the host immune system tumor response. In the lymph nodes, PD-L1 on 
antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an inhibitory 
signal to the T cell 17. This results in reduced T-cell activation and fewer activated T cells in 
circulation. In the tumor microenvironment, PD-L1 expressed on tumor cells binds to PD-1 
and CD80 on activated T cells reaching the tumor. This delivers an inhibitory signal to those 
T cells, preventing them from killing target cancer cells and protecting the tumor from immune 
elimination 18. 
Recent advances in immunotherapy offer promise for improving clinical outcomes in patients 
with advanced lung cancer. It is increasingly appreciated that cancers are recognized by the 
immune system, and under some circumstances, the immune system may control or even 
eliminate tumors 19. Studies in mouse models of transplantable tumors have demonstrated 
that manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses 
against tumors 20. This may be accomplished by blocking programmed cell death 1 (PD-1) 
from binding with their ligands, cluster of differentiation (CD) 80/86 or programmed cell death 
ligand 1/2 (PD-L1/2), respectively. 

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1.3 Nivolumab 
1.3.1 
Preclinical development and pharmacokinetics 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) 
cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative 
regulatory molecule expressed by activated T and B-lymphocytes.21 Binding of PD-1 to its 
ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation 
of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as 
self-antigens. 
The pharmacokinetics (PK), clinical activity, and safety of nivolumab have been assessed in 
subjects with NSCLC, melanoma, clear-cell renal cell carcinoma (RCC), and classical 
Hodgkin Lymphoma (cHL) in addition to other tumor types. The PK of nivolumab was studied 
in subjects over a dose range of 0.1 to 10 mg/kg administered as a single dose or as multiple 
doses of nivolumab every 2 or 3 weeks. Steady-state concentrations of nivolumab were 
reached by 12 weeks when administered at 3 mg/kg Q2W, and systemic accumulation was 
approximately 3-fold. The exposure to nivolumab increased dose proportionally over the 
dose range of 0.1 to 10 mg/kg administered every 2 weeks. Additionally, nivolumab has a 
low potential for drug-drug interactions. The clearance of nivolumab increased with 
increasing body weight. A population pharmacokinetics (PPK) analysis suggested no 
difference in CL of nivolumab based on age, gender, race, solid tumor type, baseline tumor 
size, and hepatic impairment. Although ECOG status, baseline glomerular filtration rate 
(GFR), albumin, body weight, and mild hepatic impairment had an effect on nivolumab CL, 
the effect was not clinically meaningful. When nivolumab is administered in combination with 
ipilimumab, the CL of nivolumab was increased by 24%, whereas there was no effect on the 
clearance of ipilimumab. 
Regarding the potential for drug-drug interactions with treatment with nivolumab, although 
monoclonal antibodies are not direct inhibitors/inducers of metabolizing enzymes, recent 
literature reports suggest that therapeutic proteins that are modulators of cytokines may 
indirectly affect expression of cytochrome (CYP) enzymes. Nivolumab is an IgG4 monoclonal 
antibody, which is eliminated by mechanisms similar to that of other antibodies, namely by 
non-specific catabolism (mainly by enzymes in the reticuloendothelial system) 22. These 
enzymes are not known to be inhibited or induced by drugs, and therefore it is unlikely that 
other drugs will have an impact on the PK of nivolumab. Please see investigator 
brochure/Package insert for nivolumab for additional information. 
1.3.2 
Clinical development of Nivolumab 
Nivolumab monotherapy is approved in multiple countries, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, and previously 
treated advanced RCC; it is also approved for the treatment of cHL in the US. In addition, 
nivolumab has been approved for use in combination with ipilimumab for unresectable 
melanoma in multiple countries, including the US and EU. 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and 
in combination with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, 
cH, SCLC, gastric cancer, urothelial cancer, HCC, and CRC. In confirmatory trials, nivolumab 
as monotherapy demonstrated a statistically significant improvement in OS as compared 
with the current standard of care in subjects with advanced or metastatic NSCLC, 
unresectable or metastatic melanoma, advanced RCC, or SCCHN. Nivolumab in 
combination with ipilimumab improved PFS and ORR over ipilimumab alone in subjects with 
unresectable or metastatic melanoma.23-35 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 subjects treated to date. 

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For monotherapy, the AE is similar across tumor types. The safety profile is generally 
consistent across completed and ongoing clinical trials, with no maximum tolerated dose 
(MTD) reached at any monotherapy dose tested up to 10 mg/kg. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, 
the safety profile of nivolumab monotherapy is acceptable in the context of the observed 
clinical efficacy, and manageable using established safety guidelines. Clinically relevant AEs 
typical of stimulation of the immune system were infrequent and manageable by delaying or 
stopping nivolumab treatment and timely immunosuppressive therapy or other supportive 
care. (Section 5 and 6). 
In several ongoing clinical trials, the safety of nivolumab in combination with other 
therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted 
therapies is being explored. Most studies are ongoing and, as such, the safety profile of 
nivolumab combinations continues to evolve. The most advanced combination under 
development is nivolumab + ipilimumab, which is approved in subjects with unresectable or 
metastatic melanoma and being studied in multiple tumor types Results to date suggest that 
the safety profile of nivolumab+ipilimumab combination therapy is consistent with the 
mechanisms of action of nivolumab and ipilimumab. The nature of the AEs is similar to that 
observed with either agent used as monotherapy; however, both frequency and severity of 
most AEs are increased with the combination. A dose of 3 mg/kg nivolumab/3 mg/kg 
ipilimumab exceeded the MTD, and both 1 mg/kg nivolumab/3-mg/kg ipilimumab and 3 mg/kg 
nivolumab/1 mg/kg ipilimumab were identified as the MTD.26 Across all studies conducted to 
date, drug-related AEs have included pulmonary toxicity, renal toxicity (including acute renal 
failure), endocrine abnormalities, GI toxicity, dermatologic toxicity (including rash), and 
hepatotoxicity. For nivolumab monotherapy and combination therapy, the majority of these 
AEs have been managed successfully with supportive care and, in more severe cases, a 
combination of dose delay, permanent discontinuation, and/or use of corticosteroids or 
hormone replacement therapy (endocrinopathies) as instructed in the management 
guidelines provided in (Section 5 and 6). 
1.3.3 
Clinical experience with Nivolumab in NSCLC 
Nivolumab has shown a wide range of clinical activity in advanced solid tumors including 
NSCLC. Brahmer et al 36 first reported on previously treated patients with advanced NSCLC 
who received IV nivolumab (1, 3, or 10 mg/kg) every two weeks for up to 96 weeks, with 
tumor evaluation by RECIST v1.0. Across doses and histologies, NSCLC patients (N=129, 
54% with ≥3 prior therapies) had median overall survival (OS) of 9.2-14.9 months and 1- and 
2-y OS rates of 32-56% and 12-45%, respectively [2014]. At the 3-mg/kg dose, median OS 
was 14.9 months; 1- and 2-y OS rates were 56% and 45%. Objective response rate (ORR) 
was 17% (22/129) with median response duration of 17 months. Clinical activity was 
observed across all subgroups, including <3 and ≥3 prior therapies and with/without EGFR 
or KRAS mutations. For patients with PD-L1(+) and (–) tumors, median OS was 7.8 months 
(95% CI: 5.6, 21.7) and 10.5 months (5.2, 21.2), respectively; median PFS was 3.6 months 
(1.8, 7.5) and 1.8 months (1.7, 2.3). Grade 3-4 treatment-related adverse events occurred in 
14% of patients, with the most common being fatigue (3%). 
The Checkmate-063 trial, a Phase II, single arm trial of nivolumab in patients with refractory 
squamous NSCLC, reported additional safety and efficacy data in 2015 [Rizvi et al]. One 
hundred and seventeen (117) patients with histologically or cytologically documented Stage 
IIIB or IV squamous non-small-cell lung cancer with disease progression or recurrence after 
both a platinum doublet-based chemotherapy regimen and at least one additional systemic 
treatment were enrolled. Patients received nivolumab 3 mg/kg as an intravenous infusion 
every 2 weeks (1 cycle) until disease progression or unacceptable toxic effects. Seventeen 
(14.5%) patients had an objective response as assessed by an independent radiology review 
committee. Median time to response was 3.3 months, and median duration of response was 
not reached (95% CI 8·31–not applicable); 13 (77%) of 17 responders were ongoing at the 
time of analysis. Thirty (26%) patients had stable disease (median duration 6·0 months, 95% 

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CI 4·7–10·9). Twenty (17%) patients reported Grade 3–4 treatment-related adverse events 
including fatigue (4%), pneumonitis (3%), and diarrhea (3%). There were two treatment- 
associated deaths caused by pneumonia and ischemic stroke that occurred in patients with 
multiple comorbidities in the setting of progressive disease. 37 This was followed by the 
Checkmate-017 trial, a Phase III study of nivolumab versus docetaxel in patients with squamous 
NSCLC with disease progression during or after one prior platinum-based regimen. Two 
hundred and seventy two (272) patients were randomized 1:1 to receive either nivolumab 3 
mg/kg (n=135) IV every two weeks or docetaxel 75 mg/m2 (n = 137) IV every three weeks until 
disease progression, discontinuation due to toxicity, or other reasons. The primary objective 
was overall survival (OS). Secondary objectives included investigator-assessed objective 
response rate (ORR; RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 
expression (PD-L1 testing not required for enrollment), quality of life, and safety. Superior OS 
was observed with nivolumab versus docetaxel (HR = 0.59; 95% CI: 0.44, 0.79; p = 0.00025) and 
improved PFS (HR = 0.62; 95% CI: 0.47, 0.81; p = 0.0004). ORR was 20% (27/135) for 
nivolumab and 9% (12/137) for docetaxel (p = 0.0083). Grade 3–4 drug-related AEs occurred 
in 7% (9/131) of patients treated with nivolumab, and 55% (71/129) of patients treated with 
docetaxel. No deaths were related to nivolumab; three docetaxel-related deaths were reported. 
38 
In March 2015, nivolumab 3mg/kg IV every two weeks was approved for the treatment of 
patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with 
progression on or after platinum-based chemotherapy [FDA News Release, March 2015]. 
Checkmate-057 is a phase III trial that included 582 patients with advanced non-squamous 
NSCLC randomly assigned to nivolumab 3mg/kg IV every two weeks or docetaxel 75mg/m2 IV 
every three weeks until progression or intolerance. The authors observed an ORR of 19.2% for 
nivolumab (n=292) versus 12.4% with docetaxel (n=290), and a superior duration of response 
(17.1 months vs 5.6 months, respectively). Median OS was 12.2 months for nivolumab versus 
9.4 months for docetaxel, and the one-year OS rate was 51% and 39%, respectively. Grade 
3/5 drug-related adverse events occurred in 10.5% of nivolumab patients versus 53.7% of 
docetaxel patients. There were no deaths in the nivolumab arm of the study, versus one in the 
docetaxel arm.39 
1.4 Ipilimumab 
1.4.1 Preclinical development and pharmacokinetics 
Ipilimumab is a fully human monoclonal IgG1κ 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 tumor-infiltrating T-effector cells. Inhibition of CTLA-
4 signaling can also reduce Treg function, which may contribute to a general increase in T-cell 
responsiveness, including the anti-tumor response. Traditional cytotoxic approaches to the 
treatment of cancer are associated with efficacy and toxicity limitations. Thus, there is a clinical 
need for the development of new therapies for the treatment of cancer. Blockade of CTLA-4 
(CD152) is a novel approach to the treatment of human malignancies that offers an immune-
mediated alternative to cancer treatment. 
All nonclinical pharmacokinetic (PK) studies for ipilimumab were conducted in cynomolgus 
monkeys after IV dosing. 40-46 The mean half-life (T-HALF) of ipilimumab in cynomolgus 
monkeys was long 8.5 40 to 14 47 days, and the total plasma clearance (CL) was low (0.196 
mL/h/kg) 41. Systemic exposure to ipilimumab increased as a function of dose, generally in a 
greater than dose-proportional manner 40,43. There were no apparent gender-related differences 
in exposure. An anti-ipilimumab antibody response can occur in cynomolgus monkeys, which 
in some cases may impact the PK of ipilimumab by accelerating its elimination. 40-48 The same 
response is not present in humans and thus is not relevant to human PK. Also, regardless of 

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the anti-ipilimumab response in cynomolgus monkeys,  the exposure of animals in the safety 
assessment studies to ipilimumab was demonstrated. In cynomolgus monkeys, ipilimumab 
mostly remains within the vascular system 41,49 but crosses the placenta 50; there was very little 
distribution of ipilimumab into milk. The expected in vivo degradation of mAbs is via biochemical 
pathways that are independent of cytochrome P450 enzymes. Consequently, typical mAbs, 
such as ipilimumab, are not expected to have interactions with molecules that are metabolized 
by these enzymes. 
The cynomolgus monkey was selected as the primary toxicology species because ipilimumab 
binds specifically to macaque CTLA-4, but not to homologous CTLA-4 in other traditional 
toxicology species 51, and has pharmacologic activity in monkeys. In IV repeat- dose toxicology 
studies in monkeys, ipilimumab was tolerated without adverse effects at doses up to 
30mg/kg/day administered every 3 days for 3 doses (peak serum concentrations 
≤ 682 
g/mL), 42,43,52 at 10 mg/kg (equivalent to human dose on body-weight basis) 
administered weekly for 1 month (mean area under the concentration-time curve [AUC] from time 
zero to 168 hours and AUC from time zero to 63 days of 31.6 and 90.6 mg/h/mL, respectively) 
40, at 1 mg/kg administered weekly for 10 weeks, 41 and at doses up to 10 mg/kg/day 
administered approximately monthly for up to 6months40,44,46,52 In a pivotal 6- month toxicity 
study (10 mg/kg administered on Days 0, 28, 56, 84, and 140), treatment- related findings were 
limited to decreases in absolute and relative thyroid (44% to 50%) and testicular (27% to 50%) 
weights. However, there were no corresponding microscopic changes in these organs, and 
thus, 10 mg/kg was considered to be the no observable adverse effect level.46 
Evidence of pharmacologic activity (enhancement of antigen-specific humoral immune 
responses and T-cell activation) without any generalized, nonspecific immune-cell activation was 
demonstrated in several studies. However, in an exploratory pharmacology study 44, severe 
colitis requiring euthanasia occurred after the second dose in 1 of 6 monkeys receiving 
ipilimumab at 10mg/kg approximately monthly in combination with 3 vaccines. The binding of 
ipilimumab to CTLA-4 expressed on gut-associated lymphoid tissue was confirmed in human 
and monkey tissue-binding studies 51,53,54 and suggests that these lymphocytes (T cells) exist 
in an activated state, making them susceptible to CTLA-4 blockade by ipilimumab. 
In another pharmacology study, 1 monkey receiving ipilimumab approximately twice monthly 
(doses administered at Days 4, 9, 30, 32, 58, 60, 86, and 88) at 10 mg/kg in combination 
with another immunomodulatory antibody (BMS-663513, a fully human anti-CD137 mAb) 
and simian immunodeficiency virus DNA vaccines developed dermatitis/rash in the inguinal 
area and peripheral lymphadenopathy 4 weeks following a 3-month dosing period. 48 The 
rash and lymphadenopathy resolved within approximately 2 months. Since rashes have 
been reported clinically with both BMS-663513 and ipilimumab, a relationship of this finding 
to the administration of either or both test articles is possible. Another monkey in this 
pharmacology study developed an infusion reaction while under ketamine sedation, 
accompanied by difficulty in breathing, cyanosis, thready pulse, and muffled heart sounds, 
at approximately 5 minutes following ipilimumab injection on Day 58 and approximately 2 to 
3 minutes following administration of test antigens. 48 Rechallenge of the monkey with a 
controlled infusion of ipilimumab approximately 5 months later did not evoke a similar 
reaction. Since the infusion reaction was not reproducible after a subsequent controlled 
ipilimumab rechallenge, the drug relationship to this event remains unclear, and confounding 
factors such as rapid infusion rate, immunogenicity, and anesthesia-induced hypotension 
may have had a contributing role.55-60 When administered by IV, antibody to ipilimumab 
was detected in approximately 8% of monkeys.40,42-46,48 In some of these monkeys, the 
presence of anti-drug antibodies (ADA) was observed in conjunction with accelerated 
elimination of ipilimumab from serum or plasma. No substantial irritation was observed at the 
ipilimumab injection sites in any of the IV repeat- dose studies in monkeys using ipilimumab 
concentrations and at injection rates well above those recommended for human use. 
Chinese hamster ovary-derived  
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(Process A) in its PK, bioactivity (specific T-cell activation), immunogenicity, and safety 
profiles. Further, ipilimumab derived from a new drug substance manufacturing process 
(Process C, AUC from time zero to 1008hours [AUC(0-1008h)] 46,700 μg•h/mL), utilizing a 
higher producing sub-clone of the Process B master cell bank and modifications to the 
fermentation and purification processes, was shown to have comparable PK and 
immunogenicity profiles to Process B (AUC[0-1008h] 52,100 μg•h/mL) in an exploratory 
monkey study.47In a 1-month IV combination toxicity study in monkeys, ipilimumab and 
nivolumab were consecutively co-administered weekly for 4 weeks at 3 mg/kg and 10 mg/kg, 
respectively, or at higher doses of 10 mg/kg and 50 mg/kg, respectively; a control group 
received sterile Saline for Injection, USP.61 Ipilimumab in combination with nivolumab at both 
the high-dose and low-dose levels was associated with a dose-dependent increased 
incidence of gastrointestinal (GI) toxicity (diarrhea and histologic inflammatory changes in 
the large intestine). In addition, mild increases in size/number of lymphoid follicles and mild 
expansion of the marginal zone occurred in the red pulp of the spleen. GI toxicity/colitis was 
previously observed at a very low incidence in monkeys receiving ipilimumab as 
monotherapy. 
The effects of ipilimumab on reproduction and development were studied in an enhanced 
pre- and postnatal development study in cynomolgus monkeys.50 In this study, pregnant 
monkeys received ipilimumab every 21 days from the beginning of organogenesis in the first 
trimester through delivery at dose levels that resulted in exposures (by AUC) that were either 
2.6 times (10 mg/kg) or 7.2 times (30 mg/kg) higher than the clinical exposure at a dose of 3 
mg/kg every 21 days of ipilimumab or 0.9 to 2.1 times higher than the clinical exposure at a 
dose of 10 mg/kg every 21 days of ipilimumab. Ipilimumab was shown to be present at very 
low levels in milk from adult mothers (with mean milk/serum ipilimumab concentration ratios 
that were 0.002 to 0.003). No treatment-related adverse effects on reproduction were 
detected during the first 2 trimesters of pregnancy. Maternal pregnancy outcomes for the first 
2 trimesters were comparable in control and drug-treated groups. Beginning in the third 
trimester, the ipilimumab groups experienced increased maternal weight decrements, higher 
incidences of abortion and stillbirth, premature delivery (with corresponding lower birth 
weight), and higher incidences of infant mortality in a dose-related manner compared to 
controls (≥ gestation day100; 21% and 30% for 10 and 30 mg/kg every 3 weeks [q3w], 
respectively; compared to study controls [0%] and historical controls [17.6%]). Some infant 
mortality in ipilimumab-treated groups could be attributed to extreme prematurity; however, 
the group mean durations of gestation were comparable in the 3 experimental groups (160, 
160, and 155 days in the saline, 10, and 30 mg/kg groups, respectively). Urogenital 
malformations were observed in 2 infants of mothers treated with 30 mg/kg/dose. Infants 
exposed to ipilimumab at 30 mg/kg/q3w had a lower mean body weight (BW) [-15% relative 
to control infant values] at birth. Lower BW persisted through 5 months postnatal, but the 
rate of body-weight gain increased by 3 months postnatal. At 6 months postnatal, the group- 
mean BW for the 30 mg/kg/q3w infants had increased compared to that of the control infants. 
Ipilimumab did not adversely affect the ability of infants to mount a T-cell-dependent antibody 
response to hepatitis B surface antigen at 6 and 18 weeks of age. There were no adverse 
effects observed in infants related to ipilimumab-exposure in utero with respect to clinical 
observations, morphometric measurements, neurobehavioral and skeletal evaluations, 
clinical pathology, lymphocyte phenotyping, antinuclear antibody (ANA) formation, or serum 
Ig levels through 6 months postnatal. 
In summary, other than the events described, ipilimumab generally did not result in any 
adverse toxicities in any other monkeys in general toxicity studies when administered IV at 
doses up to 30 mg/kg for 1 week, 10 mg/kg weekly for 1 month, 1 mg/kg weekly for 10 weeks, 
or 10 mg/kg monthly for 6 months. Ipilimumab in combination with nivolumab was associated 
with a dose-dependent increased incidence of GI toxicity in monkeys as compared to either 
agent alone. In addition, increased incidences of third-trimester abortion, stillbirth, premature 
delivery, low birth weight, and infant mortality occurred following IV administration of

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ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis 
through parturition at doses of 2.6 or 7.2 times the clinical exposure at a dose of 3 mg/kg or 
0.9 to 2.1 times higher than the clinical exposure at a dose of 10 mg/kg every 21 days of 
ipilimumab. Based on the results of the monkey reproductive study, ipilimumab is not 
recommended for use during pregnancy unless the potential benefit justifies the potential 
risk to the fetus. 
The population PK of ipilimumab was studied in 785 subjects (3,200 serum concentrations) 
with advanced melanoma in 4 Phase 2 studies (CA184004, CA184007, CA184008, and 
CA184022),62 1 Phase 3 study (CA184024), and 1 Phase 1 study (CA184078). The 
population PK analysis demonstrated that the PK of ipilimumab is linear, the exposures are 
dose proportional across the tested dose range of 0.3 to 10 mg/kg, and the model parameters 
are time-invariant, similar to that determined by noncompartmental analyses. 
Upon repeated dosing of ipilimumab, administered q3w, minimal systemic accumulation was 
observed by an accumulation index of 1.5-fold or less, and ipilimumab steady-state 
concentrations were achieved by the third dose. The ipilimumab CL was 16.8 mL/h from 
population PK analysis. The terminal T-HALF and Vss of ipilimumab calculated from the 
model were 15.4days and 7.47 L, respectively, which are consistent with that determined by 
noncompartmental analysis. Volume of central compartment (Vc) and peripheral 
compartment were reported to be 4.35 and 3.28 L, respectively, suggesting that ipilimumab 
first distributes into plasma volume and, subsequently, into extracellular fluid space. CL of 
ipilimumab and Vc were found to increase with increase in BW. However, there was no 
significant increase in exposure with increase in BW when dosed on a milligram/kilogram 
basis, supporting dosing of ipilimumab based on a weight-normalized regimen. The PK of 
ipilimumab is not affected by age, gender, race, and immunogenicity (ADA status); 
concomitant use of chemotherapy; prior therapy; BW; performance status; or tumor type. 
Other covariates had effects that were either not statistically significant or of minimal clinical 
relevance. 
1.4.2 Clinical development of Ipilimumab 
Ipilimumab is being investigated both as monotherapy and in combination with other 
modalities such as chemotherapy, radiation therapy, and other immunotherapies. Phase 3 
programs are ongoing in melanoma, prostate cancer, and lung cancer. 
In melanoma, 4 completed Phase 3 studies (MDX010-20, CA184024, CA184029, and 
CA184169) have demonstrated a clinically meaningful and statistically significant survival 
benefit in pretreated advanced melanoma, in previously untreated advanced melanoma, and 
in adjuvant melanoma. 
Ipilimumab monotherapy or in combination with chemotherapy has not prolonged survival in 
prostate cancer, NSCLC, and SCLC (Studies CA184043, CA184095, CA184104, and 
CA184156). Outside melanoma, combination with other checkpoint inhibitors (eg PD-1 
inhibitors) may be required to achieve clinically meaningful activity. Ipilimumab is also in 
clinical development in combination with nivolumab. The combination is approved in the US 
for the treatment of advanced melanoma. 
The unique immune-based mechanism of action is reflected in the clinical patterns of anti- 
cancer activity in some patients. Ipilimumab induces an immunologic response, and 
measurable clinical effects emerge after the immunological effects. Tumor infiltration with 
lymphocytes and the associated inflammation (documented by biopsy in some subjects) is 
likely the cornerstone of the effect of ipilimumab and can manifest in various patterns of 
clinical activity leading to tumor control. In some cases, inflammation may not be noted by 
radiological examination, and objective response is observed with the first tumor assessment 
in a manner seen in patients receiving other types of anti-cancer treatments. In other cases, 
response may be preceded by an apparent increase in initial tumor volume and/or the 
appearance of new lesions, which may be mistaken for tumor progression on radiological 
evaluations. Therefore, in patients who are not experiencing rapid clinical deterioration,

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confirmation of progression is recommended (at the investigator’s discretion) to better 
understand the prognosis, as well as to avoid unnecessarily initiating potentially toxic 
alternative therapies in subjects who might be benefiting from treatment. Immune-related 
response criteria were developed based on these observations to systematically categorize 
novel patterns of clinical activity and are currently being prospectively evaluated in clinical 
studies. 
In metastatic diseases, stabilization is more common than response and in some instances 
is associated with a slow, steady decline in tumor burden over many months, sometimes 
improving to partial and/or complete responses (CRs). Thus, the immune-based mechanism 
of action of ipilimumab results in durable disease control, sometimes with novel patterns of 
response, which contribute to its unique improvement in overall survival (OS). 
The unique immune-based mechanism of action is also reflected in the safety profile. The 
most common treatment-related AEs are inflammatory in nature, consistent with the 
mechanism of action of the drug and generally medically manageable with topical and/or 
systemic immunosuppressants. Such immunological safety events are described as 
immune-related adverse events (irAEs) or immune-mediated adverse reactions (imARs). 
The irAEs are described as AEs of unknown etiology, which were consistent with an immune 
phenomenon and considered causally related to drug exposure by the investigators. The 
irAEs primarily involve the GI tract and skin. Immune-related AEs in the liver were also 
observed, particularly in subjects receiving 10 mg/kg. Endocrinopathy and neuropathy were 
important irAEs that were observed less frequently. The imARs were adjudicated in a blinded 
fashion based on sponsor-physician data review to exclude noninflammatory etiologies, such 
as infection or tumor progression, and to consider available evidence of inflammation, such 
as tumor biopsies or responsiveness to steroids, in an effort to determine whether specific 
AEs or abnormal hepatic laboratory values were likely to be immune mediated and 
associated with ipilimumab treatment. 
The early diagnosis of inflammatory events is important to initiate therapy and minimize 
complications. Inflammatory events are generally manageable using symptomatic or 
immuno-suppressive therapy as recommended through detailed diagnosis and management 
guidelines. The management guidelines for general irAEs and ipilimumab-related GI 
toxicities, hepatitis, endocrinopathy, and neuropathy are described in Section 5, Table 9a 
and 9b. 
1.4.3 Clinical development with Ipilimumab in NSCLC. 
Activity of Ipilimumab in lung cancer was observed in a large Phase 2 study in lung cancer 
(NSCLC and SCLC; StudyCA184041) 63 in combination with chemotherapy. Two Phase 3 
studies evaluated ipilimumab has been tested in combination with chemotherapy in 
squamous NSCLC (CA184104) and SCLC (CA184156). Neither study met its primary 
endpoint of demonstrating a statistically significant prolongation of OS for the ipilimumab 
group (10 mg/kg ipilimumab/standard of care chemotherapy) over the placebo group 
(placebo/standard of care chemotherapy) among randomized subjects who received at least 
1 dose of blinded study therapy; however, no new safety concerns were identified in the 
course of standard clinical safety monitoring of the 2 studies. 
While the types of safety events observed in subjects receiving ipilimumab do not appear to 
change, even in combination with other anti-cancer agents, the proportion of subjects 
experiencing 1 type or another irAE may be impacted by the choice of combination partner. 
The skin and GI irAEs predominate in monotherapy studies. In combination with DTIC 
(melanoma), the incidence of skin and GI irAEs was lower than expected and the incidence 
of hepatic irAEs was higher. In combination with paclitaxel and carboplatin (NSCLC), the 
incidence of all types of irAEs appeared to be numerically lower compared to the incidence 
observed for ipilimumab monotherapy in the Phase 2 program. 

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1.5 Combined Immune Checkpoint Inhibition 
Nivolumab is in clinical development as a combination with ipilimumab. The combination is 
currently approved in the US in subjects with unresectable or metastatic melanoma and 
being studied in multiple tumor types. Results to date suggest that the safety profile of 
nivolumab+ipilimumab combination therapy is consistent with the mechanisms of action of 
nivolumab and ipilimumab. The nature of the AEs is similar to that observed with either agent 
used as monotherapy; however, both frequency and severity of most AEs are increased with 
the combination. A dose of 3 mg/kg nivolumab/3 mg/kg ipilimumab exceeded the MTD, and 
both 1 mg/kg nivolumab/3-mg/kg ipilimumab and 3 mg/kg nivolumab/1 mg/kg ipilimumab 
were identified as the MTD.64 Across all studies conducted to date, drug-related AEs have 
included pulmonary toxicity, renal toxicity (including acute renal failure), endocrine 
abnormalities, GI toxicity, dermatologic toxicity (including rash), and hepatotoxicity. For 
nivolumab monotherapy and combination therapy, the majority of these AEs have been 
managed successfully with supportive care and, in more severe cases, a combination of 
dose delay, permanent discontinuation, and/or use of corticosteroids or hormone 
replacement therapy (endocrinopathies) as instructed in the management guidelines 
provided in Section 5, Table 9a and 9b. 
The combination has also shown activity in NSCLC. There is clinical rationale for combining 
the two agents based on their non-redundant mechanisms of action. Preclinical data shows 
synergy between anti-PD1 and anti-CTLA4 therapies that improves antitumor activity. The 
Checkmate-012 trial, a Phase I multi-cohort randomized study, evaluated the combination of 
nivolumab and ipilimumab at 2 doses as first line therapy in NSCLC as compared to 
nivolumab monotherapy, with primary endpoint being safety and tolerability. Nivolumab 
monotherapy was given at a dose of 3mg/kg IV every 2 weeks. In combination with 
nivolumab, ipilimumab was given at a doses of 1mg/kg every 6 or 12 weeks. They 
demonstrated a cPR in 18/38 (47%) versus 15/39 (38%) in the ipilumumab combination arms 
at 12 versus 6 weeks, respectively. Median PFS was 8.1 months for nivolumab/ ipilimumab 
12-week combination versus 3.9 months for nivolumab/ ipilumumab 6-week combination. 
Median OS at 1 year for nivolumab/ ipilimumab 12-week combination was not calculated 
versus 69% for nivolumab/ ipilumumab 6-week combination. In patients with ≥ 1% PD-L1 
expression, the median PFS for nivo/ ipi every 12-weeks was 8.1 months, for nivo/ 
ipilimumab every 6-weeks was 10.6 months and for nivo alone was 3.5 months. The Grade 
3-4 treatment-related adverse events were noted in 14 (37%) patients in the ipilimumab 
every-12-weeks cohort versus 13 (33%) patients in the every-6-weeks cohort. Combination 
nivolumab/ ipilimumab therapy was considered to be tolerable with no new safety concerns 
or treatment related deaths noted during this study. In summary, the addition of nivolumab 
monotherapy resulted in higher ORR, longer PFS and numerically higher 1-year OS. 
Additionally, efficacy of combination therapy was enhanced with increasing tumor PD-L1 
expression. Though, activity was still observed in patients with <1% PD-L1. 65 Checkmate 
227 (NCT02477826) is a phase III trial that is currently underway to test the combination of 
Nivolumab 3mg/kg IV every 2 weeks with Ipilimumab 1mg/kg IV every 6 weeks, further 
stratifying based on PD-L1 expression. 
 
 
1.6 Nintedanib (BIBF1120) 
1.6.1 Preclinical development and pharmacokinetics 
 
Nintedanib (BIBF1120) is a potent, orally available triple kinase inhibitor targeting VEGFRs, 
PDGFRs, and FGFRs. Nintedanib inhibits the signalling cascade mediating angiogenesis by 
binding to the adenosine triphosphate (ATP) binding pocket of the receptor kinase domain, 
thus interfering with cross-activation via auto-phosphorylation of the receptor homodimers.

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The specific and simultaneous abrogation of these pathways results in effective growth 
inhibition of both endothelial and via PDGF- and FGF-receptors of perivascular cells, which 
may be more effective than inhibition of endothelial cell growth via the VEGF pathway alone. 
Furthermore, signalling by FGF receptors has been identified as a possible escape 
mechanism for tumour angiogenesis when the VEGF pathway is disrupted. 
Besides inhibition of neo-angiogenesis, it may alter tumour maintenance by inducing 
apoptosis of tumour blood vessel endothelial cells. Inhibition of receptor kinases may also 
interfere with autocrine and paracrine stimulation of tumour angiogenesis via activation loops 
involving VEGF, PDGF, and bFGF utilized by vascular and perivascular cells such as 
pericytes and vascular smooth muscle cells. 
 
In addition, preclinical models show that Nintedanib (BIBF1120) may have a direct anti- 
tumour effect on those malignant cells that overexpress PDGFR and/or FGFR (e.g., H1703 
NSCLC cells) 
 
 
Target 
IC50 (nmol/L) 
VEGFR (1 / 2 / 3) 
34 / 21 / 13 
PDGFR (α / β) 
59 / 65 
FGFR (1 / 2 / 3) 
69 / 37 / 108 
Flt-3 
26 
RET 
35 
Src, Lck, Lyn 
156 / 16 / 195 
 
 
In vitro, the target receptors are all inhibited by Nintedanib in low nanomolar concentrations. 
In in vivo nude mouse models, Nintedanib showed good anti-tumour efficacy at doses of 50 
to 100 mg/kg, leading to a substantial delay of tumour growth or even complete tumour stasis 
in xenografts of a broad range of differing human tumour types. Histological examination of 
treated tumours showed a marked reduction of tumour vessel density by approximately 80% 
66. 
 
The metabolism of Nintedanib (BIBF1120) was predominantly characterized by the ester 
cleavage of the methyl ester moiety yielding BIBF1202, which was further metabolized by 
conjugation to glucuronic acid yielding the 1-O-acylglucuronide. Data collected in this study 
show that Nintedanib (BIBF1120) has a favorable pharmacokinetic and excretion profile, with 
almost no elimination via the urine; only 0.7% of total -14C-radioactivity was eliminated via 
the urine 67. The metabolic characteristics are predominantly independent of cytochrome 
P450-catalyzed metabolic pathways 67. 
 
A soft gelatin capsule formulation of Nintedanib is used in humans. After oral administration, 
Nintedanib is absorbed quickly. Maximum plasma concentrations (Cmax) generally occur 2 
to 4 hours after administration. So far, no evidence for a deviation from dose proportionality 
of the pharmacokinetics of Nintedanib has been observed. Steady state is reached after 1 

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week of dosing. The terminal half-life of Nintedanib is in the range of 7 to 19 hours. 
Nintedanib is mainly eliminated via feces 67. 
Nintedanib (BIBF1120) is non-mutagenic, even at high doses. Two exploratory studies in 
rats revealed a teratogenic effect of Nintedanib (BIBF1120) with a steep dose-effect relation 
and an early onset of embryofetal deaths at low dosages. This effect was observed at dose 
levels, resulting in plasma drug concentrations comparable to or below those in humans. 
Because the concentration of Nintedanib (BIBF1120) in semen is unknown, male patients 
receiving Nintedanib (BIBF1120) and having sexual intercourse with women of childbearing 
potential should use latex condoms. Female patients of childbearing potential should be 
advised to use adequate contraception during and at least 3 months after the last dose of 
Nintedanib. 
 
 
1.6.2 Clinical development of Nintedanib 
 
Nintedanib is being evaluated in several cancers. Additionally, Nintedanib is in advanced 
phase III for the non-cancer indication idiopathic pulmonary fibrosis (IPF). As of 15 Feb 2013, 
3556 cancer patients, over 1000 patients with IPF, and 140 healthy volunteers had been 
treated with nintedanib or nintedanib matching placebo, in monotherapy or in combination 
with chemotherapy. 
 
 
Phase I Nintedanib Monotherapy 
 
Phase I dose selection studies revealed that nintedanib (BIBF1120) is generally well 
tolerated with mild to moderate adverse effects such as gastrointestinal symptoms (nausea, 
diarrhoea, vomiting, and abdominal pain) and reversible elevations of liver enzymes. Initial 
signs of clinical activity including an encouraging rate of patients with stabilisation of their 
tumour of 54% and 68%, respectively; have been observed in patients with various solid 
tumours 68. 
 
Based on the phase I dose escalation trials with nintedanib (BIBF1120) monotherapy, the 
maximum tolerated dose was defined to be 250 mg for twice daily dosing in Caucasians and 
200 mg twice daily in Japanese patients with a manageable safety profile in advanced cancer 
patients. Based on the overall safety profile, the RP2D for nintedanib, as monotherapy is 200 
mg bid. 
 
The maximum tolerated dose for combination therapy of nintedanib (BIBF1120) in 
combination with pemetrexed, docetaxel, paclitaxel/carboplatin and FOLFOX is 200mg bid. 
Combination of nintedanib (BIBF1120) with other anti-cancer drugs revealed a similar 
adverse event profile as compared to Nintedanib (BIBF1120) monotherapy except for the 
chemotherapy related toxicities. There was no change of the pharmacokinetic parameters of 
nintedanib (BIBF1120) or of the cytotoxic compounds due to the combined treatment. Dose 
limiting toxicity consisted mostly of liver transaminase elevations as in the monotherapy 
phase I trials with the exception of the combination of nintedanib (BIBF1120) with 
pemetrexed, where fatigue was the most relevant dose limiting toxicity. 
Available pharmacokinetic data indicate that the systemic exposure needed for biological 
activity can be achieved starting with doses of 100 mg Nintedanib (BIBF1120) once daily. 

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The predominant adverse events were nausea, diarrhoea, vomiting, abdominal pain and 
fatigue of mostly low to moderate severity. Dose limiting toxicities (DLT) were mainly confined 
to reversible hepatic enzyme elevations (AST, ALT, γ-GT), which increased dose- 
dependently. Most cases occurring at doses of 250 mg and above, and a very low incidence 
at doses below 200 mg and were reversible after discontinuation of Nintedanib treatment. All 
adverse events observed after single administration of single doses of Nintedanib to healthy 
volunteers were only of CTCAE grade 1 severity and fully reversible67. 
 
 
1.6.3 Clinical Experience of Nintedanib in NSCLC 
 
In a phase I open-label study, Nintedanib was tested in combination with Pemetrexed in 
patients with recurrent metastatic NSCLC of all histological subtypes who had previously 
received at least one platinum-based chemotherapy 69. Patients were treated with standard 
dose Pemetrexed (500 mg/m2 on day 1) and Nintedanib on days 2 to 21 of a 21-day cycle. 
The dose of Nintedanib was escalated from 100 mg twice daily to the MTD of 200 mg twice 
daily. The most frequent DLTs were gastrointestinal adverse effects (86.4%) including 
nausea, diarrhea, and vomiting and administration-site reactions (76.9%), mainly rash. One 
patient showed a complete response (CR), and 50% of patients showed stable disease as 
best overall response. No clinically relevant pharmacokinetic interactions between 
Nintedanib and Pemetrexed were observed. 
 
In a phase II trial in NSCLC patients the safety profile of nintedanib (BIBF1120) observed in 
phase I trials could be confirmed. Most commonly reported drug-related AEs were nausea 
(57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) 
and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations 
(9.6%) In conclusion it was generally well tolerated and displayed single agent activity in 
advanced or recurrent NSCLC patients. Median overall survival (OS) was 21.9 weeks. 
Eastern Cooperative Oncology Group (ECOG) 0–1 patients (n = 56) had a median PFS of 
11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of 
patients (ECOG 0–1 patients: 59%), with one confirmed partial response (250 mg bid.). 70 
 
LUME-Lung 1 was an international, randomized, double blind, phase III trial assessing the 
efficacy and safety of docetaxel plus Nintedanib as second line therapy for non-small-cell 
lung cancer (NSCLC). In total, 1314 patients with Stage IIIB/IV or recurrent NSCLC (all 
histologies) who had progressed after 1st line chemotherapy were randomized in 1:1 fashion 
to either receive nintedanib 200mg BID + docetaxel (n=655) or placebo BID + docetaxel 
(n=659). The study met its primary endpoint by showing a statistically significant 
improvement of PFS for all patients regardless of histology (median PFS 3.4 versus 2.7 
months; HR 0.79, p=0.0019) for nintedanib in combination with docetaxel.A significant 
improvement in OS was demonstrated in patients with adenocarcinoma; median OS 12.6 
months [95% CI 10·6–15·1] vs 10·3 [95% CI 8·6 –12·2] months; HR 0·83 [95% CI 0·70 – 
0·99], p=0·0359); the Kaplan-Meier survival curves separate at 6 months, continuing 
throughout the 36-month study observation period. One year overall survival was 52·7% 
(95% CI 46·8–57·9) in the docetaxel plus nintedanib group compared with 44·7% (38·9 – 
49·8) in the docetaxel plus placebo group; 2 year overall survival was 25·7% (95% CI 20·5– 
30·2) in the docetaxel plus nintedanib group compared with 19·1% (14·4 –23·2) in the 
docetaxel plus placebo group. In the predefined population of patients with adenocarcinoma 
who had progressed within 9 months after start of first-line therapy, overall survival was 
significantly longer in the docetaxel plus Nintedanib group than in the docetaxel plus placebo 
group (median overall survival 10·9 months [95% CI 8·5–12·6] vs 7·9 months [6·7–9·1]; HR 
0·75 [95% CI 0·60–0·92], p=0·0073). In the total population of patients (all histologies), there 
was no difference in overall survival between the two groups: median overall survival was 
10·1 months (95% CI 8·8–11·2) in the docetaxel plus nintedanib group compared with 9·1

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(8·4–10·4) months in the docetaxel plus placebo group (HR 0·94 [95% CI 0·83 –1·05], 
p=0·2720). Nintedanib plus docetaxel had a manageable safety profile with no unexpected 
safety findings). 71 
The predominant adverse events were nausea, diarrhoea, vomiting, abdominal pain and 
fatigue of mostly low to moderate intensity after monotherapy with nintedanib (BIBF1120). 
Adverse events that were more common (≥5% diﬀerence) in the docetaxel plus Nintedanib 
group than the docetaxel plus placebo group were: diarrhoea (all grades, 276 of 652 [42·3%] 
vs 143 of 655 patients [21·8%]; grade ≥3, 43 [6·6%] vs 17 [2·6%]), increases in alanine 
aminotransferase (all grades, 186 [28·5%] vs 55 [8·4%]; grade ≥3, 51 [7·8%] vs six [0·9%]), 
nausea (all grades, 158 [24·2%] vs 118 [18·0%]; grade ≥3, five [0·8%] vs six [0·9%]), increases 
in aspartate aminotransferase (all grades, 147 [22·5%] vs 43 [6·6%]; grade ≥3, 22 [3·4%] vs 
three [0·5%]), decreased appetite (all grades, 145 [22·2%] vs 102 [15·6%]; grade 
≥3, nine [1·4%] vs eight [1·2%]), and vomiting (all grades, 110 [16·9%] vs 61 [9·3%]; grade 
≥3, five [0·8%] vs three [0·5%];). Most of these adverse events were manageable with 
supportive treatment or dose reduction. 71 
 
LUME-Lung 2 was a similar randomised, double blind, phase III study of nintedanib plus 
Pemetrexed versus placebo plus Pemetrexed in patients with advanced non-squamous non- 
small cell lung cancer after failure of first line chemotherapy. Based on a pre-planned futility 
analysis of investigator-assessed PFS, enrolment was halted after 713/1300 planned 
patients had been enrolled. The analysis (based on conditional power for PFS by investigator 
assessment) suggested that the study was futile and that the primary endpoint of centrally 
assessed PFS would likely not be met. The futility analysis was based on conditional power; 
there was no formal testing of null hypothesis as planned for primary analysis no safety 
issues were identified. 
 
Even though the study was stopped prematurely, the primary endpoint of this phase III trial 
was met; treatment with Nintedanib plus Pemetrexed resulted in a significant prolongation of 
centrally reviewed PFS compared with placebo plus Pemetrexed (median PFS 4.4 vs. 3.6 
months with a HR 0.83; p=0.0435). The disease control rate was also increased significantly 
in Nintedanib-treated patients. There was no improvement in OS in Nintedanib-treated 
patients. Nintedanib 200 mg bid in combination with Pemetrexed had an acceptable and 
manageable safety profile, with no new or unexpected safety findings. The most frequent 
AEs were reversible increases in liver enzymes and gastrointestinal events. 72 
 
 
1.7 Rationale for performing this trial 
Approximately 1.6 million people worldwide are diagnosed with lung cancer annually, of 
which about 85% of cases are NSCLC 1. Locally advanced NSCLC patients have a median 
survival of 10-17 months, whereas patients with metastatic disease have a median survival 
of only 6-9 months 73. Recent developments in immune checkpoint inhibition have led to 
promising advances in cancer immunotherapy 36, including blockade of CTLA-4 (cytotoxic T- 
lymphocyte antigen 4), an inhibitory receptor found on tumor-infiltrating T cells, and 
programmed death receptor ligand (PD-L1), an inhibitory receptor expressed by cancer cells 
and antigen-presenting cells (APCs). 
 
 
Despite these advances, however, response rates vary among patients and tumor types, 
leading to intense investigation of predictors of response 74. There is growing evidence to 
suggest that the tumor microenvironment may interfere with effective immune recognition, 
even in the presence of checkpoint inhibitors 75. Of particular importance are cancer- 

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Page 22 of 118 
 
associated fibroblasts (CAFs): in addition to promoting metastasis, CAFs are able to modify 
immune cell infiltration 76, and in a study of human fibroblasts isolated from resected lung 
cancers, upregulated protein expression by CAFs was shown to correlate with shorter 
disease-free intervals and worse overall survival 77. Platelet-derived growth factor (PDGF) 
also plays a role in tumor survival by inducing myofibroblast contraction, thus restricting 
capillary-to-interstitium 
transport 
of 
drugs 
78. 
Accordingly, 
targeting 
the 
tumor 
microenvironment may represent an important synergistic approach in immunotherapy. 
Tumor survival depends in part on immune evasion, achieved by modifying immune 
checkpoints, including PD-1 and PD-L1. It is now well known that blockade of the PD-1 
receptor and PD-L1 ligand interaction leads to T-cell stimulation, overcomes tumor immune 
resistance, and potentially provides clinically meaningful outcomes. This therapeutic strategy 
has been investigated in multiple cancers, including NSCLC, with varying responses and 
unique toxicity profiles. 
 
1.7.1 Preclinical Rationale for Combined Immunotherapy and PDGFR Inhibition 
In a preclinical model of murine mastocytoma 79, dasatinib (a multiple tyrosine kinase inhibitor 
with activity against PDGFR) demonstrated enhanced anti-tumor response both alone and 
when combined with anti-OX40, a T-cell costimulatory antibody. Tumor-bearing mice were 
treated with daily gavage of vehicle or dasatinib (150 mg/kg) on days 8, 9, and 10 following 
tumor inoculation. Dasatinib significantly decreased tumor volumes and prolonged mouse 
survival, and H&E staining revealed extensive vacuolar degeneration in treated tumors, 
morphologic changes consistent with significant cell death. Treatment also significantly 
increased the tumor antigen-specific T-cell levels in the peripheral blood of tumor-bearing 
mice. With the addition of anti-OX40, the authors noted increased CD8+ effector T cells and 
enhanced infiltration of tumor-specific T cells to levels greater than those observed with either 
anti-OX40 or dasatinib alone. Furthermore, mice receiving the combination demonstrated 
the highest levels of IFN-γ production in response to antigen stimulation, as well as an 
increased ratio of CD8+ effector T cells to regulatory T cells (Tregs), thus enhancing 
intratumoral CTL infiltration. The authors concluded that such data may delineate a strategy 
by which targeted therapy and immunotherapy may be combined to achieve superior 
antitumor responses in cancer patients. 
 
1.7.2 Preclinical Data from Dr. Antonia’s Lab at Moffitt Cancer Center and FGFR 
Inhibition 
Dr. Scott Antonia, a thoracic oncologist and translational researcher at Moffitt Cancer Center, 
has developed a technique to grow out pure, short-term cell lines of cancer-associated 
fibroblasts (CAFs) from human lung cancer tumors. He has furthermore recently 
demonstrated that lung cancer CAFs are potently immunosuppressive (expressing high 
levels of PDL1, IDO, and CD73), and therefore combining a drug targeting the tumor 
microenvironment (and CAFs) in combination with anti-PD-L1 (Nivolumab) therapy may 
enhance clinical efficacy. See Figures 1-3 below. 
 
 
 
 
 
 
 
 

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Figure 1a 
       
 
   
Figure 1b 
            
 
Figure 1a. CAFs inhibit TIL activation. A TIL cell line derived from a NSCLC patient was seeded 
in the presence and absence of high and low (low) concentrations of CAFs as well as anti-CD3 for 
72 hours. Supernatants were collected ,and an IFN  ELISA was performed to determine the 
activation of the TILs. As can be observed, when the TILs are in the presence of anti-CD3 and high 
concentration of CAFs, there is no IFN  production. When the number of CAFs is reduced (low), 
their suppression on TIL activation is diminished as shown by the presence of IFN
 in the 
supernatant. Figure 1b. Nintedanib inhibits CAFs and allows TIL activation. 

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25 
CAF2 
CAF1 
 
 
 
 
Untreated 
 
IFN-γ Tx 
 
Isotype 
 
 
 
Figure 2. PDL-1 and CD73 expression increases in CAFs treated with rh-IFN. Two CAF cell 
lines derived from NSCLC patients were seeded in the presence and absence of rh-IFN. After 
72-hour incubation, the cells were collected and stained for FAP, PDL-1, and CD73. A flow 
cytometric analysis followed. As can be observed, in the presence of rh-IFN the CAF cell lines 
have an increase in PDL-1 and CD73 expression, both markers for immunosuppressive 
molecules. FAP was used as a marker to characterize the fibroblasts as CAFs. 
Figure 2. PDL-1 and CD73 expression increases in CAFs treated with rh- 
IFN. 

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Figure 3. IDO protein 
expression increases in CAFs 
treated with rh-IFN. Two CAF 
cell lines were seeded in the 
presence and absence of rh-IFN 
for 72 hours. Protein was 
extracted and run in an SDS- 
PAGE gel and transferred to a 
PVDF membrane. The membrane 
was probed against IDO1 protein 
as well as GAPDH as a loading 
control. As it can be observed, we 
were able to confirm the qRTPCR 
data, showing that also at the 
protein level, IDO1 expression 
levels increase when compared to 
untreated (untreated). 

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1.7.3 
Potential Biomarkers of FGFR Inhibition 
Under the influence of tumor-secreted interferon gamma, CAFs not only play a collaborative 
role in tumor growth, but also evasion of the immune response 80. Interferon gamma has 
further been shown to increase tumor PDL-1 expression 81 and indoleamine 2,3-dioxygenase 
1 (IDO1), which catalyzes tryptophan degradation to kynurenine and by depleting 
extracellular tryptophan suppresses lymphocyte proliferation 82. High IDO1 activity in lung 
cancer is associated with advanced disease stage, and increased serum kynurenine: 
tryptophan ratios have been shown to correlate with disease progression 83. Therefore, 
serum kynurenine: tryptophan ratios may serve as a surrogate biomarker of tumor growth, 
and the impact of Nintedanib therapy could be further quantitated by biomarker testing before 
and after initiation of treatment. 

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Figure 4. Proposed Mechanism of Action of Nintedanib. 
 
 
 
 
1.8 Proposed Clinical Rationale 
As noted previously, despite recent advances in NSCLC immunotherapy, response rates 
vary, and with evidence that targeting the tumor (with chemotherapy) and the 
microenvironment (with FGFR inhibition) results in a synergistic treatment effect, the 
combination of FGFR inhibition with immune checkpoints is a rational curiosity. Further, 
evidence for potential clinical benefit exists in preclinical models, and the addition of PDGFR 
inhibition to standard chemotherapy has been shown to be well-tolerated. If successful, 
combination therapy may further improve the outcomes of patients with a largely terminal 
cancer. Phase I clinical trials have shown that antibody mediated blockade of either PD-L1 
or PD-1 can lead to durable tumor regression in about 20% of patients with advanced non- 
small cell lung cancer (NSCLC) 36,66,84. 
 
 
1.9 Benefit – Risk Assessment 
Although considerable progress has occurred in understanding the biological characteristics 
of cancer as well as the development of more effective treatment regimens, most patients 
with locally advanced or metastatic tumors succumb to their disease. Thus, there is a 
substantial need for novel therapeutic strategies to improve the outcome for patients with 
advanced or metastatic NSCLC. 
Antiangiogenic treatment with the orally available triple angiokinase inhibitor Nintedanib 
(BIBF1120) with inhibition of VEGFR, PDGFR and FGFR offers the chance to control both 
locally recurrent and distant metastatic disease on an outpatient basis. Treatment with 
Nintedanib (BIBF1120) may have the potential to provide significant benefit to patients with 
locally advanced and/or metastatic NSCLC by slowing tumor progression and metastasis, 
since its cellular target is expressed on the tutor vasculature in most malignancies. Induction 
of endothelial cell apoptosis may result in subsequent degradation of tumor vessels and 
subsequent tumor necrosis. Additionally tumor growth may be affected by direct anti-tumor 
effects, e.g. tumor cells that express VEGFR, PDGFR, or FGFR. 
The main risks of therapy with nintedanib (BIBF1120) in adult patients are: 
• 
Gastro-intestinal AEs (diarrhoea nausea, vomiting, , abdominal pain) 
• 
Increases in liver enzymes (AST, ALT, ALKP) and bilirubin 
• 
Perforation (gastrointestinal and non-gastrointestinal) 
• 
Hypertension 

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• 
Venous thromboembolism 
• 
Bleeding 
Neutropenia and sepsis, if combined with myelosuppressive chemotherapy, such as 
docetaxel: 
Liver enzymes must be followed closely during treatment with nintedanib (BIBF1120). 
Therapy with the trial drugs must be interrupted in the event of relevant elevations of liver 
enzymes and/or of bilirubin and further treatment is to be withheld until recovery of the 
abnormal laboratory parameters. 
Hypertension is a side effect of nintedanib and a slightly increased frequency of hypertension 
has been observed in the trials with nintedanib (BIBF1120) to a mild to moderate degree and 
only few cases of CTCAE grade 3 or 4 hypertension have been observed. With respect to 
bleeding, in the LUME –Lung 1 trial involving 1314 patients more bleeding events were 
reported for nintedanib-treated squamous cell carcinoma (SCC) patients (all grades: 17.1% 
vs. 10.9%; grade ≥3: 2.9% vs. 1.3%) than for those with adenocarcinoma (all grades: 10.9% 
vs. 11.1%; grade ≥3: 1.5% vs. 1.3%). Fatal bleeding events were balanced between both 
arms regardless of histology. 
Based upon a non-clinical safety study in vitro, nintedanib (BIBF1120) may have a potential 
risk of phototoxicity (skin and eyes) in vivo. Few cases of photosensitivity reactions (less 
than 1 %) and of CTCAE grade 1 intensity only have been reported from the clinical studies 
to date. If adequate precautions are taken (avoidance of prolonged ultraviolet (UV) exposure, 
use of broad spectrum sunscreen and sunglasses), treatment with nintedanib (BIBF1120) is 
considered safe. 
 
In addition for combination trials: 
The major clinical side effects observed after therapy with nivolumab and ipilimumab are 
distinct from nintedanib (BIBF1120) induced adverse events, yet some overlap may occur 
e.g. regarding mild gastrointestinal toxicity or hepatotoxicity (please refer to Section 5.5 for 
details). In view of the low potential for drug-drug interactions of nintedanib (BIBF1120), it is 
not likely that enhanced toxicity due to pharmacokinetic interaction between the drug and the 
cytotoxic chemotherapy will occur. 
Partially overlapping toxicity profile may result in increased nausea, vomiting and diarrhea, 
and liver enzyme increases. 
 
2. 
OBJECTIVES 
2.1 Primary Objectives  
Phase I (Dose Escalation) 
Determine the MTD and RP2D of concurrent administration of nivolumab, ipilimumab, and 
nintedanib. 
 
Phase II (Single Arm Cohorts): 
To determine the efficacy of concurrent administration of nivolumab, ipilimumab, and 
nintedanib in NSCLC patients. 
(1) Arm A: Newly diagnosed or treatment-naïve patients, with a target ORR of 50%, or 
(2) Arm B: Patients who have been previously exposed to immunotherapy, such as anti-PD- 
1, anti-PD-L1 or anti-CTLA-4, with a target ORR of 20%. 

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2.2 Secondary Objectives 
Phase II: 
• 
Determine the overall survival (OS), response rate (RR), Disease Control Rate 
(DCR), Duration of response, and progression-free survival (PFS) of patients treated 
with nivolumab, ipilimumab, and nintedanib. 
• 
Examine potential predictive and resistance mechanisms in the tumors of clinical 
non- responders. 
 
 
3. 
PATIENT SELECTION 
All inclusion and exclusion criteria will be assessed within 30 days before initiation of therapy. 
All eligibility criteria must be met prior to enrolling a patient. The study will be conducted in 
accordance with Good Clinical Practice (GCP), as defined by the International Conference 
on Harmonisation (ICH), WHO, and any local directives and in compliance with the protocol. 
This clinical protocol, any amendments, and the patient informed consent will require IRB 
approval and FDA IND approval/favorable opinion before initiation of the study. Patients 
should only be treated on the study if all inclusion criteria are fulfilled. 
 
 
3.1 Core Inclusion criteria 
1. Patients must have histologic or cytological diagnosis of advanced/metastatic NSCLC with no 
curative treatment options. For those with mixed histology, there must be a predominant 
histology. 
2. Be  18 years of age on day of signing informed consent. 
3. Life expectancy of at least 3-6 months. 
4. ECOG performance status score (0 and 1) 
5. For phase I trial portion, treatment naïve or patients previously treated with chemotherapy, 
immunotherapy or targeted therapy for NSCLC are allowed. Patient who underwent curative 
intent chemotherapy and/or radiation in the neoadjuvant or adjuvant setting are allowed to enroll 
if tumor recurrence occurred greater than 6 months from completion of that therapy (and will be 
considered treatment naïve in the Stage IV setting). Patients with NSCLC tumor known to harbor 
a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR 
mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E 
mutation) are allowed to enroll if they have received prior treatment with the FDA approved 
targeted therapy. 
 
 
6. For phase II trial portion, Patients will be enrolled as two parallel cohorts: 
a. Arm A (treatment naïve): Patients who are newly diagnosed and treatment naïve. Patient 
who underwent curative intent chemotherapy and/radiation in the neoadjuvant or 
adjuvant setting are allowed to enroll if tumor recurrence occurred greater than 6 months 
from completion of therapy. Patients with NSCLC tumor known to harbor a genomic 
aberration for which FDA approved treatment is available (i.e, non-resistant EGFR 
mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF 
V600E mutation) are allowed to enroll if they have received prior treatment with the FDA 
approved targeted therapy. 
b. Arm B (Immunotherapy pre-treated group): Patients who have received prior 
immunotherapy. Patients who are primary refractory to immunotherapy (i.e., Patients 
who were previously treated with immunotherapy and did not at least achieve stable 

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disease on first imaging assessment on immunotherapy) or have relapsed disease (i.e., 
Patients that were treated with immunotherapy, achieved at least stable disease on first 
imaging assessment and subsequently developed disease progression or relapse). 
Patients with NSCLC tumor known to harbor a genomic aberration for which FDA 
approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M 
mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed 
to enroll if they have received prior treatment with the FDA approved targeted therapy. 
7. At least one measurable lesion according to RECIST v1.1 criteria. 
8. QTcB must be <470 ms for males and <480 ms for females. 
9. Adequate normal organ and marrow function as defined below: 
a. Absolute neutrophil count (ANC) >1.5 x 109/L (> 1500 per mm3) 
b. Hemoglobin 
≥ 9.0 g/dL 
c. Platelet  count 
≥ 100 x 109/L (>100,000 per mm3) 
d. Total bilirubin ≤ 1.5 X normal institutional limits. For Pts with liver metastasis: total bilirubin 
must be within normal limits. (Except patients with Gilbert Syndrome, who can have total 
bilirubin < 3.0 mg/dL). 
e. Proteinuria < CTCAE grade 3 or greater 
f. 
AST (SGOT)/ALT(SGPT) ≤1.5 X institutional upper limit of normal or ≤ 2.5 X ULN for 
patients with liver metastases. This will not apply to patients with confirmed Gilbert’s 
syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated 
in the absence of hemolysis or hepatic pathology), who will be allowed only in 
consultation with their physician. 
g. Serum creatinine CL ≤ 1.5 X ULN or creatinine clearance > 45 mL/min by the Cockcroft- 
Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination 
of creatinine clearance: 
 
 
Males: 
Creatinine 
clearance 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
. 
72 x serum creatinine (mg/dL) 
Females: 
Creatinine 
clearance 
(mL/min) 
= 
Weight  
(kg) 
x 
(140 
– 
Age) 
x 0.85 
72 x serum creatinine (mg/dL) 
 
 
10. Have archival tissue where available. 
11. In addition, patients enrolled on the clinical trial must be willing and able to provide tissue from 
a newly obtained core or excisional biopsy of a tumor lesion. Patients for whom newly obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an 
archived specimen only upon agreement from the Sponsor. 
12. Female patients of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours before receiving the first dose of study medication. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 

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13. Ability to understand and willingness to provide written informed consent signed and dated prior 
to admission to the study in accordance with ICH-GCP guidelines and to the local legislation. 
 
3.2 Core Exclusion criteria: 
14. Concurrent use of other anticancer agents including chemotherapy, targeted therapy, 
radiotherapy or immunotherapy not otherwise specified in the protocol. 
15. Concurrent use of other investigational drugs or treatment in another clinical trial with a non- 
FDA-approved medication within the past 4 weeks before start of therapy. 
16. Chemo-, or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase 
inhibitors within the past 2 weeks prior to treatment with the trial drug. 
17. Radiotherapy (except for brain and extremities or stereotactic treatment) within the past 2 weeks 
prior to treatment with the trial drug. 
18. In immunotherapy pretreated patients, any history of dose-limiting toxicity with prior 
immunotherapy agents, including grade 3/4 immune-related adverse events (irAEs); irreversible 
irAEs; Grade ≥3 irAEs that did not respond to steroid rescue; or neurologic irAE with significant 
clinical sequelae. 
19. Prior treatment with nintedanib (BIBF1120). 
20. Known hypersensitivity to nintedanib, nivolumab, ipilimumab, peanut or soy or any other trial 
drug, or their excipients. 
21. Any toxicity (>CTCAE version 5 grade 3) from previous anti-cancer therapy that has not resolved to 
a Grade 1. Persistence of clinically relevant therapy related toxicity from previous chemo and/or 
radiotherapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated 
by the investigational product may be included (e.g., hearing loss, peripherally neuropathy, 
alopecia). 
22. History of leptomeningeal carcinomatosis. 
23. Radiotherapy to a target lesion within the past 3 months prior to baseline imaging unless that 
area has demonstrated progression. 
24. Active brain metastases (e.g., stable for <2 weeks, symptomatic, no adequate previous 
treatment, requiring treatment with anti-convulsants); dexamethasone therapy will be allowed if 
administered as stable or decreasing dose for at least 3 weeks before randomization otherwise 
no steroids to exceed prednisone 10 mg/day prior to starting trial treatment. Symptomatic or 
uncontrolled CNS metastasis. 
25. Current or prior use of immunosuppressive medication 7 days before the first dose of nivolumab 
or ipilimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an 
equivalent corticosteroid. A brief course (≤28 days) of corticosteroids for prophylaxis (eg, 
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) is permitted. Topical corticosteroids are 
permitted. 
26. Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with 
vitiligo, Grave’s disease, type I diabetes mellitus or residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, or psoriasis not requiring systemic treatment 
(within the past 2 years) are not excluded. 
27. Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood 
vessels. 
28. Has known history of, or any evidence of active, non-infectious pneumonitis. 

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29. Therapeutic anticoagulation with drugs requiring INR monitoring (except low-dose heparin 
and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti- 
platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325mg per day. 
30. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with 
incomplete wound healing and/or planned surgery during the on-treatment study period. 
31. History of clinically significant hemorrhagic or thromboembolic event in the past 6 months. 
32. Known inherited predisposition to bleeding or thrombosis. 
33. Significant cardiovascular diseases (i.e., uncontrolled hypertension, unstable angina, history of 
infarction within the past 3 months prior to start of study treatment, congestive heart failure > 
NYHA II, serious cardiac arrhythmia). 
34. Coagulation parameters: International normalized ratio (INR) > 2, prothrombin time (PT) and 
partial thromboplastin time (PTT) > 50% of deviation of institutional ULN. 
35. History of another primary malignancy within the past 2 years except for: 
a. Basal cell skin cancer 
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease 
c. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer 
in situ) 
36. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy 
37. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected) 
38. History of known active primary immunodeficiency 
39. History of allogeneic organ transplant 
40. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of 
receiving study treatment. 
41. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug 
42. Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, 
infectious disease or active ulcers (gastrointestinal tract, skin) or laboratory abnormality that may 
increase the risk associated with study participation or study drug administration and in the 
judgment of the investigator would make the patient inappropriate for entry into the study 
43. Patients who are sexually active and unwilling to use a medically acceptable method of 
contraception (e.g., such as implants, injectables, combined oral contraceptives, some 
intrauterine devices or vasectomized partner for participating females, condoms for participating 
males) for the duration specified during the trial and after end of active therapy* (See Section 
3.3 for details) 
44. Pregnant or breastfeeding female patients. 
45. Psychological, familial, sociological, or geographical factors potentially hampering compliance 
with the study protocol and follow-up schedule 
46. Active alcohol or drug abuse 
47. Significant weight loss (> 20% of Body Weight) within past 6 months prior to inclusion into the 
trial 
48. History of active tuberculosis 

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3.3 
Contraception in patients with preserved reproductive capacity 
Patients will be considered to be of childbearing potential unless surgically sterilized by 
hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two 
years. 
 
 
Women of childbearing potential on the trial will be instructed to adhere to contraception for 
a period of 5 months after the last dose of nivolumab, ipilimumab or nintedanib on the trial. 
Men receiving the trial drug combination and who are sexually active with women of child 
bearing age will be instructed to adhere to contraception for a period of 7 months after the 
last dose of nivolumab , ipilimumab and nintedanib . 
 
 
A highly effective method of birth control is defined as one which results in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, certain intrauterine devices (IUDs), sexual 
abstinence, or vasectomized partner. 
In case local regulations require restrictions to the above definition, the patient 
information will specify the acceptable contraceptive methods. 
 
 
3.4 Withdrawal of consent for study 
If treatment consent is withdrawn, the patient will not receive any further investigational 
product. If study consent is withdrawn, the patient will not receive any further investigational 
product or further study observation or contact. 
 
 
4. 
TREATMENT PLAN   
4.1 Dose Preparation 
 
Table 1. Identification of Investigational Products 
Investigational 
Product 
Manufacturer 
Concentration and Formulation as Supplied 
Nivolumab 
Bristol-Myers 
Squibb 
Supplied as a clear to opalescent, colorless to pale-yellow solution. Dilute
with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection,
USP to prepare an infusion with final concentration 250mg. 
Ipilimumab 
Bristol-Myers 
Squibb 
Supplied as a clear to opalescent, colorless to pale-yellow solution. Dilute
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to
prepare a diluted solution with a nal concentration ranging from 1 mg/mL to
2 mg/mL. 
Nintedanib 
Boehringer 
Ingelheim 
Supplied as a soft gelatin capsule available in 2 dose strength of- 100mg,
and 150mg. Capsule fill composed of medium chain triglycerides, hard fat,
and lecithin in addition to drug substance. 
 
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Commercially 0.9% 
(weight/volume [w/v]) saline, 5% Dextrose, or USP will be supplied by each site. Upon 
completion of the study, copies of investigational product accountability records will be 

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returned to BI or BMS. All unused investigational product will be returned to BI or BMS 
authorized depot or disposed of upon authorization by BI or BMS according to the 
investigational site policy. All investigational products should be kept according to 
manufacturer specifications. 
4.2 Agent Administration 
Treatment will be administered on an outpatient basis. 
 
4.2.1 Nintedanib (BIBF1120) 
Nintedanib is supplied as soft gelatin capsules containing a suspension of milled active as 
the ethane sulphonate salt. It is available in four dose strengths of 100 mg (peach or orange, 
oblong capsules), and 150 mg (brown or range capsules). Shelf life for all dose strengths 
and formulations is 60 months. 
Capsules have to be stored below 30°C. Capsules should be protected from exposure to 
high 
Nintedanib Drug Summary 
 
Substance (INN): 
Not assigned 
Pharmaceutical form: 
Soft gelatin capsule 
Pharmaceutical code 
Nintedanib (BIBF1120) 
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength: 
100 mg and 150 mg capsules 
Dose: 
400 mg (200 mg twice daily), dose reduction according to section 
5 
Duration of use: 
Continuous daily dosing until progression of disease or until 
criteria for interruption of treatment (section 4) is met. 
Route of administration: 
Oral 
Posology: 
Once or twice daily (to be swallowed unchewed with a glass of 
water of about 250 mL with a dose interval of around 12 hours at 
the same times every day, usually in the morning and the evening 
after food intake) 
 
 
4.2.2 Nivolumab 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein 
consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical 
light chains. It is a clear to opalescent, colorless to pale-yellow solution, which may contain 
light (few) particulates. It does not contain a preservative. It is supplied as a single-dose vial 
containing 100mg/10 mL (10mg/mL) solution. The drug product is a sterile, non- pyrogenic, 
single-use, isotonic aqueous solution in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 (Tween™ 80), pH 6.0 
and includes an overfill to account for vial, needle, and syringe holdup. It is supplied in 10- 
cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with aluminum 
seals.

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Recommended dosing preparation, storage and use conditions: 
Nivolumab vials should be stored at refrigerated temperatures (2°C to 8°C) and should not 
be frozen. Nivolumab does not contain preservatives, and any unused portion must be 
discarded. Preparation of Nivolumab and preparation of the IV bag are to be performed 
aseptically. Total in-use storage time from needle puncture of the product vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C 
(36°F to 46°F) from time of preparation. It is recommended that the prepared final IV bag be 
stored in the dark at 2°C to 8°C until needed. If storage time exceeds these limits, a new 
dose must be prepared from new vials. The refrigerated infusion solutions in the prepared 
final IV bag should be equilibrated at room temperature for about 2 hours prior to 
administration. Care must be taken to assure sterility of the prepared solution as the product 
does not contain any antimicrobial preservative or bacteriostatic agent. 
For dose preparation steps, the following ancillary items are required: 
 
• 
IV infusion bags of 0.9% sodium chloride injection (250 mL size), USP, or 5% 
Dextrose Injection, USP with final concentration ranging from 1mg/mL to 10mg/mL. 
Saline bags must be latex-free and can be made of PVC or polyolefins (e.g., 
polyethylene), manufactured with bis (2-ethylhexyl) phthalate (DEHP) or DEHP-free. 
• 
IV infusion lines made of PVC/DEHP or PVC/tri octyl trimellitate or polyethylene or 
polyurethane. All DEHP-containing or DEHP-free lines are acceptable. Lines should 
contain a 0.22 or 0.2 µm in-line filter. The in-line filter can be made of polyethersulfone 
or polyvinylidene fluoride. 
• 
Catheters/infusion sets made of polyurethane or fluoropolymer with silicone and 
stainless steel and/or PVC components. 
• 
Syringes made of polypropylene and latex-free. 
• 
Needles made of stainless steel. 
• 
After preparation of the dose, the entire contents of the IV bag should be administered 
as an IV infusion for approximately 1 hour through intravenous line containing a 
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 
1.2 micrometer). Do not co-administer other drugs through the same intravenous 
line. Flush the IV line with a volume of normal saline equal to the priming volume of 
the infusion set used after the contents of the IV bag are fully administered, or 
complete the infusion according to institutional policy to ensure the full dose is 
administered and document if the line was not flushed. 
 
Nivolumab will be administered as intravenous infusion over 60 minutes at 3mg/kg 
for the first dose. It will then be given over 30 minutes at 3mg/kg every 2 weeks. Each 
dose of Nivolumab should be administered using the following guidelines: 
• 
Nivolumab must be administered at room temperature (25°C) by controlled infusion 
via an infusion pump into a peripheral vein. Prior to the start of the infusion, ensure 
that the bag contents are at room temperature to avoid an infusion reaction due to 
the administration of the solution at low temperatures. 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product. Fully functional 
resuscitation facilities should be available. Investigational product must not be 
administered via IV push or bolus but as a slow IV infusion. The entire content of 
each IV bag will be infused using an infusion pump. 

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Version: 8 
Date: 12 January 2024 
 
 
 
• 
The infusion lines should be attached only at time of use. Lines used for infusion 
during dose administration will need to be equipped with appropriate in-line filters. 
• 
Some investigational product may remain in the IV line after the infusion has 
completed. Fifteen to 30 mL of 0.9% sodium chloride IV solution should be added to 
the infusion bag after the investigational product has been administered to flush the 
line. The infusion rate should not be changed. 
• 
The duration of the investigational product administration will be recorded. 
 
Nivolumab Drug Summary 
 
 
Substance (INN): 
Not assigned 
Pharmaceutical form: 
Pale yellow liquid 
Pharmaceutical code 
Nivolumab 
Source: 
Bristol Meyers 
Unit strength: 
100mg/10 mL (10mg/mL) solution 
Dose: 
3 mg/kg 
Duration of use: 
Every 2 weeks until disease progression or until criteria 
for interruption of treatment (Section 5) 
Route of administration: 
Intravenous 
Posology: 
3mg/kg intravenously every 2 weeks 
 
 
 
4.2.3 
Ipilimumab 
Ipilimumab (BMS-734016, MDX-010) is a fully human IgG1κ consisting of 4 polypeptide 
chains; 2 identical heavy chains primarily consisting of 447 amino acids each with 2 identical 
kappa light chains consisting of 215 amino acids each linked through inter-chain disulfide 
bonds. 
It is formulated as a sterile, isotonic, non-pyrogenic preservative-free, clear to slightly 
opalescent, colorless to pale- yellow solution for intravenous infusion, which may contain a 
small amount of visible translucent-to-white, amorphous ipilimumab particles. 
It is supplied in single-use Type 1 flint glass vials of  50 mg/10 mL stoppered with gray butyl 
stoppers and sealed with aluminum seals. Each milliliter contains 5 mg of ipilimumab and 
the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), 
mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris 
hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7. 
Recommended dosing preparation, storage and use conditions: 
• 
Ipilimumab injection (5 mg/mL) can be used for intravenous (IV) administration 
without dilution after transferring to a polyvinyl chloride (PVC), non-PVC/non-di-(2- 
ethylhexyl)phthalate (DEHP), or glass container.Ipilimumab injection may be diluted 
in 0.9% Sodium Chloride Injection, United States Pharmacopeia (USP) or 5% 
Dextrose Injection, USP to concentrations between 1 and 4 mg/mL and stored in 
PVC, non-PVC/non-DEHP, or glass containers for up to 24 hours at 2°C to 8°C or 
room temperature/room light. The product may be infused using a volumetric pump 

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Version: 8 
Date: 12 January 2024 
 
 
 
at the protocol-specific dose(s) and rate(s) through a PVC IV solution infusion set 
with an in-line, sterile, nonpyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 
µm). 
• 
Ipilimumab injection must not be administered as an IV push or bolus injection. Care 
must be taken to assure sterility of the prepared solutions since the drug product does 
not contain any antimicrobial preservatives or bacteriostatic agents. Ipilimumab 
injection,  50 mg/10 mL (5 mg/mL), must be stored refrigerated (2°C to 8°C) and 
protected from light. Ipilimumab injection must not be frozen. Partially used vials or 
empty vials of ipilimumab injection should be discarded at the site according to 
appropriate drug disposal procedures. 
• 
Recommended safety measures for preparation and handling include protective 
clothing, gloves, and safety cabinets. 
 
Ipilimumab Drug Summary 
 
 
Substance (INN): 
Not assigned 
Pharmaceutical form: 
Pale yellow liquid 
Pharmaceutical code 
Ipilimumab 
Source: 
Bristol Meyers 
Unit strength: 
50 mg/10 mL (5 mg/mL) 
Dose: 
1mg/kg 
Duration of use: 
Every 6 weeks until disease progression or until criteria 
for interruption of treatment 
(Section 5) 
Route of administration: 
Intravenous 
Posology: 
1mg/kg intravenously every 6 weeks 
 
4.3 Clinical Trial Design 
 
The combination of nintedanib with nivolumab plus ipilimumab will first be tested in a Phase 
I trial (24 patients) to establish safety and tolerability. Once the doses for the combination of 
choice are established (recommended Phase 2 dose, R2PD) we will proceed forward with 
the Phase II trials (40 patients each) Tables 2 and 3 
 
 
Table 2. Phase I Dose Escalation for Nivolumab, Ipilimumab and Nintedanib. 
 
NSCLC 
Cohort 
(n=18) 
Immunotherapy 
Regimen 
Nintedanib* 
Immune 
Nivolumab 3 
100mg PO QD Days 1-14 (Daily dose = 100 mg) 
therapy 
mg/kg IV Q2 
pre-treated 
Weeks plus 
advanced 
Ipilimumab 1 
150mg PO QD Days 1-14 (Daily dose = 150 mg) 
or 
mg/kg Q6 
weeks 
100mg PO BID Days 1-14 (Daily dose = 200 mg) 

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metastatic 
NSCLC 
150mg PO BID Days 1-14 (Daily dose = 300 mg) 
200mg PO BID Days 1-14 (Daily dose = 400 mg) 
*Doses based upon current dosing guidelines from Boehringer-Ingelheim 
The dose-escalation design (Table 2) for nintedanib combined with ipilimumab (1mg/kg) and 
Nivolumab (3mg/kg). Each cycle will be 2 weeks long. Patients will remain on study until 
progressive disease, study withdrawal, or intolerability. 
 
 
Table 3. Phase II. Nivolumab, Ipilimumab and Nintedanib. 
 
NSCLC Cohort 
Immunotherapy 
Regimen* 
Nintedanib 
Arm A: Advanced or 
metastatic 
NSCLC 
who 
are 
immunotherapy 
naïve 
Nivolumab 
3 
mg/kg IV Q2 plus 
Ipilimumab 
mg/kg Q6 
Dose TBD based on MTD and DLT, if 
any, in Phase I dose escalation 
(N = 40) 
Arm B: Advanced or 
metastatic 
NSCLC 
with 
prior 
immunotherapy 
Nivolumab 
3 
mg/kg IV Q2 plus 
Ipilimumab 
1 
mg/kg Q6 
Dose TBD based on MTD and DLT, if 
any, in Phase I dose escalation 
(N = 40) 
Each cycle will be 6 weeks long. Patients will remain on study until progressive disease, 
study withdrawal, or intolerability. The rationale behind the Phase II, Arm B (in selecting 
patients previously treated with immunotherapy) is to demonstrate whether patients who 
failed primary immunotherapy may then gain a clinical response by targeting the 
microenvironment, as well as to demonstrate the safety and tolerability of subsequent 
immunotherapy. Many patients who are considered for clinical trials in our cancer center may 
have already been pre-treated and failed to respond; therefore, this represents a unique 
therapeutic approach. 
 
4.4 Patient enrollment: 
Phase I and phase II 
The combination of nintedanib and immunotherapy with nivolumab and ipilimumab has not 
yet been tested; therefore, we will first conduct a Phase I (Table 2) trial of this triplet 
combination utilizing a 3+3 design (Section 11). If the Nivolumab/Ipilimumab/Nintedanib arm 
is found to be safe then this will be the combination of choice moving forward in the Phase II 
(Table 3) portion (NSCLC patients who have prior immunotherapy and who are newly 
diagnosed, treatment naïve). 
Patients will be enrolled once informed consent has been obtained, screening is complete, 
and all eligibility has been confirmed. Our trial patients will receive nivolumab IV every 2 
weeks, ipilimumab IV every 6 weeks plus nintedanib 100-200 mg PO QD-BID for 2-week 
cycles. Treatment will continue until progression, intolerance, or patient withdrawal occurs. 
Patients will be assessed for treatment related toxicities and for progression of disease every 
3 cycles (6 weeks ± 7 days) for the first year. After one year, radiographic assessment will 
be performed every 12 weeks (± 7 days). Patients will enter follow-up either after confirmation 
of PD or completion of treatment. 

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We will not exclude patients on the basis of PD-L1 expression levels for the many reasons 
detailed above in the background section, but the results will need to be known to analyze 
the results. 
 
4.4.1 Specific considerations 
 
Tumor biopsies: 
Patients enrolled in either the phase I and phase II trials will undergo a core biopsy or 
excisional biopsy of a lesion prior to starting treatment and in cycle 2 day 8 +/- 7 days. There 
will be an option to also obtain a third biopsy upon progression of disease. These biopsies 
will be analyzed as detailed in clinical correlates (Section 7). 
 
 
4.4.2 Inclusion of Women and Minorities: 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4.4.3 Patient numbering 
Once a patient is enrolled in the study, he/she will be assigned a simple 3 digit number, with 
the first patient assigned to 001 and so on. A separate spread sheet with password 
protection will be maintained that contains the patient study number along with personally 
identifiable information. Password protection will be maintained in order to keep patient 
information strictly confidential. Upon signing the informed consent form, the patient will be 
assigned a patient number by the investigator or his/her designee. Once assigned to a 
patient, a patient number will not be reused. If the patient fails to be started on treatment for 
any reason, the reason will be entered on the Eligibility Tab in OnCore, and his/her 
demographic information will be entered on the Demography Tab in OnCore. All laboratory, 
radiologic, and pathologic data collected on trial participants will be assigned the unique 
treatment number and stored in the OnCore system database. 
 
4.4.4 Patients and Sites 
 
This is a single-institution study at Moffitt Cancer Center. The study may enroll 18 patients 
in phase I cohort and 40 patients in each arm of phase II trial. 
 
4.4.5 Efficacy 
 
Radiographic assessments will be performed every 6 weeks (± 7 days) for the first year. After 
one year, radiographic assessments will be performed every 12 weeks (± 7 days). Response 
will be assessed using the response evaluation criteria in solid (RECIST v1.1). 

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Patients who are found to have stable disease (SD), partial response (PR), or complete 
response (CR) will continue on study until evidence of disease progression, intolerance, or 
withdrawal from study. Response rate, overall survival, and progression-free survival will be 
determined. Patients with progressive disease by RECIST v1.1 but without rapid clinical 
deterioration may continue to be treated at the discretion of the investigator. 
 
4.4.6 Safety 
NCI CTCAE version 5.0  will be used to assess toxicities in all patients in this study. Although 
nintedanib, nivolumab, and ipilimumab are each generally well tolerated, toxicities do occur. 
Careful toxicity assessments will be performed with standard laboratory studies (CBC, BUN, 
creatinine, electrolytes, and LFTs) before each treatment. The start of adverse event 
collections will be at cycle 1 day 1 (C1D1). Abnormal Lab values and vital signs or test results 
that do not induce clinical signs/symptoms or require therapy will not be considered clinically 
significant and will not be reported as adverse events (AEs). AEs will be collected at start of 
study treatment. The collection of significant adverse events (SAE) will start upon signature 
of the ICF. All SAEs with a determination of SAE-relatedness to the investigational therapy 
will be reported as described in the data and safety-monitoring plan detailed in the protocol. 
(Section 6). 
 
 
4.6 General Concomitant Medication and Supportive Care Guidelines 
According to local standards and please also see Section 5. 
 
 
4.7 Duration of Therapy 
Nintedanib: Until disease progression as determined by the treating MD/study PI, toxicity, 
withdrawal from treatment or study, or completion of treatment. 
Nivolumab: Until disease progression or completion of treatment as determined by the 
treating MD/study PI, toxicity, withdrawal from treatment or study, or completion of treatment. 
Ipilimumab: Until disease progression or completion of treatment as determined by the 
treating MD/study PI, toxicity, withdrawal from treatment or study, or completion of treatment. 
 
 
4.8 Duration of Follow Up 
Safety Follow-up 
The End of treatment visit (See Study Calendar) is visit corresponding to when the decision 
was made to stop study medication. A mandatory Safety Follow-Up Visit should be 
conducted approximately 30 days after the end of treatment or before the initiation of a new 
anti-cancer treatment, whichever comes first. All AEs that occur prior to the Safety Follow- 
Up Visit should be recorded. Patients with an AE of grade > 1 related to the study 
medication(s) will be followed until the resolution of the AE to grade 0-1 or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur within 100 days of 
the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded. 
 
 
Follow-up visits 
 
Patients who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 8 weeks (42 ± 7 days) after 
the 30 day Safety follow up visit by radiologic imaging to monitor disease status. After 1 year, 

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the imaging time point will occur every 12 weeks (± 7 days). Every effort should be made to 
collect information regarding disease status until the start of new anti-neoplastic therapy, 
disease progression, death, end of the study, or if the patient begins retreatment with 
nintedanib combined with nivolumab plus ipilimumab as detailed in Section 5. Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
 
Survival Follow-up 
 
Once a patient experiences confirmed disease progression or starts a new anti-cancer 
therapy or has a toxicity that precludes further therapy on trial, the patient moves into the 
survival follow-up phase and should be contacted by telephone every 12 weeks (± 7 days) 
to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
 
 
4.9 Criteria for Removal from Study Treatment 
Patients should PERMANENTLY discontinue treatment with nintedanib, nivolumab and 
ipilimumab in the event of: 
➢ Unequivocal disease progression. 
➢ Intolerable Adverse Events (e.g. CTCAE version 5 grade 3 or 4) that cannot be 
managed by dose reduction 
➢ Withdrawal of informed consent 
➢ Change in the patient’s status creating an unfavorable risk/benefit in favor to stop 
study treatment 
➢ Patient is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk. 
➢ Eligibility criteria are violated and represent a safety issue for the patient 
➢ Further dose reductions considered necessary but not allowed according to the 
protocol (for nintedanib, no more than 2 dose reductions are allowed) 
➢ Pregnancy or intent to become pregnant 
➢ Any AEs that meets criteria for discontinuation as defined in Section 6 
➢ AEs related to treatment with the combination of nintedanib, nivolumab and 
ipilimumab that is Grade 3, with the exception of toxicities that do not meet criteria for 
discontinuation as defined in Section 6 
➢ Patient noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (for example, refusal to adhere to scheduled visits) 
➢ Initiation of alternative anticancer therapy including another investigational agent 
➢ Confirmation of progressive disease and investigator determination that the patient 
is no longer benefiting from treatment with nivolumab, ipilimumab and nintedanib 
➢ Investigator’s decision. 
Patients who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AEs, other), will be identified as 
having permanently discontinued treatment. 
Patients who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 4.8, including the collection of any protocol-specified blood 

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specimens, unless consent is withdrawn or the patient is lost to follow-up or enrolled in 
another clinical study. All patients will be followed for survival. Patients who decline to return 
to the site for evaluations will be offered follow-up by phone every 12 weeks (± 7 days) as 
an alternative. 
 
 
5. 
DOSING SELECTION/DELAYS/DOSE MODIFICATIONS 
5.1. Criteria for interruption of treatment with Nintedanib (BIBF1120) and Nivolumab plus 
Ipilimumab 
Treatment with nintedanib (BIBF1120) and nivolumab plus ipilimumab has to be interrupted 
in case any of the criteria listed in Table 4 is fulfilled. 
 
 
Table 4: Criteria when to interrupt treatment with nintedanib (BIBF1120) and nivolumab plus 
ipilimumab due to an adverse event 
 
If one criterion is met, Nintedanib (BIBF1120) and Nivolumab plus 
Ipilimumab has to be interrupted 
Nausea of CTCAE grade  3 despite supportive care 
Vomiting of CTCAE grade  2 despite supportive care 
Diarrhea of CTCAE grade  2 for more than 3 consecutive days despite 
supportive care 
AST and/or ALT elevations of > 2.5 x ULN in conjunction with bilirubin 
of > 1.5 x ULN 
AST and/or ALT elevations of > 5x ULN 
Other non-hematological adverse event of CTCAE grade  3 considered 
drug-related 
*Neutropenia and fever > 38,5° 
*Neutropenia CTCAE grade 4 for more than 7 days without fever 
* Platelets <50.000mm³ with bleeding 
 
 
5.2. Criteria to restart Nintedanib (BIBF1120), Nivolumab and Ipilimumab treatment 
A patient is eligible to restart nintedanib (BIBF1120),nivolumab and ipilimumab if all criteria 
listed in Table 5 are met. If a patient has to interrupt intake of nintedanib 
(BIBF1120),nivolumab and ipilimumab due to an adverse event for more than 6 weeks (± 7 
days) the decision to restart treatment with nintedanib (BIBF1120),nivolumab and ipilimumab 
needs to be discussed and agreed upon between the investigator and the sponsor. 

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Table 5: Criteria to assess eligibility to restart continue nintedanib (BIBF1120),  
nivolumab and ipilimumab 
 
 
All criteria have to be met in order to restart Nintedanib (BIBF1120) and Nivolumab 
and Ipilimumab, meaning AEs have to return to Grade 1 or baseline 
Nausea CTCAE grade  2 
Vomiting CTCAE grade  1 
Diarrhea CTCAE grade < 2 
AST and ALT < 2.5 x ULN; bilirubin < 1.5 x ULN 
no other non-hematological adverse event grade CTCAE  3 which is considered 
drug-related 
*Neutropenia CTCAE grade  1, without fever or equal to the patient’s pre-therapy 
value at study enrolment 
*Platelets CTCAE grade  1 or equal to the patient’s pre-therapy value at study 
enrolment 
The dose adjustments will be outlines in the next Section 5.4. 
5.3 Trial Treatments 
The phase I dose escalation will include a fixed dose of Nivolumab 3 mg/kg IV every 2 weeks, 
a fixed dose of Ipilimumab 1 mg/kg every 6 weeks, and escalating doses of Nintedanib 
starting at 100mg PO once daily (five dose levels) to determine the MTD to be used in the 
expansion group and the randomized phase II portion of the trial. Once a MTD is determined, 
the phase II expansion and randomized phase two portions of the trial can begin accrual. 
Cycle 1, day 1 will start with nivolumab plus ipilimumab on day 1 with continuous daily oral 
therapy with Nintedanib starting on days 1 on a 2-week cycle. Please see Section 4.3 
Clinical Trial Design for more information. 
 
Table 6. Nintedanib dose levels in phase I dose escalation phase. 
 
Dose 
Level 
Nintedanib Dose, 
Route, 
Frequency 
Nivolumab 
Dose, 
Route, 
Frequency 
Ipilimumab Dose, 
Route, 
Frequency 
Use 
-1 
100mg PO QD 
3 mg/kg IV Q2 
weeks 
1 mg/kg IV Q6 
weeks 
Experimental 
0 
150mg PO QD 
3 mg/kg IV Q2 
weeks 
1 mg/kg IV Q6 
weeks 
Experimental 
1 
100mg PO BID 
3 mg/kg IV Q2 
weeks 
1 mg/kg IV Q6 
weeks 
Experimental 
2 
150mg PO BID 
3 mg/kg IV Q2 
weeks 
1 mg/kg IV Q6 
weeks 
Experimental 
3 
200mg PO BID 
3 mg/kg IV Q2 
weeks 
1 mg/kg IV Q6 
weeks 
Experimental 

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5.3.1 Dose Selection/Modifications 
5.3.1.1 Dose Selection 
 
 
The rationale for selection of doses and details on preparation and administration of 
nivolumab, ipilimumab and nintedanib to be used in this trial is provided in Section 4.0. 
 
 
5.3.1.2 Dose Modifications of Nintedanib (BIBF1120) 
As initial measure for the management of side effects (see Section 6) treatment with 
Nintedanib should be temporarily interrupted until the specific adverse reaction has resolved 
to levels that allow continuation of therapy. Nintedanib treatment may be resumed at a 
reduced dose. Dose adjustments in 50 or 100 mg increments per day (i.e. a 50 mg reduction 
per dosing) based on individual safety and tolerability are recommended as described in 
Table 6. In case of further persistence of the adverse reaction(s), i.e. if a patient does not 
tolerate 100 mg once daily, treatment with Nintedanib should be discontinued. 
 
 
The following dose levels will be used in case dose adjustments are required for 
management of undue toxicity (see Table 7). 
Table 7: Nintedanib (BIBF1120) dose levels – example for starting dose of 200mg 
twice daily 
 
Dose- level: 
0 
-1 
-2 
-3 
-4 
Dose: 
2 x 200 
mg/day 
2 x 150 
mg/day 
2 x 100 
mg/day 
1x150 
mg/day
1X 100 mg/day
 
 
 Of note! 
 
If the dose of nintedanib (BIBF1120) had to be reduced due to toxicity, it will stay on the 
lower dose level for the entire time of administration. 
5.3.1.3 Dose modifications of Nivolumab 
Adverse events (both non-serious and serious) associated with nivolumab and /or ipilimumab 
exposure may represent an immunologic etiology. These adverse events may occur shortly 
after the first dose or several months after the last dose of treatment. Nivolumab and 
ipilimumab must be withheld for drug-related toxicities and severe or life-threatening AEs as 
per Table 9 below. The recommended dose of nivolumab is 3 mg/kg administered as an 
intravenous infusion over 60 minutes for the first dose. It will then be given over 30 minutes 
at 3mg/kg every 2 weeks until disease progression or unacceptable toxicity. There are no 
recommended dose modifications for nivolumab. Further dose adjustments are described in 
Section 5.5.2 as per package insert and Events of Clinical Interest Guidance Document for 
supportive care guidelines including use of steroids. 

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5.3.1.4 Dose modifications for Ipilimumab 
The recommended dose of ipilimumab is 1mg/kg administered intravenously over 90 
minutes every 6 weeks. 
There are no recommended dose modifications for Ipilimumab. Further dose adjustments 
are described in Section 5.5.2 as per package insert and Investigator Brochure. 
 
 
5.4. Management of adverse events 
5.4.1 Management of adverse events of Nintedanib specifically 
 
 
As initial measure for the management of side effects (see section Side effects) treatment 
with Nintedanib should be temporarily interrupted until the specific adverse reaction has 
resolved to levels that allow continuation of therapy. Nintedanib treatment may be resumed 
at a reduced dose. Dose adjustments in 50 to 100 mg increments per day (i.e. a 50 mg 
reduction per dosing) based on individual safety and tolerability are recommended as 
described in Table 6. In case of further persistence of the adverse reaction(s), i.e. if a patient 
does not tolerate 100 mg once daily, treatment with Nintedanib should be discontinued. 
 
Table 8: Recommended dose adjustments for Nintedanib (BIBF1120) 
 
CTCAE* Adverse reaction 
Dose adjustment 
Diarrhea > grade 2 for more than 7 
consecutive days despite anti-diarrheal 
treatment** 
OR Diarrhea > grade 3 
despite anti-diarrheal treatment** 
1st episode: Reduce dose from 
200 mg twice daily to 150 mg 
twice daily 
2nd episode: Reduce dose from 
150 mg twice daily to 100 mg 
twice daily 
3rd episode: Reduce dose from 
100md twice daily to 100mg once 
daily 
4th episode: Stop treatment 
Vomiting ** > grade 2 AND/OR Nausea > 
grade 3 despite anti-emetic treatment** 
AST and/or ALT elevations of > 2.5 x ULN 
in 
conjunction with bilirubin of > 1.5 x 
ULN OR AST and/or ALT elevations of > 
5x ULN 
Other 
non-hematological 
or 
hematological adverse reaction of > 
grade 3 
Elevation of AST and/or ALT values to > 
3 x ULN in conjunction with an increase of 
total bilirubin to ≥ 2 x ULN and ALKP < 2 
x ULN 
Unless there is an alternative 
cause established, it should be 
permanently discontinued 
*CTCAE: Common Terminology Criteria for Adverse Events 
** see also section 5.8. Additional precautions 
 
 
If nintedanib (BIBF1120) will be combined with compounds that are solely metabolized by 
the liver and / or induce liver enzyme elevations, both molecules should be reduced in case 

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of liver enzyme elevations according to the defined dose reductions for Nintedanib as 
mentioned above and for the other compound as mentioned in their prescribing information. 
 
5.4.2 Dose modification and toxicity management of Nivolumab and Ipilimumab 
specifically 
 
 
Nivolumab in combination with ipilimumab has already been approved for treatment of 
melanoma in the United States65. Previous studies have shown that combination of both 
agents results in a safety profile with adverse events similar to adverse events seen with 
monotherapy with each agent alone 85. However, there are some cases that have found 
greater frequency of adverse events65,85. 
Based on the mechanism of action of nivolumab and ipilimumab leading to T-cell activation 
and proliferation, there is the possibility of observing immune-related adverse events (irAEs) 
during the conduct of this study. Potential irAEs include immune-mediated enterocolitis, 
dermatitis, hepatitis, and endocrinopathies. Patients should be monitored for signs and 
symptoms of irAEs. In the absence of an alternate cause (e.g., infection or PD), signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to 
be immune-related. 
 
Table 9a. Dose Modification Guidelines for Drug-Related Adverse Events for Nivolumab and 
Ipilimumab 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing 
for 
Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, 
ALT, 
or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) 
or 
Hyperglycemia 
T1DM or 
3-4 
Hold 
nivolumab 
and 
ipilimumab for new onset Type 
1 diabetes mellitus or Grade 3- 
4 hyperglycemia associated 
with  evidence  of  beta  cell 
failure. 
Resume nivolumab and ipilimumab when 
patients are clinically and metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with nivolumab and 
ipilimumab can be continued 
while treatment for the thyroid 
disorder is instituted 
Therapy with nivolumab and ipilimumab can be 
continued while treatment for the thyroid 
disorder is instituted. 

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Toxicity 
Hold 
Treatment 
For Grade 
Timing 
for 
Restarting 
Treatment 
Discontinue Subject 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug- 
Related 
Toxicity2 
3 
or 
Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. 
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug 
has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
Table 9b: Additional Dose Modification Guidelines for Drug-Related Adverse Events for 
Nivolumab and Ipilimumab 
 
Adverse 
Reaction 
Severity * 
Dose Modification 
Toxicity management 
Adrenal 
Grade 2 adrenal 
Withhold dose when 
Nivolumab 
and/or 
Ipilimumab 
can 
cause 
insufficiency 
insufficiency 
additional 
medical 
immune-mediated 
adrenal 
insufficiency. 
intervention 
is 
Monitor patients for signs and symptoms of 
indicated  other  than 
adrenal 
insufficiency. 
Administer 
physiologic 
corticosteroids at a dose of 1 to 2 mg/kg/day 
mineralcorticoid 
prednisone 
equivalents 
followed 
by 
a 
and/or 
corticosteroid 
corticosteroid taper for severe (Grade 3) or life- 
(≤ 10mg prednisone 
threatening (Grade 4) adrenal insufficiency. 
equivalent) 
Withhold 
Nivolumab 
and 
Ipilimumab 
for 
replacementa 
moderate (Grade 2 for which additional medical 
intervention is indicated other than physiologic 
Grade  3  or  4 
Permanently 
mineralcorticoid and/or corticosteroid (≤ 10mg 
adrenal 
discontinue 
prednisone 
equivalent) 
replacementand 
insufficiency 
permanently 
discontinue 
Nivolumab 
and 
Ipilimumab  for  severe  (Grade  3)  or  life- 
threatening (Grade 4) adrenal insufficiency. 

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Skin 
Grade 3 or 4 
rash 
or 
suspected/confir 
med 
Stevens- 
Johnson 
syndrome (SJS) 
or 
 
toxic 
epidermal 
necrolysis (TEN) 
or grade 4 
Permanently 
discontinue 
Nivolumab and Ipilimumab can cause immune- 
mediated rash, including Stevens-Johnson 
syndrome (SJS) and toxic epidermal necrolysis 
(TEN), some cases with fatal outcome. For 
symptoms or signs of SJS or TEN, withhold 
Nivolumab and Ipilimumab. Refer the patient 
for specialized care for assessment and 
treatment. If SJS or TEN is confirmed 
permanently 
discontinue 
Nivolumab 
and 
Ipilimumab 
For 
immune-mediated 
rash, 
administer 
corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone 
equivalents 
followed 
by 
a 
corticosteroid taper for severe (Grade 3) or life- 
threatening 
(Grade 
4) 
rash. 
Withhold 
Nivolumab and Ipilimumab for severe (Grade 
3) 
rash 
and 
permanently 
discontinue 
Nivolumab and Ipilimumab for life-threatening 
(Grade 4) rash. 
Encephalitis 
New-onset 
moderate 
or 
severe 
neurologic signs 
or symptoms 
Permanently 
discontinue 
Nivolumab and Ipilimumab can cause immune- 
mediated encephalitis with no clear alternate 
etiology. Evaluation of patients with neurologic 
symptoms may include, but not be limited to, 
consultation with a neurologist, brain MRI, and 
lumbar puncture. 
Withhold Nivolumab and Ipilimumab in patients 
with new-onset moderate to severe neurologic 
signs or symptoms and evaluate to rule out 
infectious or other causes of moderate to 
severe 
neurologic 
deterioration. 
If 
other 
etiologies 
are 
ruled 
out, 
administer 
corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone equivalents 
for patients with 
immune-mediated encephalitis, followed by 
corticosteroid taper. Permanently discontinue 
Nivolumab 
and 
Ipilimumab 
for 
immune- 
mediated encephalitis 
Immune 
mediated 
encephalitis 
Permanently 
discontinue 
Other 
Other Grade 3 
adverse reaction 
First occurrence 
Withhold dosea 
Nivolumab and Ipilimumab can cause other 
clinically significant immune-mediated adverse 
reactions. Immune-mediated adverse reactions 
may occur after discontinuation of Nivolumab 
and Ipilimumab therapy. For any suspected 
immune-mediated adverse reactions, exclude 
other causes. Based on the severity of the 
adverse reaction, permanently discontinue or 
withhold Nivolumab and Ipilimumab, administer 
high-dose corticosteroids, and if appropriate, 
initiate hormone- replacement therapy. Upon 
improvement to Grade 1 or less, initiate 
corticosteroid taper and continue to taper over 
at least 1 month. Consider restarting Nivolumab 
and 
Ipilimumab 
after 
completion 
of 
corticosteroid taper based on the severity of the 
event 
Recurrence 
of 
same 
Grade 3 adverse 
reactions 
Permanently 
discontinue 
Life-threatening 
or 
Grade 
4 
adverse reaction 
Permanently 
discontinue 
Requirement for 
10 mg per day or 
greater 
prednisone 
or 
equivalent 
for 
more 
than  12 
weeks 
Permanently 
discontinue 
Persistent 
Grade 2 or 3 
adverse 
reactions lasting 
Permanently 
discontinue 

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12 
weeks 
or 
longer 
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for 
Adverse Events. Version 5.0 (NCI CTCAE v5). 
a. Resume treatment when adverse reaction returns to Grade 0 or 1, patients with persistent 
grade 2 adrenal insufficiency whose medical intervention is mineralcorticoid and/or 
corticosteroid replacement (≤ 10mg prednisone equivalent) may resume treatment. 
5.4.3 Dose modification and toxicity management of combination of Nintedanib and/or 
Nivolumab plus Ipilimumab 
For adverse events (AEs) that are considered at least partly due to administration of 
nintedanib, nivolumab, and ipilimumab the following dose adjustment guidance may be 
applied: 
Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required). 
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of nintedanib plus nivolumab and/or ipilimumab along with 
appropriate continuing supportive care. If medically appropriate, dose modifications are 
permitted for Nintedanib. No dose modifications for ipilimumab and nivolumab (see below). 
In addition, there are certain circumstances in which nintedanib, nivolumab, and/or 
ipilimumab should be permanently discontinued. 
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
5.4.4 QT Prolongation 
No evidence of QT prolongation potential in Nivolumab, Ipilimumab (Per investigator 
Brochure – Study CA184004), or Nintedanib in the studied dose range 86,87. 
 
 
5.5. Dose limiting toxicity 
 
The Dose limiting toxicity (DLT) period will be the first 6 weeks of treatment. Patients must 
have received at least 25% of drug to be considered evaluation for the DLT. If a patient is 
removed from treatment within the DLT assessment period for non-toxicity or a toxicity not- 
related to the study medication(s) the patient can be replaced to allow a durable assessment 
of toxicity for the triplet at discretion of the sponsor. DLT will be defined as any Grade 3 or 
higher toxicity that occurs during the DLT evaluation period where not otherwise specified 
below. Toxicity that is clearly and directly related to the primary disease or to another etiology 
is excluded from this definition. All toxicities will be graded according to NCI CTCAE v5 . 
Following the first dose of nintedanib, nivolumab and ipilimumab, subsequent administration 
can be modified based on toxicities observed (see Tables 5, 6, 8 and 9 in Section 5). Dose 
reductions for nintedanib permitted only if the patient is outside of the DLT window. 
The following will be considered DLTs: 
 
➢ Any Grade 4 irAE 
➢ Any ≥ Grade 3 colitis X 7 days despite optimal treatment 
➢ Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 

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➢ Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the 
initiation of maximal supportive care 
➢ Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 
2 within 3 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 
➢ AST/ALT elevation > 5 × ULN or total bilirubin > 3 × ULN 
➢ Grade 3 or greater adrenal insufficiency 
➢ Any ≥ Grade 3 non-irAE, except for the exclusions listed below  
The definition excludes the following conditions: 
➢ Grade 3 fatigue lasting ≤ 7 days 
➢ Grade 3 endocrine disorder (thyroid and/or pituitary) that is managed with or without 
systemic corticosteroid therapy and/or hormone replacement therapy and the subject 
is asymptomatic 
➢ Grade 3 inflammatory reactions attributed to a local antitumor response (eg, 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) 
➢ Concurrent vitiligo or alopecia of any AE grade 
➢ 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 business days. Grade 3 or Grade 4 febrile 
neutropenia will be a DLT regardless of duration or reversibility 
➢ Grade 3 or 4 lymphopenia 
➢ Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
that requires medical intervention, and improves by at least 1 grade within 3 business 
days 
➢ Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention within 
3 business days 
➢ Grade ≥3 elevation in amylase and lipase in asymptomatic patients, these laboratory 
abnormalities will be monitored if elevated. 
 
 
5.6. Additional precautions for Nintedanib (BIBF1120) 

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5.6.1 Diarrhea 
Diarrhea was the most frequently reported gastro-intestinal event and appeared in close temporal 
relationship with the administration of docetaxel in the clinical trial LUME-Lung 1. The majority of 
patients had mild to moderate diarrhea. 6.3 % of the patients had diarrhea of grade ≥3 in combination 
treatment compared to 3.6 % treated with docetaxel alone. Diarrhea should be treated at first signs 
with adequate hydration and anti-diarrheal medicinal products, e.g. loperamide, and may require 
interruption, dose reduction or discontinuation of therapy with nintedanib. 
 
5.6.2 Nausea and vomiting 
 
Nausea and vomiting, mostly of mild to moderate severity, were frequently reported 
gastrointestinal adverse events in the clinical trial LUME-Lung 1. Interruption, dose reduction 
or discontinuation of therapy with nintedanib (BIBF1120) may be required despite 
appropriate supportive care. Supportive care for nausea and vomiting may include medicinal 
products with anti-emetic properties, e.g. glucocorticoids, anti-histamines or 5-HT3 receptor 
antagonists and adequate hydration. 
In the event of dehydration, administration of electrolytes and fluids is required. Plasma 
levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur. 
 
 
5.6.3 Neutropenia and Sepsis 
 
A higher frequency of neutropenia of CTCAE grade > 3 was observed in patients treated with 
nintedanib (BIBF1120) in combination with docetaxel as compared to treatment with 
docetaxel alone in the clinical trial LUME-Lung 1. Subsequent complications such as sepsis 
or febrile neutropenia have been observed. 
Blood counts should be monitored during therapy, if nintedanib (BIBF 1120) is combined with 
a myelosuppressive agent. 
 
 
5.6.4 Hepatic Function 
 
The safety and efficacy of nintedanib has not been studied in patients with moderate (Child 
Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore treatment with nintedanib 
(BIBF1120) is not recommended in such patients. . 
Administration of nintedanib was associated with an elevation of liver enzymes (ALT, AST, 
ALKP (alkaline phosphatase), and bilirubin, with a potentially higher risk for female patients. 
These increases were reversible in the majority of cases and not associated with clinically 
manifest liver disorders. Hepatic transaminases, ALKP and bilirubin levels are recommended 
to be closely monitored after start of therapy with nintedanib (BIBF1120) (periodically, i.e. in 
the combination phase with docetaxel at the beginning of each treatment cycle). 
If relevant liver enzyme elevations are measured, interruption, dose reduction or 
discontinuation of the therapy with nintedanib may be required. 
Alternative causes of the liver enzyme elevations should be investigated and respective 
action should be taken as necessary. In case of specific changes in liver values (AST/ALT > 
3 x ULN; total bilirubin ≥ 2 x ULN and ALKP >2 x ULN) due to treatment with nintedanib 
should be interrupted. Unless there is an alternative cause established nintedanib should be 
permanently discontinued. 
 
 
5.6.5 Special populations 

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Nintedanib exposure increased linearly with patient age, was inversely correlated to weight, 
and was generally higher in patients of Asian race. This may result in a higher risk of 
developing liver enzyme elevations. Close monitoring is recommended in patients with 
several of these risk factors. In study 1199.13 (LUME-Lung 1), there was a higher frequency 
of SAEs in patients treated with nintedanib plus docetaxel with a body weight of less than 50 
kg compared to patients with a weight ≥ 50 kg; however the number of patients with a body 
weight of less than 50kg was small. Therefore close monitoring is recommended in patients 
weighing < 50 kg.

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5.7 Trial Blinding/Masking 
This is an open-label trial; therefore, the sponsor, investigator and subject will know the 
treatment administered. 
 
 
5.8 Randomization and Stratification 
There will be no randomization or stratification in this trial. 
 
 
5.9 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the Oncore database from 
screening to enrollment period. If changes occur during the trial period, or new medications 
are started to treat an immune-related AE should be recorded in the Oncore database until 
30 days after the last dose of trial treatment. Concomitant medications administered after 30 
days after the last dose of trial treatment should be recorded for SAEs as defined in Section 
6 where applicable. 
 
 
5.10 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
Antineoplastic systemic chemotherapy or biological therapy 
Immunotherapy not specified in this protocol 
Investigational agents other than nintedanib, nivolumab, and ipilimumab 
Radiation therapy 
Note: Radiation therapy to symptomatic lesions or to the brain may be allowed at the 
investigator’s discretion, provided that radiotherapy does not affect all target lesions. 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology or to treat a comorbid condition as a 
standard of care (e.g. COPD exacerbation). The use of physiologic doses of corticosteroids 
may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 

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5.11 Rescue medication and additional treatments 
Rescue medications to reverse the actions of nintedanib (BIBF1120), nivolumab, or 
ipilimumab are not available. Potential side effects of nintedanib (BIBF1120), nivolumab, and 
ipilimumab have to be treated symptomatically. Please see Section 5.5.1 for details. 
 
 
5.12 Restrictions 
Additional chemo-, immuno- or hormone therapies- are not allowed during the active 
treatment period of this trial.. 
. 
Strong P-gp inducers, e.g. rifampicin, carbamazepine, phenytoin, erythromycin, 
ketoconazole and St. John’s Wort, may decrease exposure to nintedanib. Co- 
administration of strong P-gp inducers with the study drug combination should be carefully 
considered. However if co-administered , strong P-gp inhibitors may increase exposure to 
nintedanib, e.g. ketoconazole or erythromycin. In such cases patients should be monitored 
closely for nintedanib toxicity. Management of side effects may require interruption, dose 
reduction or discontinuation of therapy with nintedanib 
 
 
6. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
6.1 Adverse Event Characteristics 
An adverse event (AEs) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received 
a pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a patient’s 
pre-existing condition. An abnormal laboratory, test or physical exam finding that requires an 
action or intervention by the investigator will be recorded. Adverse events (but not serious 
adverse events) occurring before starting study treatment but after signing the informed 
consent form are recorded on the Medical History/Current Medical Conditions Electronic 
Case Report Form (ONCORE). Abnormal Lab values, vital signs or test results that do not 
induce clinical signs/symptoms or require therapy, will not be considered clinically significant 
and will not be reported as Adverse Events. In addition, isolated abnormal laboratory values 
that are considered clinically significant (e.g., cause study discontinuation or constitutes in 
and of itself a Serious Adverse Event) should be recorded on the Adverse Events CRF. SAEs 
occurring after initiation of treatment are recorded on the Adverse Event CRF. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of 
investigational product) or non-treatment emergent. A non-treatment-emergent AE is any 
new sign or symptom, disease, or other untoward medical event that begins after written 
informed consent has been obtained but before the patient has received investigational 
product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior 
to the patient being enrolled into the study) for a documented pre-existing condition, that did 
not worsen from baseline, is not considered an AE (serious or not serious). An untoward 
medical event occurring during the prescheduled elective procedure or routinely scheduled 
treatment should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 

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A serious adverse event (SAE) is defined as any AE that results in death, is immediately life- 
threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalization, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions. 
Patients may be hospitalized for administrative or social reasons during the trial (e.g., days 
on which infusion takes place, long distance from home to site). These and other 
hospitalizations planned at the beginning of the trial do not need to be reported as an SAE. 
The severity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) v5 in the (e) CRF. 
 
 
Causal relationship of adverse event 
 
 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases, and relevant 
history. Assessment of causal relationship must be recorded for each adverse event. 
 
 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as 
an AE in the CRF. 
 
 
6.2 Definition of Adverse Events of SPECIAL Interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the Investigational Product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product. 
AESIs for nivolumab and ipilimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants, and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with 
nivolumab and ipilimumab monotherapy and combination therapy. An immune-related 
adverse event (irAE) is defined as an adverse event that is associated with drug exposure 
and is consistent with an immune-mediated mechanism of action and where there is no clear 
alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an irAE diagnosis. Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
 
 
AESIs observed with nivolumab and/or ipilimumab include: 
• 
Colitis 
• 
Pneumonitis 
• 
ALT/AST increases / hepatitis / hepatotoxicity 

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• 
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
• 
Dermatitis 
• 
Nephritis 
• 
Ocular side effects (uveitis, iritis, or episcleritis 
• 
Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase, increased 
serum amylase) 
 
 
6.2.1 Pneumonitis 
Adverse events of pneumonitis are of interest for BI, as pneumonitis has been reported with 
anti-PD-1 monoclonal antibodies as well as anti-CTLA-4 monoclonal antibodies. Initial work- 
up should include high-resolution CT scan, ruling out infection, and pulse oximetry. 
Pulmonary consultation is highly recommended. 
 
 
Guidelines for the management of patients with immune-mediated events including 
pneumonitis are outlined in Section 5, Table 9a and 9b. 
 
 
6.2.2 Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti- 
PD-L1, anti-PD-1, and anti-CTLA-4 therapy). As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of monoclonal antibodies can 
be caused by various mechanisms, including acute anaphylactic (immunoglobulin E- 
mediated) and anaphylactoid reactions against the monoclonal antibodies, and serum 
sickness. Acute allergic reactions may occur, may be severe, and may result in death. Acute 
allergic reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, 
pruritus, angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, 
fatigue, headache, hypertension, myalgia, vomiting, and unresponsiveness. 
Guidelines for management of patients with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined below 
Severe or life-threatening infusion reactions: Discontinue nivolumab and ipilimumab. 
Mild to moderate infusion reactions: Interrupt or slow the rate of infusion. 
 
6.2.3 Hepatic function abnormalities (hepatotoxicity) 
Increased transaminase levels have been reported during treatment with anti-PD-L1, anti- 
PD-1, and anti-CTLA-4 antibodies 36,85. The clinical manifestations of Nivolumab and 
ipilimumab treated patients included general weakness, fatigue, nausea, and/or mild fever 
and increased liver function tests such as AST, ALT, alkaline phosphatase, and/or total 
bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 
2.5 × ULN and concurrent increase in total bilirubin to be greater than 1.5 × ULN. Concurrent 
findings are those that derive from a single blood draw or from separate blood draws taken 
within 8 days of each other. 

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Follow-up investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective evidence 
that clearly supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with 
distended gallbladder) or an agent other than the investigational product. Guidelines for 
management of patients with hepatic function abnormality are outlined in Section 5, Table 
9a and 9b. 
 
 
6.2.4 Gastrointestinal disorders 
Diarrhea/colitis can be observed as a treatment emergent SAE when nivolumab and 
ipilimumab is used as monotherapy or in combination. In rare cases, colon perforation may 
occur that requires surgery (colectomy) or can lead to a fatal outcome if not properly 
managed. Guidelines on management of diarrhea and colitis in patients receiving nivolumab 
and ipilimumab are provided in Section 5, Table 9a and 9b. 
 
 
6.2.5 Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- 
and hypothyroidism. Guidelines for the management of patients with immune-mediated 
endocrine events are provided in Section 5, Table 9a and 9b. 
 
 
6.2.6 Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation. Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in Section 5, Table 9a and 9b. 
 
 
6.2.7 Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis. 
Guidelines for the 
management of patients with immune-mediated neurotoxic events are provided in Section 
5, Table 9a and 9b. 
 
 
6.2.8 Nephritis 
Monitor for signs and symptoms that may be related to changes in renal function (e.g. routine 
urinalysis, elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, proteinuria, etc) 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, infections etc.) 
 
 
Guidelines for the management of patients with immune-mediated neurotoxic events are 
provided in Section 5, Table 9a and 9b. 
 
 
6.2.9 Immune-related adverse events 
Based on the mechanism of action of nivolumab and/or ipilimumab leading to T-cell activation 
and proliferation, there is a possibility of observing irAEs during the conduct of this 

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study65,88. Potential irAEs may be similar to those seen with the use of Nivolumab and/or 
ipilimumab and may include immune-mediated enterocolitis, dermatitis, hepatitis 
(hepatotoxicity), pneumonitis, and endocrinopathies 36,65,84,89. These AEs are inflammatory 
in nature and can affect any organ. Patients should be monitored for signs and symptoms 
of irAEs. In the absence of an alternate etiology (eg, infection or PD), an immune-related 
etiology should be considered for signs or symptoms of enterocolitis, dermatitis, pneumonitis, 
hepatitis, and endocrinopathy. In addition to the dose modification guidelines provided in 
Section 5, Table 9a and 9b, it is recommended that irAEs are managed according to the 
general treatment guidelines outlined for nivolumab and ipilimumab. These guidelines 
recommend the following: 
 
Patients should be evaluated to identify any alternative etiology. 
• 
In the absence of a clear alternative etiology, all events of an inflammatory nature 
should be considered immune related. 
• 
Symptomatic and topical therapy should be considered for low-grade events. 
• 
Systemic corticosteroids should be considered for a persistent low-grade event or for 
a severe event. 
• 
More potent immunosuppressives should be considered for events not responding to 
systemic steroids (eg, infliximab or mycophenolate). 
• 
If the Investigator has any questions in regards to an AE being an irAE, the 
Investigator should immediately contact the Study Physician 
 
The following events are considered as Protocol-specified adverse events of special 
interests (AESI) for Nintedanib: 
➢ Any gastrointestinal- and non-gastrointestinal perforation, leakage, fistula formation, 
abscess 
 
 
In such cases, the following additional information will need to be collected and 
documented in the respective comment field of the CRF page and the respective 
narratives of the SAE. That has to be forwarded to BI 
• 
Location of perforation, leakage, fistula, abscess 
• 
Location/extent of abdominal tumor manifestations, 
• 
Imaging & reports (CT, ultrasound, endoscopy, pathology, etc.) 
• 
Prior surgery (location, wound healing complications) 
• 
Concomitant diseases with GI involvement (e.g., M Crohn, vasculitis, 
tuberculosis, diverticulitis) 
• 
Thromboembolic events (or predisposition) 
 
 
➢ Drug-induced liver injury is under constant surveillance by sponsors and regulators 
and is considered a protocol-specified adverse event of special interest (AESI). 
Timely detection, evaluation, and follow-up of laboratory alterations of selected liver 
laboratory parameters to distinguish an effect of the investigational drug from other 
causes are important for patient safety and for the medical and scientific 
interpretation of the finding. The following are considered as protocol-specified AESI: 

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• 
An elevation of ALT and / or AST > 5x ULN without bilirubin elevation 
measured in the same blood draw sample 
• 
An elevation of AST and/or ALT >2.5 fold ULN combined with an elevation 
of bilirubin to >1.5 fold ULN measured in the same blood draw sample 
 
 
Patients showing above laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met and according to Section 5, Table 9a,9b and 
appendix 13.1 of this clinical trial protocol. 
 
 
Protocol-specified AESI are to be reported in an expedited manner similar to Serious 
Adverse Events, even if they do not meet any of the seriousness criteria. 
 
6.3 Recording of adverse events and serious adverse events 
Adverse events will be collected from time of start of study treatment to 100 days from end 
of treatment or the initiation of new anti-cancer therapy, whichever is earlier. Serious Adverse 
events will be collected from time of consent to 100 days after end of treatment or the 
initiation of new anti-cancer therapy, whichever is earlier. AEs will be recorded CTCAE v 5 
using a recognized medical term or diagnosis that accurately reflects the event. Adverse 
events will be assessed by the investigator for severity, relationship to the investigational 
product, possible etiologies, and whether the event meets criteria of an SAE and therefore 
requires immediate notification to BI and BMS Patient Safety. 
 
 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 
 
In addition, the following variables will be collected for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) or study drug(s) 
• 
Study recording period and follow-up for adverse events and serious adverse events 

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During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
 
If a subject discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
assessments. 
 
 
The investigator is responsible for following all SAEs until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
 
SAEs, AESIs, and non-serious AEs relevant for a reported SAE or AESI are to be reported 
to BI and BMS using the FDA MedWatch Form and providing as much detail regarding the 
SAE/AESI/non-serious AEs as possible. With receipt of follow-up information, all remaining 
fields on the SAE form are to be completed or updated. 
 
 
The investigator does not need to actively monitor patients for adverse events once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE(s) or AESI(s) 
that occurred after the patient has completed the clinical trial (including any protocol specified 
follow-up period/Residual effect period), it should be reported to BI if investigator considers 
it as relevant to the BI or Bristol-Myers Squibb Company study drug. Please see Section 6.4 
on how to report SAEs, AESIs, or non-serious AEs. 
 
 
6.4 SAE, AESI and non-serious AE Reporting to Boehringer Ingelheim (BI) and/or Bristol- 
Myers Squibb (BMS) 
A serious adverse event is any adverse event occurring at any dose or during any use of a 
BI and/ or BMS product that: 
Results in death; 
Is life threatening; 
Results in persistent or significant disability/incapacity; 
Results in or prolongs an existing inpatient hospitalization; 
Is a congenital anomaly/birth defect; 
Is a new cancer (that is not a condition of the study); 
Is associated with an overdose; 
Is an important medical event 
 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 100 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to BI and/ 
or BMS product, must be reported within 24 hours to the Sponsor, BI Unique Entry Point and 
BMS. 

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All SAEs/ AESI will be forwarded to BI Unique Entry Point and BMS will be handled in the 
same manner as SAEs. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to BI or BMS product that is brought to the attention of the investigator 
at any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor, BI and BMS where appropriate. 
 
 
The investigator shall report all SAEs, AESIs, and non-serious AEs which are relevant to a 
reported SAE or AESI by fax or other secure method using FDA medwatch form to the BI 
Unique Entry Point (include BI SAE cover letter form with each medwatch transmission) and 
BMS at 1-800-721-5072 as required above and the FDA as required. 
. 
BI Unique Entry Point: 
Boehringer Ingelheim Pharmaceuticals, Inc. 
900 Ridgebury Road 
Ridgefield, CT 06877 
Fax: 1-203-837-4329 
 
 
Suspected adverse reactions for nivolumab and/or ipilimumab will be reported to Bristol- 
Myers Squibb using the FDA MedWatch or to the FDA directly at 1-800-FDA-1088 
(www.fda.gov/medwatch). 
 
 
BMS AE/SAE contact information: 
Bristol-Myers Squibb Corporate Headquarters 
345 Park Avenue 
New York, NY 10154 
Email address: Worldwide.Safety@BMS.com 
Phone number: +1-609-818-3804 
 
 
6.5 Other Events Requiring Reporting 
6.5.1 Reporting of deaths 
All deaths that occur during the study or within the protocol-defined 100-day post-last dose 
of Nivolumab, ipilimumab or nintedanib safety follow-up period must be reported as follows: 
 
 
Death that is clearly the result of disease progression should be documented but should not 
be reported as an SAE. 
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to as a SAE within 24 hours (see Sections 6.3 and 
6.4, for further details) of notification of the SAE. The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should assign 
main and contributory causes of death. 
Deaths with an unknown cause should always be reported as a SAE. A post mortem maybe 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to BI and BMS within the usual timeframes. 

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Deaths that occur following the protocol-defined 101-day and beyond post-last-dose of 
nivolumab, ipilimumab or nintedanib safety follow-up period will be documented as events 
for survival analysis but will not be reported as an SAE. 
6.5.2 Overdose 
An overdose is defined as a patient receiving a dose of nivolumab, ipilimumab or nintedanib 
in excess of that specified in the Investigator’s Brochure, unless otherwise specified in this 
protocol. 
Any overdose of a study patient with nivolumab, ipilimumab, or nintedanib with or without 
associated AEs/SAEs is required to be reported within 24 hours of knowledge of the event 
to BI and BMS. Patient Safety or designee using the designated FDA MedWatch form will 
be sent to the BI Unique Entry Point and /or BMS (see Section 6.4 for contact information). 
If the overdose results in an AE, the AE must also be recorded as an AE (see Section 6.3 
and 6.4). Overdose does not automatically make an AE serious, but if the consequences of 
the overdose are serious, for example death or hospitalization, the event is serious and must 
be recorded and reported as an SAE (see Section 6.3 and 6.4). There is currently no specific 
treatment in the event of an overdose of Nintedanib, ipilimumab, and/or nivolumab. 
Appropriate supportive treatment should be provided if clinically indicated. In the event of 
overdose, the subject should be observed closely for signs of toxicity. 
If a dose of BI and/or BMS product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect” to the BI Unique Entry Point and/or Bristol 
Myers Squibb (see Section 6.4 for contact information). 
6.5.3 Hepatic function abnormality 
Hepatic function abnormality (as defined in Section 6.2.3) in a study patient, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to BI and/or BMS. Patient Safety or designee using 
the designated FDA MedWatch form will be sent to the BI Unique Entry Point and BMS (see 
Section 6.4 for contact information), unless a definitive underlying diagnosis for the 
abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to investigational 
product has been confirmed. 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study patient will 
be based on the clinical judgment of the investigator. 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
patient must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by BI and BMS. 
 
 
6.5.4 Pregnancy 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the investigational products 
(IP) should be discontinued immediately. 
Pregnancy is regarded as an SAE. Congenital abnormalities or birth defects and 
spontaneous miscarriages should be reported and handled as SAEs. Elective abortions 
without complications should not be handled as AEs. The outcome of all pregnancies 

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congenital abnormality) should be followed up and documented even if the patient was 
discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the appropriate BI and BMS representatives within 1 day, i.e., 
immediately, but no later than 24 hours of when he or she becomes aware of it. The 
designated BI and BMS representatives will work with the Investigator to ensure that all 
relevant information is provided to the BI and BMS Patient Safety data entry site within 24 
hours of notification of the SAEs. The same timelines apply when outcome information is 
available. 
 
 
Paternal exposure 
 
Male patients should refrain from fathering a child or donating sperm during the study and 
for 7 months after the last dose of nivolumab, ipilimumab, and nintedanib combination 
therapy or 90 days after the last dose of nivolumab and ipilimumab, whichever is the longer 
time period. 
Should the investigator become aware of a pregnancy in the partner of a male study patient 
who has received IP this should be reported within 24 hours of knowledge of the event to BI 
and BMS. Patient Safety or designee using the designated FDA medwatch form will be sent 
to the BI Unique Entry Point and BMS (see Section 6.4 for contact information). 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner. Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use. The 
sponsor will endeavor to collect follow-up information on such pregnancies provided the 
partner of the study patient provides consent. 
Pregnancy is regarded as a SAE. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of any conception occurring from 
the date of the first dose until 100 days after the last dose or the initiation of new anti-cancer 
therapy, whichever is earlier (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the patient was withdrawn from the study. 
 
 
6.5.5 Dose-Limiting Toxicity 
All DLT events (described in Section 5.6.) that occur in individual patients at any time during 
the treatment course or the follow-up period must also be reported as Adverse Event of 
Special Interest (AESI) (see Section 6.2, 6.3, 6.4) 
 
 
6.6 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRBs and investigators in 
accordance with all applicable global laws and regulations. 
 
 
7. 
CORRELATIVE/SPECIAL STUDIES 
7.1 Laboratory Correlative Studies 
TISSUE 

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Overview of Tissue Correlates of Interest 
The following molecular testing may be requested on biopsy specimens obtained in the trial: 
ALK, EGFR, KRAS, ROS-1, PD-L1 status, RET, Met, PTEN, BRAF, PI3K and Her2 neu if 
not already in the EMR. In addition, PD-L1 status by immunohistochemistry and quantitation 
of tumor infiltrating lymphocytes will be determined on all biopsy specimens. While the 
molecular underpinnings of PD-L1 expression on tumor cells are poorly understood, this 
would likely provide insight into mechanisms of anti-PD-1 therapy and potential predictive 
biomarkers. Other potential tumor assessments can include staining for fibroblast-associated 
protein (FAP), a CAF marker, IDO (a marker of CAF inhibition) and CD4/CD8/PD-L1 staining 
to determine the presence of tumor-infiltrating lymphocytes (TILs). Samples will also be 
assessed for mutational load , nanostring for GEP for key immune markers and AQUA for 
Protein expression of genes (Navigate) that correlate to lack of response to immunotherapy. 
 
Tissue IHC Assessments on Pre- and On-Immunotherapy Biopsies. 
 
Tumor assessments will include immunohistochemical staining for fibroblast-associated 
protein (FAP) a CAF marker, IDO (a marker of CAF inhibition), and PD-L1. While the 
molecular underpinnings of PD-L1 expression on tumor cells as well as CAF expression in 
the TME are poorly understood, our approach would likely provide insight into mechanisms 
of anti-PD-1 therapy and potential predictive biomarkers. This will be done by a fluorescence- 
based IHC (FIHC) panel developed by Navigate to reliably and objectively quantify by 
Automated Quantitative Analyses (AQUA) the tumor associated immune cells using 
conventional FFPE whole tissue sections.90 The high-throughput clinical trial laboratory 
workflow consists of automated stainers (Biocare), Vectra 2 Image Acquisition platform 
(Perkin Elmer) and AQUA Image Analysis software (see Figure 5) that enables objective, 
quantitative, and standardized biomarker assessments.90 It has been successfully tested in 
different tumor indications including Metastatic Melanoma (Bordeaux et al, AACR Annual 
Meeting, April 2016) NSCLC, gastric cancer (Kim et al, Tri-Con, San Francisco, March 2016) 
and diffuse large B-cell lymphoma (Tran et al., ASH Annual Meeting, New Orleans, 
December 2015. All assays were evaluated in multiple analytical runs and patient specimens 
to verify reproducibility and the prevalence of biomarkers prior to this clinical trial application. 
For the study, we will be interested in interrogating the patient enrichment, TIL, and T cell 
activation panels, those most likely to predict for benefit to Immunotherapy. (See Table 10). 
Ultimately through this approach we will be set to analyze the biological role and predictive 
value of innate and adaptive immune cells in the tumor microenvironment by AQUA and 
compare results across the predictive value of the IHC and Immunoscore analyses for 
example. 

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Table 10: Exploring tumor immunity continuum by multiplex AQUA 
 
 
 
Here are the proposed FIHC by AQUA tests for exploring tumor microenvironment. All 
markers are validated for exploratory clinical trials, except the functional myeloid derived 
suppressor cells (MDSC )** which remains under development. 
 
 
Figure 5. Schematic illustration of FIHC AQUA assay workflow 
 
 
 
 
Multiplexing is achieved by sequential application and removal of same species primary 
antibodies via microwave treatments. Fluorescent images are acquired on the Vectra 
Imaging system that acquires tissue regions of interest based on pattern recognition 
algorithms. Vectra images are analyzed by proprietary AQUA analysis algorithms, which 
remove the subjectivity of the traditional scoring system and provide more continuous and 
reproducible measures of protein expression in terms of biomarker intensity, percent 
positivity, and receptor-ligand interactions. 
 
 
Determination of the Immunoscore of Pre- and On-Immunotherapy Biopsies. 
To determine the baseline level of immune response to individual tumors and whether there 
is improved response with treatment, we will use Immunoscore to assess the TILs. 
Immunohistochemistry will be used to quantify the relative numbers of CD3, CD4, CD8, and 
CD45RO positive T-cells. Immunoscore for each biopsy will be determined as previously 

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described. The density (low vs high) of two types of cells (CD4 and CD8) will be assessed 
at two different locations (IM, invasive margin; and CT, center of tumor). The Immunoscore 
ranges from 0 (low density at both locations) to 4 (high density of both cell types at both 
locations). 
 
Tissue Molecular Methods. 
On the banked biopsy FFPE tissue blocks, protein expression of genes of interest will be 
confirmed using IHC staining by Moffitt Cancer Center Tissue Core. Procedures for IHC 
staining of the markers below have been developed and optimized in-house. The slides will 
then be sent to our Analytical Microscopy Core, scanned, and digitally quantified by image 
analysis for percent staining for each marker. The experienced pathologist will then 
determine accuracy not only of the software to identify CAFs versus tumor cells but also IM 
versus CT and for quantitation. Readouts will be provided to the study team for interpretation 
and statistical correlations. 
PD-L1 expression will be measured using the immunohistochemistry assay based on the 
FDA approved anti-PD-L1 monoclonal antibody. We will test, however, not select patients 
on the basis of PD-L1 expression for reasons outlined above (see Innovation). Most 
importantly, improved outcomes were seen with Nivolumab in both PD-L1 negative or 
positive 88. Positive staining is currently defined cut-off value of ≥ 1% in a minimum number 
of 100 evaluable cells. 
 
 
Mutational Load and Analysis. 
Acquired mutations may influence response to immunotherapeutic agents. Molecular 
profiling is standard of care for advanced NSCLC; thus the following molecular test results 
will be collected from the electronic medical records where available: ALK, EGFR, K-RAS, 
ROS-1, PD-L1 status, RET, Met, PTEN, BRAF, PI3K and Her2 neu. Next Generation 
Sequencing (NGS) panel will be performed on both tumor and blood samples to precisely 
identify all somatic mutations and to quantify mutational load. Results from molecular 
analyses including mutational load and specific genes will be correlated with patient 
outcomes, potentially helping to address some of the critical barriers for effective 
personalized treatment. 
 
 
NanoString Methods and Analysis. 
Both hypothesis-driven and exploratory discovery-driven studies will be performed. Standard 
protocols used routinely in the Moffitt Molecular Biology Core will be used to generate gene 
expression data using the NanoString technology with the PanCancer Immune Profiling 
Panel 91. This panel contains probes to quantitate 770 immune function genes that broadly 
identify key subsets of immune cells, assess T-cell function, antigen processing, 
chemokines, cytokines, immunosuppressive molecules, and a host of additional immune- 
related functions. Genes identified using this analysis that correlate with clinical response or 
resistance will be confirmed using will be confirmed using AQUA on sections from the banked 
tissue blocks. Briefly, hybridization buffer containing the capture and reporter probes will be 
added to total RNA extracted from the biopsies, with hybridization excess probes removed 
with Prep Station. The probe-transcript complexes will then be immobilized on streptavidin- 
coated cartridges and analyzed on the Digital Analyzer. These analyses will be led by the 
MCC Molecular Core and tissue samples will be processed through the MCC Tissue Core. 
 
 
AQUA for Primary and Secondary Resistance Mechanisms. 

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The protein expression of the genes discovered to correlate with lack of clinical response 
such as IC receptors on T-Cells (LAG3 and TIM3), suppressive cells (MDSC, T reg) and 
enzymes (IDO) will be confirmed using AQUA on the biopsy tissue blocks (See Table 11). 
Specifically, we will focus upon interrogating the T cell suppression and myeloid panels, 
those most likely to predict for resistance to immunotherapy. When looking for resistance 
mechanisms and with the potential limitations in available tissue, the Genoptix approach is 
ideal as their 3 color slide using AQUA for immunotherapy biomarker assessments requires 
a minimum of only five slides while providing critical information on resistance. Ultimately 
through this approach we will be set to analyze the biological role and resistance value of 
innate and adaptive immune cells in the TME by AQUA. 
 
Statistical Analysis for IHC and Immunoscore. 
The primary analysis is to test if there is any expression change due to the treatment. Two 
sets of biomarkers in tumor will be measured: 1) FAP, IDO and PD-L1 IHC studies and 2) 
Analysis of Immunoscore. These will be done by comparing pre- and post-treatment levels 
of FAP, PD-L1, IDO, and the Immunoscore using paired t-test due to the nature of continuous 
measurement for these biomarkers. Any significant change (at 5% family-wise error rate, i.e., 
adjusted p<0.05/4=0.0125) will be considered to be caused by the treatment effect. Subset 
analyses for the immunotherapy naïve and immunotherapy pre-treated patients will be 
performed separately using the same statistical strategy. Each cohort will have a total sample 
size of 40 patients. It will give 80% power to detect a 0.55 standard deviation difference of 
the change (pre to post) for each biomarker controlled at 5% family-wise error rate based on 
paired t-test. 
 
 
Statistical Plan for NanoString and Mutational Load. 
Data Analysis 
We will discover and develop predictive biomarkers for clinical response. Six types of 
continuous measurements will be included: gene expression, mutation burden, 
Immunoscore, AQUA, blood flow cytometry panel and tumor PD-L1 and FAP expression. 
For analysis of gene expression, we will use the PanCancer Immune profiling panel, which 
contains over 770 immune function genes. For genes associated with resistance or 
response, linear models for microarray data (LIMMA) 92 will be used to identify differentially 
expressed genes (responders vs non-responders). Additional comparison between 
responders and non-responders will be performed in patients who receive the treatment of 
nivolumab plus/minus nintedanib. Genes with adjusted P < 0.05 will be considered 
statistically significant. For the significant genes, the profiling score will be generated by 
principal component analysis (PCA) using the first principal component (PC1). Two-sample 
t-test will be used to evaluate if the profiling score is associated with clinical response. Other 
pathway analysis will be also examined, such as gene set enrichment analysis 93. Similarly, 
we will use two-sample t-test to study if the immunoscore, mutation burden, AQUA, blood 
panel and tumor PD-L1 and FAP expression are different between responders and non- 
responders. To build a predictive model, logistic regression model will be used by 
incorporating the profiling score (from gene expression), mutation burden, Immunoscore, 
AQUA, blood panel and tumor PD-L1 and FAP expression. Stepwise procedure will be 
applied to develop a robust model to well predict response. Alternative approach is to employ 
Lasso regression 94, a variable selection method, to identify the most relevant variables for 
the final model. In addition, 10-fold cross validation will e used to evaluate the robustness of 
the model. Receiver operating characteristic curve analysis will be then performed for the 
final model. The same statistical strategy will be applied to subset analyses for the 
immunotherapy naïve and immunotherapy pre-treated patients separately. 

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Power analysis 
Assuming reaching to 50% response rate for the immunotherapy naïve cohort (n=40) and 
20% response rate for the cohort with previous immunotherapy experiences (n=40), it will 
lead to 20 responders and 20 non-responders in the immune naïve cohort and 8 responders 
and 32 non-responders in the cohort with previous immunotherapy experiences. For the 
immunotherapy naïve cohort, it will give a power of 96% to detect a difference of 1.2 standard 
deviation (SD) for the profiling score in gene expression between responders versus non- 
responders with a two-sided 5% type I error based on two-sample t-test. The power will be 
84% for the cohort with previous immunotherapy experiences. The same power will hold for 
the other measurements: mutation burden, Immunoscore, AQUA, blood panel and tumor 
PD-L1 and FAP expression. 
 
 
Statistical Plan for AQUA. 
Primary resistance (or primary refractory) to immunotherapy is defined as patients who were 
previously treated with immunotherapy and did not at least achieve stable disease on first 
imaging assessment on immunotherapy. While secondary resistance ( or relapsed) is 
defined as patients that were treated with immunotherapy, achieved at least stable disease 
on first imaging assessment and subsequently developed disease progression or relapse. 
Therefore, clinical response becomes three categories: response, primary resistance, and 
secondary resistance (the last two are non-responders). One-way ANOVA will be used to 
analyze which genes and/or pathways are associated with primary resistance and which 
ones are related to secondary resistance using the LIMMA methods 92. Pathway score will 
be calculated using the PC1 by principal component analysis for genes belonged to the 
pathway. 
 
 
BLOOD 
 
 
Determination of Predictive Signatures in Peripheral Blood. 
The peripheral blood is a rich source of immune cells and may serve as a surrogate for 
immune responses. On a qualified BD LSR Fortessa TM platform, in accordance with good 
clinical trial practice (GCLP) guideline95-97, Immunologists have designed a broad T-cell and 
myeloid flow cytometry panels composed of multiple exhaustion markers, checkpoint 
receptors, activation markers and myeloid suppression markers. A variety of methodologies 
inclusive of, but not limited to ex vivo culture, flow cytometry, IHC, qRT-PCR, genetic 
mutation detection and fluorescent in-situ hybridization (FISH) have been identified. These 
high complexity panels have been tested and, for example, can serve as powerful tools for 
comprehensive examination of ipilimumab and IFNá effects in a small volume of peripheral 
blood specimen. Both traditional and automated algorithms will be used to determine blood- 
based immune signatures predictive of response to immunotherapies. By completing these 
blood analyses we aim to have a more comprehensive analysis of the circulating immune 
cells which is of particular significance as some patients may not have sufficient tissue for 
the entire proposed tumor based immune cell analyses. We hope this proactive approach to 
also include blood specimens analyses will be viewed as a strength. 

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Table 11. Proposed flow cytometry panels for exploring immune modulation in peripheral 
blood 
 
 
 
Blood Analyses Pre-Treatment and for Potential Primary and Acquired Resistance 
Mechanisms. 
Peripheral blood samples will be taken prior to initiation of study therapy, at designated time- 
points, prior to, on-treatment and at the end of treatment visit (see Section 8/Study calendar 
for additional details on the blood sample collection schedule) for preparation of blood 
analysis. Blood samples will be assessed for immune or lung cancer-related factors that will 
predict or correlate with resistance to the combination of nivolumab, ipilimumab and 
nintedanib. Dr. Antonia’s Lab at Moffitt will lead the analysis of the blood samples. PBMC 
from blood will be prepared with Ficoll gradient prior to freezing for future studies. Plasma 
will be harvested and samples will be frozen at -80C in protocol-designated box for plasma 
biomarker studies. 
Determination of Kynurenine:Tryptophan ratio. 
Serum levels of tryptophan and kynurenine may also be useful as blood markers of immune 
enhancement through targeting the tumor microenvironment and CRP as a marker of 
inflammation/stress. Serial blood collections will be obtained in heparinized tubes (green 
tops). Cells will be centrifuged, with resulting supernatant (plasma) immediately stored at - 
80ºC until needed. 
 
 
Blood Molecular Methods. 
The method for determining tryptophan and kynurenine in human plasma is validated under 
ICH and FDA guidance for bio-analytical method validation. The samples are prepared by 
protein precipitation using perchloric acid to treat the plasma before injection into an ultra- 
HPLC/MS system. Stable isotope-labeled internal standards are utilized for both tryptophan 
and kynurenine. Separation is achieved with a C18 column under gradient pumping 
conditions with mobile phases of water and methanol, both containing 0.1% acetic acid. 
Multiple reaction monitoring is employed where the following molecular transitions are 
utilized for tryptophan and kynurenine respectively; 205.1 to 146.0 and 209.1 to 198.1, 151.2, 
124.1. Resulting patient sample concentrations are determined from calibration curves 
determined for each analyte. Tryptophan calibration is linear from 10020,000 ng/ml, and 
kynurenine is linear 10-2,000 ng/ml. Data reporting is presented in a molar ratio between the 
two analytes. 
 
 
Statistical Analysis for IHC, Immunoscore and T/K ratio. 

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The blood samples will be analyzed for T/K ratio by the same methods as the IHC and 
Immunoscore. 
 
7.2 Special Studies: Medical History, Electrocardiogram, Weight, and Vital Signs 
Physical examinations will be performed on study days noted in the Study Calendar (Tables 
15 and 16). 
Physical examination 
Physical examinations will be performed according to the assessment schedule. Height will 
be measured at Screening only. Additionally, targeted physical examinations are to be 
utilized by the Investigator on the basis of clinical observations and symptomatology. 
Situations in which physical examination results should be reported as AEs are described in 
Section 6. 
Electrocardiograms 
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout 
the study. At screening, a single ECG will be obtained on which QTcB must be <470 ms for 
males and <480 ms for females. In case of clinically significant ECG abnormalities, including 
a QTcB value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief period 
(eg, 30 minutes) to confirm the finding. Situations in which ECG results should be reported 
as AEs are described in Section 6. 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules. 
On infusion days, patients receiving Nivolumab/ Ipilimumab treatment will be monitored 
during and after infusion of IP as presented in the bulleted list below. 
Supine BP will be measured using a semi-automatic BP recording device with an appropriate 
cuff size, after the patient has rested for at least 5 minutes. BP and pulse will be collected 
from patients receiving Nivolumab/ Ipilimumab treatment before, during, and after each 
infusion at the following times: 
Prior to the beginning of the infusion (measured once from approximately 30 minutes before 
up to 0 minutes [i.e., the beginning of the infusion]). 
Approximately halfway through the infusion. 
At the end of the infusion (approximately ±5 minutes). 
A 1-hour observation period is required after the first infusion of Nivolumab and Ipilimumab. 
If no clinically significant infusion reactions are observed during or after the first cycle, 
subsequent infusion observation periods can be at the Investigator’s discretion (suggested 
30 minutes after each Nivolumab infusion). 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated. The date 
and time of collection and measurement will be recorded on the appropriate eCRF. Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated. 
Body weight is also recorded along with vital signs. 
Situations in which vital signs results should be reported as AEs are described in Section 6. 
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 
skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 

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musculoskeletal (including spine and extremities), and neurological systems and at 
screening only, height. 
The following clinical laboratory tests will be performed (see the Schedule of Assessments) 
o Coagulation parameters: Activated partial thromboplastin time and International 
normalized ratio to be assessed at baseline as the patient is to undergo a fresh biopsy 
and then at the time of on-treatment biopsy 
o Complete blood count 
o Comprehensive metabolic profile 
o Urinalysis 
o Pregnancy test (female subjects of childbearing potential only) 
▪ 
Urine or serum human chorionic gonadotropin 
o Thyroid Stimulating Hormone 
o Free T3 and free T4 
o Correlative studies ( per Section 7) 
 
 
Table 12. Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular 
hemoglobin 
Total white cell count 
Mean corpuscular 
hemoglobin concentration 
 
 
 
Table 13. Clinical chemistry (Serum or Plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase 
Lactate dehydrogenase 
Alanine aminotransferase 
Creatinine 
Total protein 
BUN 
Aspartate 
aminotransferase 
Potassium 
Bicarbonate 
Sodium 
Calcium 
Total bilirubina 
Chloride 
 
a If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect bilirubin 

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Table 14. Urinalysis Tests 
Blood 
Protein 
Glucose 
Specific gravity 
Ketone 
Color and appearance 
pH 
a Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red blood cells 
 
 
Additional studies on the blood evaluating for enhancement of immune response will be 
performed. These additional studies include plasma assessments for cytokines include 
quantitative assessment of interferon gamma pre- and post-drug exposure, may be 
considered to further demonstrate the anticipated enhancement of cytotoxic T-cell activity, 
as interferon-gamma induces PD-L1 expression in tumor cells. As commented previously, 
serum levels of tryptophan and kynurenine may also be useful as blood markers of immune 
enhancement through targeting the tumor microenvironment and CRP as a marker of 
inflammation/stress. 

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8 
STUDY CALENDAR 
Table 15. Study Calendar: Phase 1 Dose escalation trial of Nintedanib combined with 
Nivolumab and Ipilimumab in advanced-stage NSCLC. 
 
 
Screening1 
C1 
D1 
C1 
D8 
C2 
D1 
C2 
D8 
C3 
D1 
C4 
D1 
C5 D1 
and 
beyond 
End of 
Treatment visit 
(time of 
discontinuation) 
30+/-14 
days; 
Post study 
follow-up 
post last 
dose of 
study drug 
Follow up Visit10 
Every 8 weeks after 
the End of 
Treatment visit. 
Survival Follow 
up 
Every 12 weeks 
Vitals, 
including 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
H&P/ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/ diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
testing 
(if 
applicable) 
X 
X 
X 
X 
X 
X 
TSH/FT4/FT3 2 
X 
X 
X 
X 
X 
X 
PT/PTT/INR 
X6 
X6 
X6 
Urinalysis 
X 
ECG8 
X 
Echo/MUGA 
X 
CT 
Scan 
(Thorax 
+/- 
Abdomen) 
X 
X 
X 
X 
Tumor 
Measurement 
3 
X 
X 
X 
Toxicity 
Assessment9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archival tumor 
collection 5 
X 
Nintedanib 
X 
X 
X 
X 
X 
X 
X 
Nivolumab IV 
q2 weeks 
X 
X 
X 
X 
X 
Ipilimumab Q6 
weeks 
X 
X 
Tumor biopsy 4 
X 
X 
X7 
Blood 
Biomarkers 
X 
X 
X 
X 
X 
Post-Study 
anticancer 
therapy 
X 
X 
X 
Survival status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All study visits, labs, treatments, procedures and scans have a +/- 7 day window. End of treatment is the date when the decision is made to 
remove the patient from study (which may differ from the last date of treatment). Pregnancy testing (urine of blood) in WOCP must be completed 
within 7 days of C1D1 
1. 
Screening window will be 30 days prior to initiation of therapy or enrollment. 
2. 
To be collected every other cycle (~ every 4 weeks) 
3. 
Tumor measurement assessments with CT thorax/ abdomen will occur at baseline and every 6 weeks while patient is on the study. After 
1 year, the imaging time point will occur every 12 weeks (± 7 days). 
4. 
Tumor biopsy should be obtained pre-treatment and on C2D8 +/- 7 days where required and feasible. Blood draw for blood biomarkers 
on C2D8 +/- 7 days and end of treatment time points should be done on the same day as the tumor biopsy. 
5. 
Archival tissue should be obtained where available. 
6. 
Coagulation studies to be done at the time of screening and any time the patient requires a biopsy. 
7. 
End of treatment biopsy as feasible per investigator discretion. 
8. 
At Screening, a single ECG will be obtained on which QTcB must be <470 ms for males and <480 ms for females. In case of clinically 
significant ECG abnormalities, including a QTcB value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (eg, 
30 minutes) to confirm the finding. 
9. 
Only serious adverse events will be collected during the screening window. 
10. Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and should be 
assessed every 8 weeks (56 ± 7 days) after the End of Treatment visit by radiologic imaging to monitor disease status. After 1 year, the 
imaging time point will occur every 12 weeks (± 7 days). 

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Note: In case that, during the conduction of the trial, a discrepancy was noted between the protocol content and this calendar, the information or 
requirements included in the calendar will be followed. 
 
 
Table 16. Study Calendar: Phase II Trial of Nintedanib combined with Nivolumab and Ipilimumab in 
advanced-stage NSCLC (Arm A and Arm B) 
 
 
Screening1 
C1 
D1 
C1 
D8 
C2 
D1 
C2 
D8 
C3 
D1 
C4 
D1 
C5 D1 
and 
beyond 
End of 
Treatment visit 
(time of 
discontinuation) 
30+/-14 
days; 
Post 
study 
follow-up 
post 
 last 
dose of study 
drug 
Follow up Visit10 
Every 8 weeks 
after the End of 
Treatment visit 
Survival Follow up 
Every 12 weeks 
Vitals, including 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
H&P/ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/ diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
testing 
(if 
applicable) 
X 
X 
X 
X 
X 
X 
TSH/FT4/FT32 
X 
X 
X 
X 
X 
X 
PT/PTT/INR 
X6 
X6 
X6 
X 
Urinalysis 
X 
ECG8 
X 
Echo/MUGA 
X 
CT 
Scan 
(Thorax 
+/- 
Abdomen) 
X 
X 
X 
X 
Tumor 
Measurement 3 
X 
X 
X 
Toxicity 
Assessment9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archival tumor 
collection 5 
X 
Nintedanib 
X 
X 
X 
X 
X 
X 
X 
Nivolumab IV q2 
weeks 
X 
X 
X 
X 
X 
Ipilimumab Q6 
weeks 
X 
X 
Tumor biopsy 4 
X 
X 
X7 
Blood 
Biomarkers 
X 
X 
X 
X 
X 
Post-Study 
anticancer 
therapy 
X 
X 
X 
Survival status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
All study visits, labs, treatments, procedures and scans have a +/- 7-day window. End of treatment is the date when the decision is made to 
remove the patient from study (which may differ from the last date of treatment). Pregnancy testing (urine of blood) in WOCP must be completed 
within 7 days of C1D1. 
1. 
Screening window will be 30 days prior to initiation of therapy or enrollment. 
2. 
To be collected every other cycle (~ every 4 weeks). 
3. 
Tumor measurement assessments with CT thorax/ abdomen will occur at baseline and every 6 weeks while patient is on the study. 
After 1 year, the imaging time point will occur every 12 weeks (± 7 days). 
4. 
Tumor biopsy should be obtained pre-treatment and on C2D8 +/- 7 days where required and feasible. Blood draw for blood 
biomarkers on C2D8 +/- 7 days and end of treatment time points should be done on the same day as the tumor biopsy. 
5. 
Archival tissue should be obtained where available. 
6. 
To be done at the time of screening and anytime the patient requires a biopsy. 
7. 
End of treatment biopsy as feasible per investigator discretion. 
8. 
At Screening, a single ECG will be obtained on which QTcB must be <470 ms for males and <480 ms for females. In case of 
clinically significant ECG abnormalities, including a QTcB value >470 ms, 2 additional 12-lead ECGs should be obtained over a 
brief period (eg, 30 minutes) to confirm the finding. 
9. 
Only serious adverse events will be collected during the screening window. 
10. Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and should 
be assessed every 8 weeks (56 ± 7 days) after the End of Treatment visit by radiologic imaging to monitor disease status. After 1 
year, the imaging time point will occur every 12 weeks (± 7 days). 
Note: In case that, during the conduction of the trial, a discrepancy was noted between the protocol content and this calendar, the information or 
requirements included in the calendar will be followed. 

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9. 
MEASUREMENT OF EFFECT 
9.1 Antitumor Effect 
In addition to a baseline scan, confirmatory scans should also be obtained 6 weeks following 
initial documentation of objective response. Response and progression will be evaluated in 
this study using the new international criteria proposed by the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used. 
 
9.1.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with nivolumab, ipilimumab or nintedanib. 
Evaluable for objective response. Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for response. These patients will have their response 
classified according to the definitions stated below. Note: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable. 
Evaluable non-target disease response. Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for non-target disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
 
9.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions 
and short axis for nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 
mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously 
irradiated area might or might not be considered measurable. If the investigator thinks it 
appropriate to include them, only lesions that have clearly shown disease progression since 
prior irradiation will be considered or allowed. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: 

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Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. “Cystic lesions” thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or disease sites) including any measurable lesions over 
the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
 
9.1.3 Methods for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). Use of 
MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI that greatly impact 
image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is 
variable globally. As with CT, if an MRI is performed, the technical specifications of the 

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scanning sequences used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up should be the same as 
was used at baseline and the lesions should be measured/assessed on the same pulse 
sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
9.2 Other Response Parameters 
9.2.1 Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
 
9.2.2 Evaluation of non-target lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 

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9.2.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 
Table 17. For Patients with Measurable Disease (i.e., Target Disease) 
 
 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best 
Overall 
Response 
when 
Confirmation 
is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
Documented at least once 
>4 weeks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be 
made to document the objective progression even after discontinuation of treatment. 
 
 
Table 18. For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target 
Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non- 
PD 
No 
Non-CR/non-PD* 
Not 
all 
evaluated 
No 
Not evaluated 
Unequivocal 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint 
for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised 
 
 
The response to immunotherapy may differ from the typical responses observed with 
cytotoxic chemotherapy including the following 98: 
 
 
• 
Response to immunotherapy may be delayed 
• 
Response to immunotherapy may occur after PD by conventional criteria 
• 
The appearance of new lesions may not represent PD with immunotherapy 

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• 
SD while on immunotherapy may be durable and represent clinical benefit. 
 
 
Based on the above-described unique response to immunotherapy and based on guidelines 
from regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation 
of anti-cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune 
modulating anti-cancer compounds, the study may wish to implement the following in 
addition to standard RECIST 1.1 criteria: 
 
 
RECIST will be modified so that PD must be confirmed at the next scheduled visit, preferably, 
and no earlier than 4 weeks after the initial assessment of PD in the absence of clinically 
significant deterioration. Treatment with nintedanib with nivolumab plus ipilimumab would 
continue between the initial assessment of progression and confirmation for progression. 
In addition, patients may continue to receive nintedanib with nivolumab plus ipilimumab 
beyond confirmed PD in the absence of clinically significant deterioration and if investigators 
consider that patients continue to receive benefit from treatment. 
Modification of RECIST as described may discourage the early discontinuation of 
immunotherapies and provide a more complete evaluation of its anti-tumor activity than 
would be seen with conventional response criteria. Nonetheless, the efficacy analysis will 
be conducted by programmatically deriving each efficacy endpoint based on RECIST 1.1 
criteria. 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than nintedanib plus nivolumab plus 
ipilimumab or with symptomatic progression that requires urgent medical intervention (e.g., 
central nervous system metastasis, respiratory failure due to tumor compression, spinal cord 
compression). 
 
9.2.4 Efficacy variables 
The efficacy analysis will be based on the treated population, which includes all patients who 
receive any dose of either investigational product. The following efficacy endpoints will be 
analyzed. 
 
 
• 
Objective response is defined as confirmed CR or confirmed PR based on modified 
RECIST guidelines version 1.1. The ORR will be estimated by calculating the proportion of 
patients who achieve OR; the 80% CI and 95% CI for the OR rate will be estimated using 
the exact binomial distribution. 
 
 
• 
Disease control is defined as CR, PR, or SD based on RECIST guidelines version 1.1 
with modifications. The disease control rate (DCR) will be estimated by the proportion of 
patients who achieve DC, and its 80% CI and 95% CI will be estimated using the exact 
binomial distribution. 
 
 
• 
Progression-free survival will be measured from the start of treatment with Nivolumab 
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any cause, whichever occurs first. For patients who are alive and progression-free at the 
time of data cut-off for analysis, PFS will be censored at the last tumor assessment date. 
The Kaplan-Meier will be used to estimate the PFS curve and the PFS rate at time points of 
interest 99. 
 
 
• 
Duration of response is defined as the duration from the first documentation of OR to the 
first documented disease progression or death due to any cause, whichever occurs first. For 
patients who are alive and progression-free at the time of the data cut-off for the analysis, 
DoR will be censored at the last tumor assessment date. The DoR will only be evaluated for 
the subgroup of patients with an OR and will be calculated using the Kaplan-Meier method. 
 
 
• 
Overall survival will be determined as the time from the start of treatment with nivolumab 
plus ipilimumab plus nintedanib until death due to any cause. For patients who are alive at 
the time of data cut-off, OS will be censored on the last date when patients are known to be 
alive. The Kaplan-Meier method will be used to estimate the OS curve and the OS rate at 
time points of interest. 
 
 
Patients who have disease control following completion of 12 months of treatment or patients 
who are withdrawn from nivolumab plus ipilimumab with nintedanib treatment for reasons 
other than confirmed PD will continue to have objective tumor assessments. 
 
 
10. DATA REPORTING / REGULATORY CONSIDERATIONS 
 
 
10.1 
Data Reporting 
10.1.1 Risks to patients 
Human Patient Involvement, Characteristics and Design 
Human patients who have the diagnosis of advanced NSCLC are eligible to participate in the 
clinical trial described in this proposal. In this trial, patients with stage IV NSCLC will be 
treated with nivolumab plus ipilimumab plus nintedanib. Those with stable disease, a partial 
response, or complete response will remain on maintenance treatment until progression, 
intolerance, or withdrawal. The suggested doses, frequency, and administration route for the 
treatment are per prior studies that have already established the potential risks. The 
responsibilities of the collaborating investigators, data collection and management and 
protection are outlined in the DSMP below. A new Investigational New Drug (IND) application 
will be submitted to cover the proposed use of the nintedanib in combination with nivolumab 
plus ipilimumab in the Research Plan. The protocol will require IRB, FDA IND, and SRC 
approval prior to initiation of the trial. All patients must willingly sign the informed consent 
document prior to trial enrollment. 
 
 
Sources of Materials 
From the patients enrolled on the trial, tissue specimen, data and records will be obtained. 
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Further details on records and data collections and management are outlined in the protocol 
and the DSMP below. 
Potential Risks 
The potential risks are outlined clearly and in detail in the informed consent. Women who are 
pregnant, lactating or breast feeding are not eligible. The tissue acquisition and biopsy 
procedures will be reviewed by the IRB. In addition, any changes in the protocol procedures 
or desired biospecimen types an amendment to the protocol and consent are provided to the 
IRB for consideration of the benefits to research and the impact on patient care, well-being, 
harm and discomfort. 
10.1.2 
Adequacy of protection against risk 
 
 
a. Recruitment and Informed Consent 
Patients who present to the Thoracic Oncology Program at the Moffitt Cancer Center who 
have advanced NSCLC are offered participation in the clinical trial described in this proposal. 
The trial is explained in detail to the patients by one of the physician co-investigators on the 
trial, the patients are given the opportunity to read the informed consent document, they are 
given a chance to ask questions, and finally they sign the informed consent document in the 
presence of a witness. The physician who participates in the informed consent process also 
documents, in a clinic note, the nature of the consent process that occurred. 
 
 
b. Protection Against Risk 
To protect participants from excess risk, the above-mentioned study procedures and dose- 
escalation scheme were instituted. Additional protection is provided through the data safety 
and monitoring plan described below. Complete patient care, including the clinical 
management of all toxicities will be provided by physicians at the Moffitt Cancer Center. The 
clinical data are kept in the patient's individual Moffitt Cancer Center hospital record. 
Research data are kept in a locked room with limited access and through Oncore (a Web- 
based, password-protected database), with privacy protected to the full extent of the law. All 
documents, data and study records collected for the purposes of this study will be stored 
indefinitely at the MCC. All researchers and staff with access to this information will follow 
procedures to prevent disclosure of information to anyone who is not an investigator on this 
study. Procedures will include data handling practices, network protection, password 
protection, proper storage and handling of all files and specimens, and secured facilities. All 
study materials that include patient identifiers, such as contact information and completed 
questionnaires (paper if used), will be kept in locked cabinets and accessed only by 
authorized study personnel. Blood, urine, and tissue samples will be labeled with a study 
identification number and no other patient identifiers. Study personnel who have completed 
appropriate credentialing will conduct medical record abstraction or electronic transfers of 
data under IRB-approved protocols. Authorized research investigators, the Department of 
Health and Human Services, and the USF Institutional Review Board may inspect the 
records. Final approvals have been obtained from the IRB. Great care will be taken to protect 
patient privacy throughout the study in accordance with MCC policies. 
 
Additional protection is provided through the data safety and monitoring plan described 
below. 
c. Potential Benefits of the Proposed Research to Human Patients and Others 

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There is potential benefit that patients may experience is an improved outcome when 
exposed to the triplet combination therapy. The potential benefit to others is as yet unknown. 
For Stage IV NSCLC, an incurable disease where patients will inevitable progress, the risks 
to the patient are reasonable in relation to the anticipated benefits to research participants 
and others. 
d. Importance of the Knowledge to be Gained 
The knowledge gained from this trial will serve as the foundation of larger biomarker driven 
Immunotherapy trials that may lead to a new standard in the treatment armamentarium in 
the fight against Stage IV NSCLC. For Stage IV NSCLC, an incurable disease where patients 
will inevitable progress, the risks to the patient are reasonable in relation to the importance 
of the knowledge that reasonably may be expected to result. 
 
 
10.2 Safety and Monitoring Plan 
 
 
The Data Safety & Monitoring Plan (DSMP) will ensure that this trial is well designed, 
responsibly managed, appropriately reported, and that it protects the rights and welfare of 
patients. The following internal and external review and monitoring processes provide 
oversight and active monitoring of this trial: 
 
 
The Principal Investigators (PI) 
The Clinical Trials Office (CTO) 
The Scientific Review Committee (SRC) 
The Protocol Monitoring Committee (PMC); 
The Research Compliance Division (RCD) of the Cancer Center's Compliance Office; 
Institutional Review Board (IRB). 
The protocol includes a section that specifies the following with respect to Adverse Event 
reporting: what constitutes an adverse event (versus what is a serious adverse event), the 
entities to which adverse events should be reported, the timing of this reporting, and the 
person or persons responsible for reporting. This includes prompt (within one day of 
knowledge of the event) reporting to the IRB for unanticipated risks to patients and reporting 
in writing within five working days to the IRB and sponsor. 
 
 
10.2.1 Scientific Review Committee (SRC) 
The Cancer Center maintains two fully boarded Scientific Review Committees (SRC) that 
meet every other week (the first Wednesday and third Thursday of every month) as well as 
one Behavioral Ad-Hoc SRC. 
Each SRC conducts a formal internal peer review of all clinical protocols and general 
scientific oversight of interventional clinical research. Protocols are reviewed for scientific 
merit, adequate study design, safety, availability of targeted study population, and feasibility 
of timely completion of all proposed research projects to be conducted by its assigned 
programs at the Cancer Center. Each SRC is responsible for evaluating the risk/benefit 
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review and approval process. The SRC will refer any potential conflicts of interest identified 
in the proposed research to the Conflict Committee. 
10.2.2 
PI responsibility 
The PI of each study is ultimately responsible for every aspect of the design, conduct and 
actions of all members of the research team. This includes the final analysis of the protocol. 
The PI is responsible for ensuring that: 
All protocols include a DSMP and procedures for its implementation commensurate with the 
risk and complexity of the study. The DSMP must include a structured adverse event 
determination, monitoring and reporting system, including standardized forms and 
procedures for referring and/or treating patients experiencing adverse events. The plan must 
include data and safety-monitoring procedures for patients enrolled who may be receiving a 
part of their protocol-required treatment at community sites. 
In all cases, the PI of the study will have primary responsibility for ensuring that the protocol 
is conducted as approved by the SRC and IRB. The PI will ensure that the monitoring plan 
is followed, that all data required for oversight of monitoring are accurately reported to a 
DSMB and/or to the PMC and IRB as required, that all adverse events are reported according 
to protocol guidelines, and that any adverse actions reflecting patient safety concerns are 
appropriately reported. 
 
 
10.2.3 
Protocol Monitoring Committee (PMC) 
The PMC monitors its assigned ongoing research protocols for: adverse event reporting, 
data and safety monitoring, and internal audit findings. The PMC, upon review of any agenda 
item, may approve the study for continuation, require revisions, suspend or close a protocol. 
Study investigators, designated to be reviewed by the PMC for data and safety monitoring, 
shall provide a statistical report of the study’s progress and summary of adverse events and 
deviations based on the phase of the study and the associated risk of the study or more often 
if applicable. The external DSMB (if applicable) shall forward its report for high-risk studies 
designated for external review at least annually or more often if applicable. 
The PMC meets monthly and reviews accrual, patterns and frequencies of all adverse 
events, protocol violations and when applicable, internal audit results. 
 
 
10.2.4 
Research Compliance Division (RCD) 
RCD of the Corporate Compliance Office is the coordinating center for internal audits of 
clinical trials conducted at the Cancer Center and its affiliates. The audit procedure is a 
formal, comprehensive, source document review of all clinical trials. External audit reports 
that meet the criteria of the internal audit may be accepted in lieu of an internal audit. 
The RCD shall provide a report to the PMC of internal audit findings for PMC action. A 
representative of the RCD will be present to discuss the audits with the PMC. For cause, 
audits will be discussed during an executive session of the PMC. Only members (voting and 
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10.2.5 
Internal and external monitoring 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory documents 
and case report forms will be monitored internally according to Moffitt Cancer Center 
Monitoring Policies. Monitoring will be performed regularly by the MCC Clinical Monitoring 
Core for accuracy, completeness, and source verification of data entry, validation of 
appropriate informed consent process, reporting of SAEs and adherence to the protocol, 
Good Clinical Practice (GCP) guidelines, and applicable regulatory requirements. 
 
 
10.2.6 
The Institutional Review Board (IRB) 
The trial will not be initiated without approval of the appropriate Institutional Review Board 
(IRB). All administrative requirements of the governing body of the institution will be fully 
complied with. This protocol, consent procedures, and any amendments must be approved 
by the IRB in compliance with current regulations of the Food and Drug Administration. A 
letter of approval will be sent to the institution(s) funding the study prior to initiation of the 
study and when any subsequent modifications are made. The IRB will be kept informed by 
the investigator as to the progress of the study as well as to any serious or unusual adverse 
events. 
 
 
10.2.7 Suspension/termination 
The PMC and/or the IRB may vote to suspend or terminate approval of a research study not 
being conducted in accordance with the IRB, the Cancer Center and/or regulatory 
requirements or that has been associated with unexpected problems or serious harm to 
patients. The PMC/IRB will notify the PI in writing of such suspension or terminations. It is 
the responsibility of the PMC/IRB Chairperson to ensure prompt written notification of any 
suspensions or terminations of PMC/IRB approval to the relevant Federal Agencies, 
including OHRP, FDA, the study sponsor/funding source and if applicable, the Affiliate 
Program. 
 
 
10.2.8 Trial discontinuation 
 
 
For reasonable cause, the Investigator and/or sponsor may terminate this study prematurely. 
Conditions that may warrant termination include, but are not limited to: the discovery of an 
unexpected, significant, or unacceptable risk to the patients enrolled in the study or if the 
accrual goals are met. A written notification of termination will be issued. 
 
 
10.2.9 Monitoring of the study and regulatory compliance 
The Principal Investigator and the Clinical Research Coordinator assigned to the case will 
be primarily responsible for maintaining all study-related documents including the clinical 
research forms. ONCORE will serve as the study database of record. All CRF entries will be 
verified with source documentation and will be maintained by the Data Management 
Specialist and Clinical Research Coordinator. The patient casebooks will be secured in a 
locked office in the Thoracic Research Department. The review of medical records will be 
done in a manner to assure that patient confidentiality is maintained. 

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10.2.10 Protocol modifications 
No modifications will be made to the protocol without the agreement of the investigators. 
Changes that significantly affect the safety of the patients, the scope of the investigation, or 
the scientific quality of the study will require Institutional Review Board approval prior to 
implementation, except where the modification is necessary to eliminate apparent immediate 
hazard to human patients. Any departures from the protocol must be fully documented in the 
case report form and the source documentation. 
 
 
10.2.11 Patient privacy 
In order to maintain patient confidentiality, all case report forms, study reports, and 
communications relating to the study will identify patients by initials and assigned patient 
numbers. The US Food and Drug Administration (FDA) may also request access to all study 
records, including source documentation for inspection. 
 
 
10.2.12 Institutional and individual conflicts of interest 
Conflict of interest (COI) can be defined as any situation in which financial or personal 
obligations may compromise or present the appearance of compromising an individual’s or 
group’s professional judgment in conducting, reviewing or reporting research. Research 
personnel, IRB members, research administration officials, The Cancer Center, the 
University of South Florida, and research sponsors may all have certain conflicts of interest. 
Such conflicts of interest may arise because of the intellectual property involved in research 
discoveries or industry-academic partnerships or from financial incentives many 
pharmaceutical and biotech companies offer researchers or physicians for conducting 
research or enrolling patients, or due to particular role relationships with particular 
institutions. The processes for managing individual and institutional conflicts of interest will 
focus on disclosure of the conflict, managing the conflict, and prohibiting the activity when 
necessary to protect the public interest or the interest of The Cancer Center. 
Prior to the activation of a trial and ongoing thereafter, individuals who are involved in the 
design, conduct and reporting of the trial will be required to disclose to the SRC any and all 
financial or other interests that are, or may perceive to be, related to the trial in which they 
are actively involved in. The SRC will determine if a conflict exists, and if so, assure that the 
COI is managed, reduced, or eliminated. This information will accompany a protocol when it 
is presented to the IRB. The IRB will retain the highest authority for determining that the 
conflict of interest has been properly disclosed, managed or eliminated. 
The PMC will ensure ongoing monitoring of conflict of interest through monthly review of 
conflict of interest disclosures. If a COI exists, the PMC will ensure that a plan to manage, 
reduce, or eliminate the COI is developed and submitted to the IRB for approval and the 
protocol is amended accordingly. Members of the SRC, PMC, and/or IRB who have a 
conflicting interest in a study will not take part in the discussion or voting of such research, 
except to answer questions of the respective committee. The RCD will be responsible for 
maintaining a secure data system for tracking and timely reporting of disclosure information 
to the SRC or PMC for review as appropriate. The RCD will be responsible for ensuring 
coordination and communication of COI between the Cancer Center and the IRB. The IRB 
has the final authority to determine that the COI has been managed sufficiently to assure the 
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10.2.13 Records retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to 
the conduct of this study and the distribution of investigational drug, including CRFs, consent 
forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 2 years after marketing application approval. If no application is 
filed, these records must be kept 2 years after the study is discontinued and the U.S. FDA 
and the applicable national and local health authorities are notified. 
 
 
11. STATISTICAL CONSIDERATIONS 
11.1 Description of Analysis Sets 
 
 
11.1.1 Safety analysis set 
The safety analysis will be based on the treated population that includes all patients who 
receive at least one dose of any of the investigational products. 
 
 
11.1.2 Efficacy analysis set 
The efficacy analysis will be based on the treated population which includes all patients who 
received any dose of the nivolumab plus ipilimumab combined with nintedanib in the Phase 
II trial, depending upon treatment arm and all patients have had to have at least one post 
treatment imaging available for ORR assessments. 
11.2 Methods of Statistical analysis 
 
 
11.2.1 MTD Determination 
The recommended phase 2 dose for nintedanib with the combination of nivolumab and 
ipilimumab will be provided by the phase I dose escalation phase. The recommended dose 
for Phase II trials is conventionally defined as the dose level just below this toxic dose level 
or the highest dose level if MTD is not reached. 
 
 
11.2.2 Efficacy Analyses 
Statistical Design and Sample Size Justification 
Phase I dose escalation. 
The primary objective of this phase I dose escalation is to find a maximum tolerated dose 
(MTD) corresponding to a risk of DLT occurring in 30% of patients. Five dose levels of 
Nintedanib have been identified for experimentation (100 mg PO QD as dose level -1, 150 
mg PO QD as dose level 0,100mg PO BID as dose level 1, 150mg PO BID as dose level 2, 

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and 200mg PO BID as dose level 3), and due to safety concerns the first cohort of patients 
will receive the lowest dose (does level 1). The study uses the 3+3 rule-based design for 
dose escalation with cohorts of three patients. There will be no increase in the doses beyond 
cohort 3 dosing of the Nintedanib. A maximum of 24 patients will be enrolled for the Phase I 
dose escalation. Dose escalation will proceed according to the following scheme as shown 
in Table 19. 
Table 19.: 3+3 Dose Escalation Scheme 
 
Number of 
Patients with DLT 
at a Given Dose 
Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped. This 
dose level will be declared the 
maximally administered dose (highest 
dose administered). Three (3) 
additional patients will be entered at 
the next lowest dose level if only 3 
patients were treated previously at that 
dose. 
1 out of 3 
Enter at least 3 more patients at this dose 
level. 
• 
If 0/3 patients experience DLT, 
proceed to the next dose level. 
• 
If ≥2 suffer DLT, then dose escalation 
is stopped, and this dose is declared 
the maximally administered dose 
(MAD). Three additional patients will 
be entered at the next lowest dose 
level if only 3 patients were treated 
previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the dose to be used in the 
expanded cohort and will be 
considered recommended phase 2 
dose. 
 
 
 
Phase II Statistical Design 
Once the MTD or RP2D is known, we intend to conduct a parallel Phase II trial of Nivolumab 
plus Ipilimumab plus nintedanib in NSCLC patients (a) who are newly diagnosed, 
immunotherapy naïve (Arm A) or (b) who either have been previously exposed to single 
agent immunotherapy such as anti-PD-1 or anti-PD-L1 (Arm B) 
Total sample size is 80 patients. The sample size is 40 patients for newly diagnosed 
immunotherapy naïve (Arm A). The sample size is also 40 patients for previously exposed 
to single agent immunotherapy (Arm B). 
Bayesian two-stage design for early phase II study 

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The study design evaluates futility in the 1st stage (interim analysis) and efficacy in the 2nd 
stage. The first stage will enroll 20 patients. If it passes a threshold (a certain number of 
patients with response), the 2nd stage will enroll another 20 patients. If the total number of 
patients with response is above another threshold, we consider the treatment is promising. 
The thresholds and statistical sensitivity analysis for power and type I error are evaluated 
and determined by Bayesian posterior probability and predictive probability which are used 
to estimate response rate with a non-informative beta prior, beta(1,1). Since first CT (to 
determine ORR) is schedule for 6 weeks post first dose (minimum follow-up) and we 
anticipate 2-3 patients per month, we expect the 1st interim analysis will be conducted in one 
year from study start up. 
We consider that the treatment arm is not worse than the historical control if the posterior 
probability of response rate greater than a least favorable response rate, p0 (e.g., 30%), is 
higher than 0.95 (i.e., prob(rate of response>p0 |data)>0.95) ). This definition helps 
determine the threshold for the total number of patients with response for efficacy and the 
predictive probability. We evaluate various early stopping rules by exploring different cutoff 
of the predictive probability, d. This leads to a wide range of early stopping rules from 
aggressive to conservative rules (Table 20-21). Results indicate the aggressive stopping rule 
with d=0.2 gives a higher probability to terminate the trial earlier (58-60%) while remaining 
reasonable power (81-85%) and type I error (5-6%) in two cohorts (immunotherapy naïve 
and immunotherapy treated previously). For this reason, the aggressive stopping rule is used 
to evaluate futility and efficacy in both cohorts. 
Here are brief comments of the Bayesian approach and Simon two-stage design: 
These stopping rules are comparable to Simon mini-max two-stage design with 5% type I 
error and 80% power for a total sample size of 39. In fact, our experiences indicate the 
aggressive setting gives the same stopping rule. Thus we consider Simon two-stage design 
could be a special case of the Bayesian approach. 
The Bayesian approach gives investigators more freedom to determine number of patients 
in interim analysis and total sample size. In our case of 50% vs. 30% response rate, the 
Simon mini-max two-stage design requires 39 patients (with 19 in the 1st stage) while the 
Simon optimal two-stage design requires 46 patients (with 15 in the 1st stage) for 5% type I 
error and 80% power. These numbers may not be convenient. In contrast, given a total of 
n=40 with the first 20 patients for the interim analysis, the Bayesian approach is able to 
develop a similar stopping rule with comparable power and type I error. 
The Bayesian approach provides a higher resolution of sensitivity analysis in terms of 
probability of early termination, type I error, and power, by exploring the cutoff of predictive 
probability, d, and other potential parameters, such as θ in prob (objective response rate> 
p0 |data)> θ and prior beta distribution. Such comprehensive sensitivity analysis allows 
investigators to better determine an appropriate stopping rule for trials. 
The Bayesian approach uses predictive probability to evaluate the future success given at 
interim stage. If the chance is little, it may not be considered as ethically sound to continue 
the trial. In contrast, group sequential trials uses interim p-values for optimizing operating 
characteristics. As a result, the stopping rule may allow trials with very low probabilities of 
success to continue. (For details, Saville et. al. highlights the strength of Bayesian predictive 
probabilities for interim monitoring. Ref: Saville BR, Connor JT, Ayers GD, et al: The utility 
of Bayesian predictive probabilities for interim monitoring of clinical trials. (Clin Trials 11:485- 
493, 2014). 
 
Table 20: Summary of various early stopping rules for the immunotherapy naïve cohort 
Early 
stopping rule 
True objective response rate 
Probability of early stopping 
Power/ 
Type I error 
Aggressive 
0.20 
0.91 
<0.01 

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(d=20%) 
0.30 
0.60 
0.06 

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0.40 
0.25 
0.41 
0.50 
0.06 
0.85 
Moderate 
(d=5%) 
0.20 
0.80 
<0.01 
0.30 
0.43 
0.06 
0.40 
0.12 
0.44 
0.50 
0.02 
0.85 
Conservative 
(d=1%) 
0.20 
0.62 
<0.01 
0.30 
0.24 
0.07 
0.40 
0.05 
0.43 
0.50 
<0.01 
0.87 
 
 
 
 
 
 
 
 
Table 21: Summary of various early stopping rules for the immunotherapy treated previously 
cohort 
Early stopping rule 
True response rate 
Probability of early stopping 
Power/ 
Type I error 
Aggressive 
(d=20%) 
0.02 
0.94 
<0.01 
0.07 
0.58 
0.05 
0.17 
0.12 
0.67 
0.20 
0.07 
0.81 
Moderate 
to 
Conservative 
(d=5%) 
0.02 
0.66 
<0.01 
0.07 
0.23 
0.06 
0.17 
0.02 
0.69 
0.20 
0.01 
0.84 
 
 
A summary for aggressive stopping rules with d=0.2 is given below. The details are in 
Appendix II. 
Immunotherapy naïve: A response rate of 30% is treated as a least favorable response rate 
and 50% as a promising response rate. The stopping rule is if the 1st stage has 6 or less 
patients with response (out of the first 20 patients), the treatment is ineffective and will be 
stopped. If there are 7 or more with response, additional 20 patients will be enrolled in the 
2nd stage. If a total of patients with response is 17 or more (out of a total of 40 patients), the 
treatment is considered as promising and deserves for further examination in future 
randomized phase II or phase III trials. Statistical sensitivity analysis shows this design will 
have 85% power to claim the treatment effective (for a true response rate of 50%) and 6% 
type I error (for a true response rate of 30%). The probability to stop the treatment in the 1st 
stage is 61% when the true rate of response is 30%. If the response rate is 20%, the chance 
to stop the trial earlier increases to 91%. 
Immunotherapy treated previously: A response rate of 7% is treated as a least favorable 
response rate and 20% as a promising response rate. The stopping rule is if the 1st stage 
has 1 or less patients with response (out of the first 20 patients), the treatment is ineffective 
and will be stopped. If there are 2 or more with response, additional 20 patients will be 
enrolled in the 2nd stage. If a total of patients with response is 6 or more (out of a total of 40 

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patients), the treatment is considered as promising and deserves for further examination in 
future randomized phase II or phase III trials. Statistical sensitivity analysis shows this design 
will have 81% power to claim the treatment effective (for a true response rate of 20%) and 
5% type I error (for a true response rate of 7%). The probability to stop the treatment in the 
1st stage is 59% when the true rate of response is 7%. If the response rate is 2%, the chance 
to stop the trial earlier increases to 94%. 
Appendix II includes detailed statistical sensitivity analysis of the aggressive stopping rule 
for the immunotherapy naïve cohort and for the immunotherapy treated previously cohort. 
Data analysis 
The primary endpoint of the study for phase I will be safety and tolerability. Patient 
demographics and toxicity will be summarized overall using descriptive statistics. Continuous 
data will be summarized with number of patients (n), mean, standard deviation, median, 
minimum, maximum. Categorical data will be summarized using frequency counts and 
percentages. 
The primary endpoint of the study for phase II will be ORR. Objective tumor response rates 
and disease control rate will be calculated through binomial distribution with a 2-sided 95% 
CI. Overall survival (OS) is defined as from start date of treatment to death on study from 
any cause. PFS is defined as from start date of treatment to the first occurrence of disease 
progression or death on study from any cause, whichever occurs earlier. The event is defined 
as first occurrence of disease progression or death. Otherwise it is considered as censored. 
Kaplan-Meier method will be used for the survival analysis. For each endpoint (ORR, DCR, 
OS, PFS) in each arm of the Phase II, all patients enrolled in the study will be included in the 
analysis (intent-to- treat analysis). No adjustments to the data are intended for dealing with 
missing values or patients who withdraw prior to completing the study. 
 
 
12 ETHICAL AND REGULATORY REQUIREMENTS 
 
 
12.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
 
 
12.2 
Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC and US Code of 
Federal Regulations Title 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
 
 
12.3 
Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 

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protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Boehringer-Ingelheim before study initiation. 
 
 
12.4 
Informed Consent 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the 
written informed consent document or a separate assent form. Informed consent must be 
obtained before conducting any study-specific procedures (i.e. all of the procedures 
described in the protocol). The process of obtaining informed consent should be documented 
in the patient source documents. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study they must adhere to the contraception requirement for 
the duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
 
12.5 Optional Biopsy Consent Form 
Studies with an optional biopsy component will have a separate signature page covering 
those studies. This form will be adapted for each Study based on a standard template used 
globally for all Studies. The optional biopsy informed consent form will be submitted for 
ethical approval together with the Study Protocol and the main informed consent form of the 
Study. If a patient opts not to participate in the optional biopsy assessments, this in no way 
affects the patient’s ability to participate in the main research Study. 
 
 
12.6 Amendments to the Protocol 
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by BI and Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the 
safety of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, BI should be notified of this action and the IRB/IEC/REB at the study 
site should be informed within 10 working days. 
 
 
12.7 Study Drug Supply and Resupply, Storage, and Tracking/Drug Accountability 
Study drugs must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, nivolumab, ipilimumab and nintedanib 
should be stored according to the instructions specified on the drug labels. Clinical supplies 
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Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and the medication number 
but no information about the patient. 
The investigator will maintain an accurate record of the shipment and dispensing of study 
drug. Patients will be asked to return all unused study drug and packaging at the end of the 
study or at the time of study drug discontinuation. 
 
 
12.8 
Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations 
Publication of results: Any formal presentation or publication of data from this trial may be 
published after review and comment by BI and BMS prior to any outside submission. BI and 
BMS must receive copies of any intended communication in advance of publication (at least 
fifteen working days for presentational materials and abstracts and thirty working days for 
manuscripts). These requirements acknowledge BI’s responsibility to provide peer input 
regarding the scientific content and conclusions of such publications or presentations. 
Principal Investigator and principal institution shall have the final authority to determine the 
scope and content of its publications, provided such authority shall be exercised with 
reasonable regard for the interests of BIand BMS and, in accord with the trial contract and 
shall not permit disclosure of BI’s and BMS’s confidential or proprietary information. 
 
 
12.9 
Disclosure and Confidentiality 
The investigator agrees to keep all information provided by BI’s and BMS’s in strict 
confidence and to request similar confidentiality from his/her staff and the IRB/IEC/REB. 
Study documents provided by BI (investigators' brochures and other material) will be stored 
appropriately to ensure their confidentiality. The information provided by Boehringer- 
Ingelheim to the investigator may not be disclosed to others without direct written 
authorization from BI and BMS, except to the extent necessary to obtain informed consent 
from patients who wish to participate in the trial. 
 
 
12.10 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described at Moffitt Cancer Center standard operating procedures and: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 91/507/EEC, 
The Rules Governing Medicinal Products in the European Community. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human Patients). 
 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
 
 
12.11 Data Sharing 
De-identified clinical data will be shared with other investigators and institutions as 
approved.  We may also receive de-identified clinical data from outside sites as well.  No PHI 

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will be shared /sent to any outside sites or received from any outside sites. A data sharing 
agreement will be set up with each site before any data sharing occurs. Joint publication may 
occur.  

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LIST OF ABBREVIATIONS 
 
ABBREVIATIONS 
 
dosing interval 
z 
terminal rate constant of the analyte in plasma 
5-HT3 
5-Hydroxy-Tryptamin receptor 3 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancers 
Alt 
Alanine AminoTransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
Ast 
Aspartate AminoTransferase 
ATP 
adenosine triphosphate 
AUC 
area under the concentration curve 
bFGR 
basic fibroblast growth factor 
BI 
Boehringer Ingelheim 
BIBF 1202 
metabolite of Nintedanib (BIBF1120) 
BID 
twice daily 
BLQ 
below limit of quantitation 
BP 
blood pressure 
BS 
free base 
CA 
Competent (Regulatory) Authority 
CD 
cluster of differentiation 
CDBB 0213 
degradation product of Nintedanib (BIBF1120) 
CDS 
Corporate Drug Safety 
CL/F 
apparent clearance of the analyte in plasma following extravascular 
administration 
Cmax 
maximum measured concentration of the analyte in plasma 
CML 
Clinical Monitor Local 
Cpre 
predose concentration of the analyte in plasma immediately before dosing 
Cr 
Complete Response 
CRA 
Clinical Research Associate 
CRF/eCRF 
Case Report Form / electronic Case Report Form 
CRO 
Clinical Research Organisation 
ct 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMF 
Clinical Trial Master File 
CTP 
Clinical Trial Protocol 
CTR 
Clinical trial report 
CV 
Coefficient of variation 
DCE-MRI 
Dynamic Contrast-Enhanced Magnetic Resonance Imaging 
DCF 
Data Clarification Form 
dl/dL 
deciliter 
DLT 
dose limiting toxicity 
dmc 
Data Monitoring Committee 
DNA 
Desoxyribo Nucleic Acid 
DOC 
Documentation of Change 
EC/IEC 
(Independent) Ethics Committee 
ECG 
Electro Cardio Gram 
ecog 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EDTA 
Ethyledediaminetetraacetic acid 
ELISA 
enzyme-linked immunoasorbent assay 
eortc 
European Organisation for Research and Treatment of Cancer 

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EORTC QLQ 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire 
EORTC QLQ LC 13 European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire Lung Cancer module 
eot 
End Of Treatment 
EQ 5D 
EurolQual quality of life questionnaire 
ES 
monoethanesulfonate 
eu 
European Union including countries belonging to the European Economic 
Area 
F 
fraction of dose systemically available, bioavailability 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
fgf 
Fibroblast Growth Factor 
FGFR 
fibroblast growth factor receptor 
FGR 
fibroblast growth factor 
Flt-1 
synonym for vascular endothelial growth factor receptor 1 
Flt-4 
synonym for vascular endothelial growth factor receptor 4 
ft3 
free thriiodothyronine 
ft4 
free thyroxine 
Fu 
Follow-Up 
g 
acceleration of gravity; gram 
GCP 
Good Clinical Practice 
g-csf 
Granulocyte Colony Stimulating Factor 
Gd-DTPA 
gadolinium chelate 
GFR 
glomerular filtration rate 
GGT 
gamma glutamyl transpeptidase 
GI 
gastrointestinal 
GLDH 
Glutamate DeHydrogenase 
gMean 
geometric mean value 
HDPE 
high density polyethylene 
HPLC 
high performance liquid chromatography 
HPLC-MS/MS 
high performance liquid chromatography-tandem mass spectroscopy 
hr 
hour 
hrqol 
Health Related Quality Of Life 
IAUC 
initial area under the curve 
IAUC60 
initial area under the curve at 60 minutes 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IEC/EC 
Independent Ethics Committee 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ivrs 
Interactive Voice Response System 
KDR 
human homolog of vascular endothelial growth factor Receptor2 (Flk-1) 
L 
litre 
lap 
Leucine Amino Peptidase 
Lck 
Lymphocyte-specific protein-tyrosine kinase, member of the Src family of 
kinases 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
ln 
natural logarithm 
LPO 
last patient out 
Lyn 
Yamaguchi sarcoma viral (v-yes-1) oncogene homolog, cellular protein 
tyrosine kinase member of the Src family of kinases 

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MCV 
mean corpuscular volume 
med. 
Medication 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
ml/mL 
millilitre 
mm 
millimeter 
mmHg 
millimeter mercury 
mri 
Magnetic Resonance Imaging 
MS/MS 
tandem mass spectrometry 
MTD 
maximum tolerated dose 
MTP 
major tumor progression 
n.a. 
not applicable 
NC 
not calculated 
NCI 
National Cancer Institute 
ng 
nanogram 
No. 
number 
NOA 
not analyzed 
NOAEL 
no observed adverse effect 
NOP 
no peak detected 
NOR 
no valid result 
NOS 
no sample obtained 
nsclc 
Non-Small Cell Lung Cancer 
NYHA 
New York Heart Association 
ºC 
degree centigrade 
on d. 
On Demand 
OPU 
Operative Unit (of BI) 
os 
Overall Survival 
p 
probability 
PAS 
periodic acid-Schiff 
pd 
Progressive Disease 
PDGF 
platelet derived growth factor 
PDGFR 
platelet derived growth factor receptor 
pfs 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
p.o. 
per OS (by mouth) 
p-p-plot 
probability plot 
PPS 
Per Protocol Set 
pr 
Partial Response 
pt 
Prothrombin Time 
ptt 
Partial Thromboplastin Time 
qol 
Quality Of Life 
RA 
accumulation factor 
RBC 
red blood cell 
recist 
Response Evaluation Criteria in Solid Tumors 
s 
second 
SAE 
Serious Adverse Event 
sd 
Stable Disease 
SI 
Systėme Internationale 
SIAE 
significant adverse event 
SOP 
Standard Operating Procedure 
Src 
Src tyrosine kinase 
ss 
(At) steady state 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t 
time 

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t1/2 
terminal half-life of the analyte in plasma 
TDMAP 
Trial Data Management and Analysis Plan 
tmax 
time from dosing to peak concentration (Cmax) in plasma 
TNM 
Tumor, (lymph) Node, Metastasis 
tsh 
Thyroid Stimulating Hormone 
TTM 
termination of trial medication 
UGT1A1 
udp glucuronosyltransferase 1A1 
UICC 
Union Internationale Contre le Cancer 
ULN 
upper limit of normal 
US-NCI 
United States –National Cancer Institute 
vegf 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
Vz/F 
apparent volume of distribution during the terminal phase z following an 
extravascular dose 
wbc 
White Blood cell Count 
who-dd 
World Health Organisation Drug Dictionary 
γ-GT 
γ-Glutamyl Transferase 
μmol 
micromole 

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13. APPENDICES 
13.1 APPENDIX I : Hy’s Law 
Procedures for the follow-up of a potential DILI case (Hy`s Law case) in IIS with Nintedanib 
(BIBF 1120) 
 
 
 
Introduction 
Drug-induced liver injury 
Drug-induced liver injury (DILI) has been the most frequent single cause of safety-related drug marketing 
withdrawals for the past 50 years (e.g., iproniazid), continuing to the present (e.g., ticrynafen, 
benoxaprofen, bromfenac, troglitazone, nefazodone). Accordingly, detection of drug-induced liver injury 
of an investigational compound has become an important aspect of patient´s safety guarding in drug 
development. 
The US-FDA has published a Guidance for Industry entitled, “Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation” which outlines the detection, evaluation, follow-up and reporting of drug-induced 
liver injury in clinical trials. Drugs that have the potential for inducing severe liver injury may be identified 
by marked peak aminotransferase elevations (10x-, 15xULN), or the combination of hepatocellular injury 
(aminotransferase elevation ≥3xULN) and altered liver function (hyperbilirubinemia ≥2xULN) which is 
defined as potential “Hy´s law case” if not explained by other causes including evidence of biliary 
obstruction (i.e., significant elevation of alkaline phosphatase, ALP, >2X ULN) or some other explanation 
of the injury (e.g., viral hepatitis, alcohol hepatitis, concomitant use of other known hepatotoxic drugs). 
This constellation predicts a poor outcome and although very rare, these potential cases have to be well 
characterized as soon as being identified as other confounding conditions may be the cause. 
In further consideration of this FDA Guidance, any potential “Hy’s Law case” has to be reported in an 
expedited manner to the FDA (i.e., even before all other possible causes of liver injury have been 
excluded) and be followed-up appropriately. The follow-up includes a detailed clinical evaluation and 
identification of possible alternative etiologies for the “Hy´s Law case” constellation such as concomitant 
diseases (e.g. Hepatitis B) and/or other concomitant therapies that might potentially be hepatotoxic. 
Although rare, a potential for drug-induced liver injury is under constant surveillance by sponsors and 
regulators. Therefore, this study requires timely detection, evaluation, and follow-up of laboratory 
alterations of selected liver laboratory parameters to ensure patients´ safety. 
 
 
Definition 
The following changes in the laboratory values are considered to be a protocol-specific significant 
adverse event for all patients with normal values for ALT/AST at baseline: 
• 
an elevation of ALT and / or AST > 5x ULN without bilirubin elevation measured in the same 
blood draw sample 
• 
an elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of bilirubin to >1.5 
fold ULN measured in the same blood draw sample. 
• 
Patients showing these laboratory abnormalities need to be followed up until the protocol specific 
retreatment criteria have been met 
• 
For patients with elevated ALT/AST values at baseline special considerations apply, if they are 
eligible for inclusion into the trial, e.g. if liver metastasis are present and do not qualify as 
exclusion criterion. For those special cases the BI and BMS contact person should be involved. 

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Procedures 
Protocol-specified significant events are to be reported in an expedited manner similar as Serious 
Adverse Events, even if they do not meet any of the seriousness criteria and documented in the eCRF 
Replication of the following laboratory tests for confirmation within 48 hours: 
 
• 
AST, ALT, 
• 
Bilirubin measurement (total and direct bilirubin) 
• 
Alkaline Phosphatase 
• 
Haptoglobin 
• 
Complete blood count and cell morphology 
• 
Reticulocyte count 
• 
CK 
• 
LDH 
The results of these repeated laboratory tests must be documented on the eCRF /CRF forms and 
reported immediately via the SAE form to BI and BMS. 
 
• 
An evaluation of the patient within 48 hours with respect to but not limited to: 
 
Abdominal ultrasound or clinically appropriate other imaging and investigations adequate to rule out 
biliary tract, pancreatic, intra- or extrahepatic pathology, e.g. bile duct stones, neoplasm, hepatic tumor 
involvement, biliary tract, pancreatic or intrahepatic pathology, vascular hepatic conditions such as 
portal vein thrombosis or right heart failure. These data need to be collected, documented in the 
respective field of the eCRF / CRF / additional documentation form, and the respective SAE form has 
to be updated and forwarded to BI and BMS. 
• 
Detailed history of current symptoms and concurrent diagnoses and medical history 
• 
Detailed history of concomitant drug use (including non-prescription medications, herbal and 
dietary supplement preparations and eg steroids as concomitant supportive treatment), alcohol 
use, recreational drug use, and special diets detailed history of exposure to environmental 
chemical agents 
 
 
 
 
In case that both imaging and laboratory value did not unequivocally confirm cholestasis as the reason 
of ALT / AST increase, in particular if AP < 2x ULN, then please complete the following laboratory tests: 
 
 
• 
Clinical chemistry 
alkaline phosphatase, cholinesterase (either plasma or red blood cell), albumin, PT or INR, CK, 
CK-MB, coeruloplasmin*, α-1 antitrypsin*, transferrin, ferritin, amylase*, lipase*, fasting glucose*, 
cholesterol, triglycerides 
• 
Serology 
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-HCV, RNA if 
Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG)*, Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti- 
HEV IgM positive)*, Anti-Smooth Muscle antibody (titer)*, Anti-nuclear antibody (titer)*, Anti-LKM (liver- 

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kidney microsomes) antibody*, Anti-mitochondrial antibody*, Epstein Barr Virus (VCA IgG, VCA IgM), 
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM) 
• 
Hormones, tumor marker 
• 
TSH* 
• 
Hematology 
• 
Platelets*, eosinophils* 
 
 
*If clinically indicated and in case those additional investigations are needed (e.g. immunocompromised 
patients. 
Initiate close observation of all patients with elevated liver enzyme and bilirubin elevations by repeat 
testing of ALT, AST, bilirubin (with fractionation into total and direct) and AP at least weekly until the 
laboratory values return to normal or to the values as defined in the protocol. 
In case that transaminases and/or bilirubin increase despite cessation of the experimental therapy, more 
frequent intervals will be warranted. 
Depending on further laboratory changes, additional parameters identified e.g. by reflex testing will be 
followed up based on medical judgement and Good Clinical Practices 
 
 
 
 
13.2 APPENDIX II: Detailed statistical sensitivity analysis for the phase II trial 
Statistical sensitivity analysis of the aggressive stopping rule for the immunotherapy naïve 
cohort 
The interim analysis for futility will be done for the first 20 patients. A Bayesian approach for 
futility and efficacy analysis is used to calculate posterior probability and predictive probability 
for the rate of response with a non-informative beta prior, beta(1,1). We consider a 30% rate 
or less of response as ineffective. Thus, we expect the treatment is promising and not worse 
than the historical control if the posterior probability of the rate (response) greater than 30% 
is higher than 0.95 (i.e., prob(rate of response>30% |data)>0.95). With a total 40 patients in 
treatment arm, it will need at least 17 patients with response to meet the criteria. Therefore, 
we use the number of 17 patients to guide the predictive probability. Specifically, for the first 
20 patients in the interim analysis, there are 21 ways for number of patients with response 
from 0, 1, to, 20. In each case, given the number of patients with response, 𝑠𝑠, in the first 20 
patients, we calculate predictive probability of 17 − 𝑠𝑠 or more patients with response in the 
remaining 20 patients of the 2nd stage (Table A1 and Figure 
A1), i.e., ∑20 
೦20೦ 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+𝑠𝑠+𝑖𝑖,1+(20−𝑠𝑠)+(20−𝑖𝑖)). Calculation of the predictive probability is 
𝑖𝑖=17−𝑠𝑠 
𝑖𝑖 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+𝑠𝑠,1+(20−𝑠𝑠)) 
based on beta binominal distribution for the number of patients with response in the future 
remaining 20 patients (2nd stage) given a beta distribution for the rate of response, 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1 + 
𝑠𝑠, 1 + 20 − 𝑠𝑠). For example, if there are 6 patients with response in the first 20 patients, the 
predictive probability of 11 or more patients with response in the future remaining 20 patients 
(2nd stage) would be ∑20 
೦20೦ 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+6+𝑖𝑖,1+(20−6)+(20−𝑖𝑖)) = 0.08. Figure A1 lists predictive 
𝑖𝑖=11 
𝑖𝑖 
 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+6,1+(20−6)) 
probability for all scenarios of number of patients with response in the first 20 patients (interim 

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analysis) and number of patients with response needed in the remaining 20 patients of the 
2nd stage to have at least a total of 17 patients with response. With a 20% cutoff for the 
predictive probability, the stopping rule is if there are 6 or less patients with response for the 
first 20 patients in the interim analysis (i.e., small chance to reach a total of 17 patients with 
response at the end of study), we consider the treatment is ineffective and will be stopped. 

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Sensitivity analyses of this stopping rule are presented in Table A2 and Figure A2. For the 
futility analysis, it is evaluated using the probability of trial stopped in the interim analysis. 
For the efficacy evaluation, it is based on the probability of passing the interim analysis and 
a total number of 17 or more patients with response (the probability is called power when the 
true response rate is 50% and called type I error when the true response rate is 30%). Results 
show that this design will have 85% power to claim the treatment effective (for a true response 
rate of 50%). If the true rate of response is 30%, the chance to reach a total of 17 patients 
with response at end of the study is 0.06 (Type I error). The probability to stop the arm in the 
1st stage is 61%. When the true rate of response is 20%, the chance to reach a total of 17 
patients with response at end of the study is <1%. The corresponding probability to stop the 
trial earlier increases to 91%. 
 
 
Table A1: Bayesian Predictive Probability 
 
Number of patients with response 
in the 1st interim analysis 
Number of patients with response needed in the 
remaining patients of the 2nd stage 
Predictive 
probability 
0 
17 
0.0000 
1 
16 
0.0000 
2 
15 
0.0000 
3 
14 
0.0004 
4 
13 
0.0034 
5 
12 
0.0203 
6 
11 
0.0805 
7 
10 
0.2222 
8 
9 
0.4477 
9 
8 
0.6919 
10 
7 
0.8723 
11 
6 
0.9625 
12 
5 
0.9926 
13 
4 
0.9991 
14 
3 
0.9999 
15 
2 
1.0000 
16 
1 
1.0000 
 
 
 
 
 
Table A2: Sensitivity Analysis 

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True 
rate 
Probability of early stopping the 
treatment arm 
Probability to have at least 17 patients with 
response 
0.2 
0.20 
0.9125 
0.0009 
0.25 
0.25 
0.7846 
0.0103 
0.3 
0.30 
0.6093 
0.0587 
0.35 
0.35 
0.4191 
0.1897 
0.4 
0.40 
0.2521 
0.4087 
0.45 
0.45 
0.1313 
0.6546 
0.5 
0.50 
0.0569 
0.8484 
 
 
 
 
 
 
Figure A1: Bayesian Predictive Probability 

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Figure A2: 
Sensitivity Analysis 

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Detailed statistical sensitivity analysis of the aggressive stopping rule for the immunotherapy 
treated previously cohort 
The interim analysis for futility will be done for the first 20 patients. A Bayesian approach for 
futility and efficacy analysis is used to calculate posterior probability and predictive probability 
for the rate of response with a non-informative beta prior, beta(1,1). We consider a 7% rate 
or less of response as ineffective. Thus, we expect the treatment is promising and not worse 
than the historical control if the posterior probability of the rate (response) greater than 7% is 
higher than 0.95 (i.e., prob(rate of response>7% |data)>0.95). With a total 40 patients in the 
treatment arm, it will need at least 6 patients with response to meet the criteria. Therefore, we 
use the number of 6 patients to guide the predictive probability and efficacy. Specifically, for 
the first 20 patients in the interim analysis, there are 21 ways for number of patients with 
response from 0, 1, to, 20. In each case, given the number of patients with response, 𝑠𝑠, in 
the first 20 patients, we calculate predictive probability of 6 − 𝑠𝑠 or more patients with 
response in the remaining 20 patients of the 2nd stage (Table B1 and Figure 
B1), i.e., ∑20 
೦20೦ 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+𝑠𝑠+𝑖𝑖,1+(20−𝑠𝑠)+(20−𝑖𝑖)). Calculation of predictive probability is based on 
𝑖𝑖=6−𝑠𝑠 
𝑖𝑖 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+𝑠𝑠,1+(20−𝑠𝑠)) 
beta binominal distribution for the number of patients with response in the remaining 20 
patients of the 2nd stage given a beta distribution for the rate of response, 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1 + 𝑠𝑠, 1 + 
20 − 𝑠𝑠). For example, if there is 1 patient with response in the first 20 patients, the predictive 
probability of 5 or more patients with response in the remaining 20 patients of the 2nd stage 
would be ∑20 ೦20೦ 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+1+𝑖𝑖,1+(20−1)+(20−𝑖𝑖)) = 0.081. Figure B1 lists predictive probability for 
𝑖𝑖=5 
𝑖𝑖 
 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏(1+1,1+(20−1)) 
all scenarios of number of patients with response in the first 20 patients (interim analysis) 
and number of patients with response needed in the remaining 20 patients of the 2nd stage 
to have at least a total of 6 patients with response. With a 20% cutoff for the predictive 
probability, the stopping rule is if there are 1 or less patients with response for the first 20 
patients in the interim analysis (i.e., little chance to reach a total of 6 patients with response 
at the end of study), we consider the treatment is ineffective and will be stopped. 
Sensitivity analyses of this stopping rule are presented in Table B2 and Figure B2. For the 
futility analysis, it is evaluated using the probability of trial stopped in the interim analysis. 
For the efficacy evaluation, it is based on the probability of passing the interim analysis and 
the total number of 6 or more patients with response (the probability is called power when 
the true response rate is 20% and called type I error when the true response rate is 7%). 
Results show that this design will have 81% power to claim the treatment effective (for a true 
response rate of 20%). If the true rate of response is 7%, the chance to reach a total of 6 
patients with response at end of the study is 0.05 (Type I error). The probability to stop the 
arm in the 1st stage is 59%. When the true rate of response is 2%, the chance to reach a 
total of 6 patients with response at end of the study is <1%. The corresponding probability to 
stop the trial earlier increases to 94%. 

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Table B1: Bayesian Predictive Probability 
 
number of patients with response in 
the 1st interim analysis 
number of patients with response needed in the 
remaining patients of the 2nd stage 
predictive 
probability 
0 
6 
0.0086 
1 
5 
0.0810 
2 
4 
0.3073 
3 
3 
0.6445 
4 
2 
0.8974 
5 
1 
0.9879 
 
 
 
 
 
 
 
 
 
 
Table B2: Sensitivity Analysis 
 
true 
rate 
probability 
of 
early 
stopping 
the 
treatment arm 
probability to have at least 6 patients with 
response 
0.02 
0.02 
0.9396 
0.0002 
0.07 
0.07 
0.5892 
0.0543 
0.12 
0.12 
0.2899 
0.3251 
0.17 
0.17 
0.1229 
0.6712 
0.2 
0.20 
0.0702 
0.8142 
0.22 
0.22 
0.0479 
0.8813 
0.27 
0.27 
0.0148 
0.9671 

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Figure B1: Bayesian Predictive Probability 
 

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Figure B2: Sensitivity Analysis 
 
 
 
 
 
 
 
 
 
 
 

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13.3 ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- 
care. Totally confined to bed or chair. 
5 
Dead. 
*  As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
13.4 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
13.5 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
13.6 See Events of Clinical Interest Guidance Document 

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