Clinical trial NCT03502746
Conditions: Mesothelioma, Malignant
Sponsor: Arkadiusz Z. Dudek, MD
Start date: 2018-06-26; Completion date: 2023-11-09
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the combination of Nivolumab and Ramucirumab in patients with previously-treated mesothelioma.

Detailed description:
The programmed death ligand 1 (PD-L1) \[16\] and VEGFR2 \[34\] are highly-expressed on mesothelioma cells, and are therefore attractive options for this cancer. We chose to study the combination of ramucirumab with nivolumab because of the potential efficacy of these two agents in mesothelioma and because of the potential synergistic activity between them \[30\]. As previously discussed, immunotherapies such as anti-PD-1 inhibitors must contend with a hostile, immunosuppressive tumor microenvironment due to angiogenesis that results in hypoxia. This hypoxia decreases the ability of antibodies to infiltrate the tumor. We hypothesize that the normalization of tumor vasculature (by reducing the area of the tumor that is hypoxic) with an anti-VEGF strategy (i.e., ramucirumab) used in synergy with a PD-1 inhibitor will facilitate the infiltration of T-lymphocytes into tumor parenchyma. We will conduct a phase II study based on this premise using nivolumab and ramucirumab as second-line therapy in patients with malignant mesothelioma who have failed standard doublet platinum and anti-folate therapy.

Arms: arm 1: Nivolumab 240mg IV + Ramucirumab 8mg/kg IV
Interventions: intervention 1: Nivolumab intervention 2: Ramucirumab
Intervention descriptions: intervention 1: Nivolumab 240mg, IV over 30 minutes. intervention 2: 8mg/kg, IV over 60 minutes.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN LUN15-299 
 
 
 
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Phase II Study of Nivolumab and Ramucirumab for Patients with Previously-Treated 
Mesothelioma: 
Hoosier Cancer Research Network LUN15-299 
 
 
Sponsor Investigator 
Arkadiusz Dudek, MD, PhD  
HealthPartners Regions Cancer Care and Frauenshuh Cancer Care Centers 
 
 
Co-Investigators  
Manish Patel, DO 
University of Minnesota 
 
Statistician 
Min Xi, PhD 
HealthPartners Institute 
Bloomington, Minnesota 
 
 
Trial Supported by  
Eli Lilly and Company (I4T-US-I009) 
Bristol-Myers Squibb Company (CA209-776) 
 
 
Trial Management by 
Hoosier Cancer Research Network 
7676 Interactive Way Suite 120  
Indianapolis, IN 46278 
 
 
Investigational New Drug (IND) Application # 
137645 
 
 
 
 
 
Initial Protocol Version Date: 17OCT2017 
Amended Protocol Version Date: 
28DEC2017 (LEAD SITE ONLY) 
14AUG2019 
19MAY2021 
 


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PROTOCOL SIGNATURE PAGE  
 
 
Phase II Study of Nivolumab and Ramucirumab for Patients with Previously-Treated 
Mesothelioma:  
Hoosier Cancer Research Network LUN15-299 
 
 
VERSION DATE:  19MAY2021 
 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable ethical review board(s). 
 
 
 
 
 
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STUDY SYNOPSIS 
 
TITLE 
Phase II Study of Nivolumab and Ramucirumab for Patients with 
Previously-Treated Mesothelioma 
PHASE  
Phase II 
OBJECTIVES 
Primary Objectives 
• Evaluate response rate [complete response (CR) + partial response 
(PR)] of nivolumab in combination with ramucirumab in subjects with 
previously-treated mesothelioma. Response assessment will be 
performed using modified RECIST 1.1 criteria as described by Byrne et 
al. [35]. 
 
Secondary Objective(s) 
• Characterize adverse effects (AE) of nivolumab in combination with 
ramucirumab in subjects with previously-treated mesothelioma. 
• Measure progression-free survival (PFS) rate at 24 weeks with the 
combination of the anti-Programmed Death 1 (PD-1) agent, nivolumab 
and the anti-vascular endothelial growth factor receptor 2 (VEGFR2) 
antibody, ramucirumab in subjects with previously-treated 
mesothelioma. 
• Measure overall survival (OS) at 2 years after treatment with 
nivolumab in combination with ramucirumab in subjects with 
previously-treated mesothelioma. 
 
Correlative Objectives 
• Correlate programmed death-ligand 1 (PD-L1) expression in tumor 
tissue (from biopsy before treatment) with best clinical response 
(modified RECIST 1.1 criteria) in subjects with previously-treated 
mesothelioma. 
• Correlate change in PD-L1 expression in tumor tissue from before 
therapy (assessed within 14 days before treatment) to after 4 cycles (8 
weeks) of therapy with best clinical response (modified RECIST 1.1 
criteria) at the end of Cycle 4 (Week 8) in subjects with previously-
treated mesothelioma. 
• Correlate cytokine genes expressions and change in tumor tissue (such 
as IL-1, IL-2, IL-6, GM-CSF, IL-10, IL-12, T-bet, IRF1, IFNγ, CXCL1, 
CXCL9, CXCL10, CCL2 and 5) from before therapy (assessed within 
14 days before treatment) to after 4 cycles (8 weeks) of therapy with 
best clinical response (modified RECIST 1.1 criteria) at the end of 
Cycle 4 (Week 8) in subjects with previously-treated mesothelioma. 
• Correlate change in soluble PD-L1 level in plasma during therapy 
(assessed pre-dose Cycles 1 and 5 [Days 1 and 57 of treatment period, 
respectively]), with best clinical response (modified RECIST 1.1 
criteria) at the end of Cycle 4 (Week 8) in subjects with previously-
treated mesothelioma. 


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• Correlate change in number of CD8+, Granzyme B+ T cells in tumor 
tissue from before therapy (assessed within 14 days before treatment) to 
after 4 cycles (8 weeks) of therapy with best clinical response (modified 
RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in subjects with 
previously-treated mesothelioma.  
STUDY DESIGN 
Single arm, phase II cohort study  
KEY 
ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
1. Male or female ≥ 18 years of age at time of consent. 
2. Histologically-confirmed malignant mesothelioma not amenable to 
curative surgery and who have received at least one pemetrexed-
containing chemotherapy regimen. 
3. Has an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1. 
4. Adequate hepatic function within 28 days prior to study registration 
defined as meeting all of the following criteria: 
• total bilirubin < 1.5 mg/dL (25.65 μmol/L) OR direct bilirubin ≤ 
ULN for subjects with total bilirubin levels > 1.5 mg/dL (except 
subject with Gilbert’s Syndrome, who can have total bilirubin < 3.0 
mg/dl) 
• aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 × ULN for 
subjects with known hepatic metastases 
• alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN for 
subjects with known hepatic metastases 
5. Adequate hematologic function within 28 days prior to study 
registration defined as meeting all of the following criteria: 
• hemoglobin ≥ 8 g/dL, subjects requiring transfusion will not be 
eligible to start study  
• and absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
• and platelet count ≥ 100 × 109/L 
6. Adequate renal function within 28 days prior to study treatment by 
either of the following criteria: 
• Serum creatinine ≤ 1.5 the ULN 
• if serum creatinine > 1.5 the ULN, estimated glomerular filtration 
rate (GFR) ≥ 40 mL/min  
7. Adequate coagulation functioning within 28 days prior to study 
registration defined by either of the following criteria: 
• INR ≤1.5, and a partial thromboplastin time (PTT) (PTT/aPTT) < 
1.5 x ULN (unless receiving anticoagulant therapy) 
• Subjects on full-dose anticoagulant must be on a stable dose 
(minimum duration 14 days) of oral anticoagulant or low molecular 
weight heparin (LMWH). Patients receiving warfarin must be 
switched to low molecular weight heparin and have achieved stable 
coagulation profile prior to first dose of protocol therapy. See 
section 3.1 for additional information. 


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8. Subjects must be willing to undergo a CT-guided biopsy (i.e., image-
guided percutaneous lung biopsy) to obtain tumor tissue within 28 days 
before initiation of treatment and after 4 cycles (8 weeks) of treatment.  
9. Women of childbearing potential (WOCP) must not be pregnant 
(confirmed by a negative pregnancy test: a serum β-HCG with a 
sensitivity of 50 mIU/ml within 24 hours of study registration or urine 
dipstick) or breast-feeding. Women are not considered to be of 
childbearing potential provided they meet at least one of the following: 
1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year), or 3) not 
heterosexually active for the duration of the study.  
10. Women of childbearing potential (WOCP) must be willing to birth 
control as outlined in Section 5.6.2.  
11. Men who are not surgically or medically sterile must agree to use 
contraception as outlined in Section 5.6.2.  
12. Measurable disease, defined as at least 1 tumor that fulfills the criteria 
for a target lesion according to modified RECIST 1.1 criteria and 
obtained by imaging within 28 days prior to prior to study registration. 
13. Prior intracavity cytotoxic or sclerosing agents (including bleomycin) is 
acceptable. 
14. Radiation therapy must be completed > 28 days of study registration, 
and the measurable disease must be outside of the radiation port. 
15. Pemetrexed-containing chemotherapy must be completed > 28 days of 
study registration. 
16.  No prior malignancy is allowed except for adequately treated basal cell 
or squamous cell skin cancer, in situ cervical cancer, localized Gleason 
≤ grade 7 prostate cancers. Subjects with other solid tumors treated 
curatively and without evidence of recurrence for at least 3 years prior 
to enrollment may be eligible for study after discussion with the 
sponsor-investigator  
TREATMENT 
PLAN 
Dosing will occur in 2-week cycles. On Day 1 of each cycle, the nivolumab 
intravenous infusion is given first followed 60 minutes later (first two 
cycles) or 15-30 minutes later (subsequent cycles) by the ramucirumab 
infusion. Nivolumab will be administered as a 30-minute intravenous 
infusion dosed at a flat dose of 240 mg. Ramucirumab will be administered 
as a 60-minute intravenous infusion dosed at 8 mg/kg. A scheduled blood 
draw for research purposes will occur prior to the nivolumab infusion on 
Day 1 of Cycles 1 and 5. Research biopsies will be done within 14 days of 
starting treatment and after 4 cycles (8 weeks) of treatment. 
STATISTICAL 
CONSIDERATIONS 
The primary study endpoint is the response rate [complete response (CR) + 
partial response (PR)] of patients for the therapy. A previous study 
identified a response rate of 20% for pembrolizumab, an anti PD-1 agent, in 
patients with malignant mesothelioma [39]. We hypothesize a response rate 


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of 40%. Controlling for a probability of Type I error at 0.05 (one-sided), our 
sample size is estimated to be 33 to ensure 80% statistical power in 
successfully detecting an alternative response rate of 0.40, compared to a 
null rate of 0.20. With estimated up to 5% of patients that are not evaluable 
for primary endpoint, sample size will be increased to 35. Sample size 
analyses were conducted using the PASS software (NCSS, Kaysville, Utah, 
USA). 
TOTAL NUMBER 
OF SUBJECTS  
35 subjects 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 24 months 
ESTIMATED 
STUDY DURATION  Estimated 36 months 
 
 
 


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INDEX 
SECTION                                                                                                                  
PAGE 
STUDY SYNOPSIS ............................................................................................................................3 
SCHEMA ...............................................................................................................................................8 
ABBREVIATIONS.............................................................................................................................9 
1. 
BACKGROUND AND RATIONALE ................................................................................. 12 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 15 
3. 
ELIGIBILITY CRITERIA .................................................................................................... 16 
4. 
SUBJECT REGISTRATION ................................................................................................ 19 
5. 
TREATMENT PLAN ............................................................................................................. 20 
6. 
DOSE DELAYS AND MODIFICATIONS ......................................................................... 26 
7 
STUDY CALENDAR & EVALUATIONS ......................................................................... 34 
8 
CRITERIA FOR DISEASE EVALUATION ..................................................................... 36 
9 
BIOLOGICAL CORRELATIVES ...................................................................................... 39 
10 
DRUG INFORMATION ........................................................................................................ 41 
11 
ADVERSE EVENTS............................................................................................................... 47 
12 
STATISTICAL CONSIDERATIONS ................................................................................. 53 
13 
TRIAL MANAGEMENT ...................................................................................................... 55 
14 
DATA HANDLING AND RECORD KEEPING ............................................................... 56 
15 
ETHICS .................................................................................................................................... 57 
16 
REFERENCES ........................................................................................................................ 58 
17 
APPENDIX 1: Nivolumab Management Algorithms ........................................................ 61 


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SCHEMA 
 
Phase II Study of Nivolumab and Ramucirumab for Patients with Previously-Treated Mesothelioma. 
HCRN LUN15-299 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1: Treatment with 240 mg nivolumab infused over 30 min followed by 8 mg/kg ramucirumab infused over 60 min. 
• 
For the first two cycles, the infusions will be separated by a 60-minute interval.  
• 
For cycle 3 and beyond, the infusions will be separated by a 15-30 minute interval, provided the subject did 
not show any untoward effects during the first two cycles. 
2: Disease assessment will be performed every 4 cycles (8 weeks) for 6 months, then every 6 cycles (12 weeks) until 
disease progression for a maximum of 2 years from initiation of study treatment. 
Cycle = 14 days1 
Nivolumab (Day 1) 
+ 
Ramucirumab (Day 1) 
CR, PR or SD 
Disease Assessment every 4, 6 cycles2 
Progression or significant toxicity 
Follow for progression and 
survival for 2 years (±2 months) 
from initiation of study treatment. 
Continue treatment 
up to 24 months. 
Discontinue treatment. 
Subjects with histologically-confirmed malignant mesothelioma not amenable to surgery 
and who have received at least one pemetrexed-containing chemotherapy regimen. 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
ANC 
absolute neutrophil count 
Anti-PD-1 antibody 
anti-programmed death 1 antibody 
Anti-PD-L1 antibody 
anti-programmed death-ligand 1 antibody 
ALK 
Anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASCO 
American society of clinical oncology 
AST 
aspartate aminotransferase 
ATE 
arterial thromboembolic event 
BCG 
Bacillus Calmette–Guérin 
CCL 
chemokine (C-C motif) ligand 
CI 
Confidence interval 
CIK 
cytokine-induced killer 
cm 
centimeter 
CNS 
Central nervous system 
CR 
complete response 
CT 
computed tomography 
CTC 
cytotoxic T cell 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTLA4 
cytotoxic T-lymphocyte-associated antigen 4 
CXCL 
chemokine (C-X-C motif) ligand 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DKA 
diabetic ketoacidosis 
dL 
deciliter 
DSMC 
Data Safety Monitoring Committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
Estimated Glomerular Filtration Rate 


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GFR 
Glomerular filtration rate 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HR 
Hazard ratio 
HCl 
Hydrochloric acid 
HCRN 
Hoosier Cancer Research Network 
Hgb 
hemoglobin 
HIF-1 
hypoxia-inducible factor-1 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
hr 
hour 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFNγ 
interferon gamma 
IHC 
immunohistochemistry 
IgG 
Immunoglobulin G 
IL 
interleukin 
IND 
Investigational New Drug 
INR 
international normalized ratio 
I/O 
input/output 
IRB 
Institutional Review Board 
irDCR 
Immune-related disease control rate 
IRF1 
Interferon regulatory factor 1 
IV 
intravenous 
kg 
kilogram 
lb 
pound 
LD 
long diameter 
MDSC 
myeloid-derived suppressor cell 
mg 
milligram 
min 
minute 
mL 
milliliter 
mm3 
cubic millimeters 
MRI 
Magnetic resonance imaging 
N/A 
Not applicable 
NaOH 
Sodium hydroxide 
NCI 
National Cancer Institute 


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NDC 
National Drug Code 
NK Cells 
Natural Killer Cells 
NS 
Normal saline 
NSAID 
Non-steroidal anti-inflammatory drugs 
NSCLC 
Non-small cell lung cancer 
OS 
overall survival 
PD 
Progressive disease 
PD-1 
programmed death 1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PET-CT 
positron emission tomography/ computed tomography 
PFS 
progression-free survival 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
RR 
response rate 
SAE 
serious adverse event 
SD 
stable disease 
T1DM 
Type 1 diabetes mellitus 
T3 
Triiodothyronine 
T4 
Free thyroxine  
TAM 
tumor-associated macrophage 
TSH 
Thyroid stimulating hormone 
UA 
urinalysis 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
VEGF 
Vascular endothelial growth factor 
VEGFR2 
Vascular endothelial growth factor receptor 2 
VTE 
Venous thromboembolism 
WOCP 
women of childbearing potential 
wt 
weight 


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1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Introduction 
Malignant mesothelioma is a rare yet highly aggressive cancer for which radiation and surgical 
therapy are typically poor options. Cisplatin in combination with pemetrexed is now a standard 
first-line treatment for malignant mesothelioma [1]. However, once patients fail treatment with a 
pemetrexed-containing regimen, there is no standard of care available.  
 
Anti-angiogenic therapy in conjunction with standard platinum and anti-folate chemotherapy has 
been shown to be effective in malignant mesothelioma patients. In a recently presented 
multicenter study with 445 patients, Zalcman et al. showed that the addition of bevacizumab, an 
anti- vascular endothelial growth factor (VEGF) monoclonal antibody, to standard cisplatin and 
pemetrexed resulted in improved progression-free and overall survival [2]. Progression-free 
survival (PFS) was median 9.6 months (95% confidence interval [CI]: 8.5-10.6) in bevacizumab 
arm vs. 7.5 months (95% CI: 6.8-8.1) in the reference arm (adj. hazard ratio (HR) = 0.62, 95% 
CI [0.50-0.75], p < 0.0001). Overall survival was median: 18.8 months (95% CI: 15.9-22.6) vs. 
16.1 months (95% CI: 14.0-17.9) for the reference arm, (adj. HR = 0.76 [95% CI: 0.61; 0.94], p 
= 0.012). Additionally, added toxicity was minimal with similar rates of G3-4 hematologic 
events in both arms. Hypertension, proteinuria, hemorrhage and thrombotic events were in line 
with previously reported rates for bevacizumab in other cancer types. 
 
Immunotherapy of cancer became a very attractive concept after the recent introduction of 
checkpoint inhibitors. In a recently presented study describing the effect of a CTLA4 targeting 
antibody, in second line therapy of mesothelioma, 29 patients were treated with tremelimumab. 
The study met its primary endpoint since at a median follow-up of 14.5 months, 4 immune-
related partial responses (irPR) were observed. Eleven patients had stable disease of median 
duration 7.7 months (range 2.6-16.6+), and the related immune-related disease control rate 
(irDCR) was 51.7%. Median overall survival (OS) was 11.3 months (95% CI: 5.6-17.0) [3]. The 
results of this study led to an ongoing “Randomized, double-blind, placebo-controlled study of 
tremelimumab for second- and third-line treatment of unresectable pleural or peritoneal 
mesothelioma” study” (NCT01843374). 
 
Thus, there are two potential treatment options for patients with mesothelioma who have failed 
on first-line treatment with a pemetrexed-containing regimen: immunotherapy and anti-
angiogenic (anti-VEGF) therapy. After describing one mode of immunotherapy in more detail 
below, including its effects on another lung cancer, non-small cell lung cancer (NSCLC), we 
present the case that combining immunotherapy with anti-angiogenic therapy might provide a 
more efficacious response to using immunotherapy alone.  
 
The Programmed Death 1 (PD-1) Receptor, Its Programmed death-ligand 1 (PD-L1), and a 
Novel Immunotherapy: Anti-PD-1 Antibody  
An increasing body of evidence, both from lab based animal models and from clinical 
epidemiology, suggests that the immune system operates as a significant barrier to tumor 
formation and progression. One of the hallmarks of cancer is its ability to evade immune 
destruction. The Programmed death 1 (PD-1) receptor is expressed on activated T- and B-cells. 
Its major ligand Programmed death-ligand 1 (PD-L1) is typically expressed on a subset of 


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macrophages, but can be induced by inflammatory cytokines in a variety of tissue types [4-8]. 
When activated T-cells expressing PD-1 encounter PD-L1, T-cell effector functions are 
diminished. PD-1 also binds PD-L2 (B7-DC), which is expressed selectively on macrophages 
and dendritic cells [8-10]. These unique expression patterns suggest that PD-L1 promotes self-
tolerance in peripheral tissues, while PD-L2 may function in lymphoid organs, although the role 
of PD-L2 in immunomodulation is not as well understood [11]. Multiple tumor types have been 
shown to express PD-L1 and PD-L2, effectively co-opting a native tolerance mechanism [12-15].  
Especially pertinent to this protocol is the fact that PD-L1 is highly expressed on mesothelioma 
tumor cells and within the tumor stroma [16]. It has been postulated that antibodies that block the 
interaction between PD-1 and PD-L1 in tumors may preferentially release the cytotoxic function 
of tumor-specific T cells with fewer systematic toxic effects than those that are seen with other 
immune checkpoint inhibitors, such as CTLA-4 [17].  
 
Two large, dose-escalation, phase 1 clinical trials evaluating the safety of the anti–PD-1 antibody 
nivolumab (formerly known as BMS936558) and the anti–PD-L1 antibody BMS936559 showed 
significant antitumor activity in subjects with advanced melanoma, lung carcinoma, and renal 
cell carcinoma, among other cancers, thus validating the PD-1–PD-L1 axis as a therapeutic target 
[18-20]. Most clinical responses were durable beyond 1 year [19,20].  Toxic effects were 
generally of low grade.  
 
A recent randomized, open-label, phase 3, international study comparing nivolumab to docetaxel 
in patients with advanced squamous-cell non–small cell lung cancer who had disease progression 
during or after first-line chemotherapy showed that OS, PFS and response rate (RR) were 
significantly better with nivolumab than docetaxel. The median overall survival was 9.2 months 
(95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 
7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (HR, 
0.59; 95% CI, 0.44 to 0.79; p<0.001). At 1 year, the OS rate was 42% (95% CI, 34 to 50) with 
nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The RR was 20% with nivolumab 
versus 9% with docetaxel (P=0.008). The median PFS was 3.5 months with nivolumab versus 
2.8 months with docetaxel (HR for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; 
p<0.001). Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in 
the nivolumab group as compared with 55% of those in the docetaxel group [21]. 
 
Despite the renewed hope for cancer immunotherapy, survival benefits from adoptive cell 
immunotherapy alone remain modest. One of the critical challenges that adoptive cell 
immunotherapy faces is the immunosuppressive tumor microenvironment. The tumor 
microenvironment contains a vasculature that is structurally and functionally abnormal. In 
certain regions of tumors, the vessels are leaky, twisted, and lack stabilizing pericytes and 
basement membrane. The structurally abnormal tumor vessels do not provide nutritive blood 
flow. The immature tumor vessels contribute to an abnormal tumor microenvironment with one 
of the key characteristics being that of hypoxia [22]. Abnormal tumor vasculature and 
subsequent tumor hypoxia contribute to immune tolerance of tumor cells by impeding the 
homing of cytotoxic T cells into tumor parenchyma and inhibiting their antitumor efficacy [23]. 
These obstacles might explain why the promising approach of adoptive cell immunotherapy does 
not exert significant antitumor activity [24]. Hypoxia contributes to immune suppression by 
activating hypoxia-inducible factor (HIF-1) and the VEGF pathway, which plays a determining 


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role in promoting tumor cell growth and survival [25]. Tumor hypoxia creates an 
immunosuppressive microenvironment via the accumulation and subsequent polarization of 
inflammatory cells toward immune suppression phenotypes, such as myeloid-derived suppressor 
cells (MDSC) [26], tumor-associated macrophages (TAM) [27], and dendritic cells [28]. 
Adoptive cell immunotherapy alone is not efficient enough to decrease tumor growth as its 
antitumor effect is inhibited by the immunosuppressive hypoxic tumor microenvironment.  
 
Antiangiogenic therapy could normalize tumor vasculature and decrease hypoxic tumor 
area and thus may be an effective modality to potentiate immunotherapy. 
Recent studies have demonstrated that there is an interaction between immune response and 
tumor angiogenesis. Huang et al. demonstrated that lower doses of an anti-VEGF receptor 2 
(VEGFR2) antibody treatment enhanced the anti-cancer efficacy of a vaccine therapy in a model 
of immune tolerant breast cancer [29]. Furthermore, it was demonstrated that lower doses of the 
same anti-angiogenic treatment normalized breast tumor vasculature and improved tissue 
distribution of functional vasculature within the tumor. As stated earlier, myeloid-derived 
suppressor cells (MDSC) and tumor-associated macrophages (TAM) promote tumor progression 
by suppressing innate anti-cancer immunity. Low doses of this treatment decreased the number 
of MDSCs and increased the number of TAMs. On profile analysis, however, these TAMs were 
polarized from an immunosuppressive (M2-like) to an immune-stimulatory (M1-like) phenotype. 
A low dose of the anti-angiogenic treatment was also demonstrated to enhance tumor infiltration 
by CD4+ and CD8+ T-cells. An improvement in tumor vasculature and polarization of TAMs 
was shown to reduce immune-regulatory signals, and facilitated recruitment of activated CD8+ T 
cells that could exact an anti-tumor effect. 
 
Similarly, Shi et al. demonstrated that using an anti-angiogenic agent rh-endostatin improved the 
anti-cancer effect of adoptive cytokine-induced killer (CIK) cells against lung carcinoma [30]. 
The proposed mechanism was a synergistic therapeutic effect in which endostatin contributed to 
structural normalization of tumor vasculature. They also demonstrated that the addition of 
endostatin augmented homing of the CIK cells and intratumoral CD3(+) T lymphocytes, 
suggesting that the addition of an anti-angiogenic agent normalized vasculature, reduced hypoxia 
and altered the tumor microenvironment to enhance tumor infiltration by transferred CIK cells 
and T-lymphocytes.  
 
Ramucirumab (IMC-1121B) is a fully human monoclonal antibody (IgG1) developed for the 
treatment of solid tumors. It is directed against the VEGFR2. By binding to VEGFR2 it works as 
a receptor antagonist blocking the binding of VEGF to VEGFR2. VEGFR2 is known to mediate 
the majority of the downstream effects of VEGF in angiogenesis. On April 21, 2014, the FDA 
approved ramucirumab as a single agent or with paclitaxel, for treatment of advanced gastric or 
gastro-esophageal junction adenocarcinoma if the disease has progressed despite 
fluoropyrimidine- or platinum-containing chemotherapy [31,32]. On December 12, 2014, the 
FDA approved ramucirumab in combination with docetaxel, for treatment of metastatic NSCLC 
with disease progression on or after platinum-containing chemotherapy [33]. 
 
 
 


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1.2. 
Study Rationale  
The programmed death ligand 1 (PD-L1) [16] and VEGFR2 [34] are highly-expressed on 
mesothelioma cells, and are therefore attractive options for this cancer. We chose to study the 
combination of ramucirumab with nivolumab because of the potential efficacy of these two 
agents in mesothelioma and because of the potential synergistic activity between them [30]. As 
previously discussed, immunotherapies such as anti-PD-1 inhibitors must contend with a hostile, 
immunosuppressive tumor microenvironment due to angiogenesis that results in hypoxia. This 
hypoxia decreases the ability of antibodies to infiltrate the tumor. We hypothesize that the 
normalization of tumor vasculature (by reducing the area of the tumor that is hypoxic) with an 
anti-VEGF strategy (i.e., ramucirumab) used in synergy with a PD-1 inhibitor will facilitate the 
infiltration of T-lymphocytes into tumor parenchyma. We will conduct a phase II study based on 
this premise using nivolumab and ramucirumab as second-line therapy in patients with malignant 
mesothelioma who have failed standard doublet platinum and anti-folate therapy.  
 
2. 
OBJECTIVES AND ENDPOINTS 
 
2.1. 
Objectives 
 
2.1.1. Primary Objective 
• Evaluate response rate [complete response (CR) + partial response (PR)] of nivolumab in 
combination with ramucirumab in subjects with previously-treated mesothelioma. 
Response assessment will be performed using modified RECIST 1.1 criteria as described 
by Byrne et al. [35]. 
 
2.1.2. Secondary Objectives 
• Characterize adverse effects (AE) of nivolumab in combination with ramucirumab in 
subjects with previously-treated mesothelioma. 
• Measure progression free survival (PFS) rate at 24 weeks with the combination of the anti 
PD-1 agent, nivolumab and the anti VEGFR2 antibody, ramucirumab in subjects with 
previously-treated mesothelioma. 
• Measure overall survival (OS) at 2 years after treatment with nivolumab in combination 
with ramucirumab in subjects with previously-treated mesothelioma.  
 
2.1.3. Correlative Objectives 
• Correlate PD-L1 expression in tumor tissue (from biopsy before treatment) with best 
clinical response (modified RECIST 1.1 criteria) in subjects with previously-treated 
mesothelioma. 
• Correlate change in PD-L1 expression in tumor tissue from before therapy (assessed 
within 14 days before treatment) to after 4 cycles (8 weeks) of therapy with best clinical 
response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in subjects with 
previously-treated mesothelioma. 
• Correlate cytokine genes expressions in tumor tissue (such as IL-1, IL-2, IL-6, GM-CSF, 
IL-10, IL-12, T-bet, IRF1, IFNγ, CXCL1, CXCL9, CXCL10, CCL2 and 5) from before 
therapy (assessed within 14 days before treatment) to after 4 cycles (8 weeks) of therapy 
with best clinical response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) 
in subjects with previously-treated mesothelioma. 


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• Correlate change in soluble PD-L1 level in plasma during therapy (assessed pre-dose 
Cycles 1 and 5 [(Days 1 and 57 of treatment period, respectively]) relative to baseline 
with best clinical response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) 
in subjects with previously-treated mesothelioma. 
• Correlate change in number of CD8+, Granzyme B+ T cells in tumor tissue from before 
and during therapy (assessed within 14 days before treatment) to after 4 cycles (8 weeks) 
of therapy with best clinical response (modified RECIST 1.1 criteria) at the end of Cycle 
4 (Week 8)  in subjects with previously-treated mesothelioma.  
 
3. 
ELIGIBILITY CRITERIA 
Study entry is open to adults regardless of gender or ethnic background. While there will be 
every effort to seek out and include women and minorities, the subject population is expected to 
be no different than that of other advanced solid tumor cancer studies at each participating 
institution. 
 
3.1. 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
1. Male or female ≥ 18 years of age at time of consent. 
2. Histologically-confirmed malignant mesothelioma not amenable to curative surgery and 
who have received at least one pemetrexed-containing chemotherapy regimen. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
4. Adequate hepatic function within 28 days prior to study registration defined as meeting 
all of the following criteria: 
• total bilirubin < 1.5 mg/dL (25.65 μmol/L) OR direct bilirubin ≤ ULN for subjects 
with total bilirubin levels > 1.5 mg/dL (except subject with Gilbert’s Syndrome, 
who can have total bilirubin < 3.0 mg/dl) 
• aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 × ULN for subjects with 
known hepatic metastases 
• alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN for subjects with 
known hepatic metastases 
5. Adequate hematologic function within 28 days prior to study registration defined as 
meeting all of the following criteria: 
• hemoglobin ≥ 8 g/dL, subjects requiring transfusion will not be eligible to start 
study  
• and absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
• and platelet count ≥ 100 × 109/L 
6. Adequate renal function within 28 days prior to study registration by either of the 
following criteria: 
• serum creatinine ≤1.5 times the ULN, or creatinine clearance (measured via 24-
hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times 
the ULN, a 24-hour urine collection to calculate creatinine clearance must be 
performed) 
• subject’s urinary protein is ≤1+ on dipstick or routine urinalysis (UA; if urine 
dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must 
demonstrate <1000 mg of protein in 24 hours to allow participation in this 
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7. Adequate coagulation functioning within 28 days prior to study registration defined by 
either of the following criteria: 
• INR < 1.5, and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN 
(unless receiving anticoagulant therapy) 
• Subjects on full-dose anticoagulation must be on a stable dose (minimum duration 
14 days) of oral anticoagulant or low molecular weight heparin (LMWH). Patients 
receiving warfarin must be switched to low molecular weight heparin and have 
achieved stable coagulation profile prior to first dose of protocol therapy. For 
heparin and LMWH there should be no active bleeding (that is, no bleeding 
within 14 days prior to first dose of protocol therapy) or pathological condition 
present that carries a high risk of bleeding (for example, tumor involving major 
vessels or known varices).  
8. Subjects must be willing to undergo a CT-guided biopsy (i.e., image-guided percutaneous 
lung biopsy) to obtain tumor tissue within 28 days before initiation of treatment and after 
4 cycles (8 weeks) of treatment.  
9. Women of childbearing potential (WOCP) must be willing to use birth control as outlined 
in Section 5.6.2. 
10. Men who are not surgically or medically sterile must agree to use contraception as 
outlined in Section 5.6.2.  
11. Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion 
according to modified RECIST 1.1 criteria, and obtained by imaging within 28 days prior 
to study registration. 
12. Prior intracavity cytotoxic or sclerosing agents (including bleomycin) is acceptable. 
13. Radiation therapy must be completed > 28 days before study registration, and the 
measurable disease must be outside of the radiation port. 
14. Pemetrexed-containing chemotherapy must be completed > 28 days before study 
registration. 
15. Must provide written informed consent and HIPAA authorization approved by an 
Institutional Review Board (IRB). NOTE: HIPAA authorization may be included in the 
informed consent or obtained separately. 
16. All previous toxicity resolved to Grade 1 or less. 
 
3.2. 
Exclusion Criteria 
1. Any Grade 3-4 GI bleeding within 3 months prior to study registration. 
2. History of deep vein thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis 
are not considered “significant”) during the 3 months prior to study registration. 
3. Any arterial thromboembolic events, including but not limited to myocardial infarction, 
transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months 
prior to study registration. 
4. Cirrhosis at a level of Child-Pugh B (or worse), or cirrhosis (any degree) with a history of 
hepatic encephalopathy, or clinically meaningful ascites resulting from cirrhosis. 
Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or 
paracentesis. 
5. Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg 
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6. Prior history of GI perforation/fistula (within 6 months of study registration) or risk 
factors for perforation. 
7. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to study 
registration. 
8. Active brain metastases or carcinomatous meningitis. Subjects with neurological 
symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. 
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the first dose 
of study drugs and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at least 14 
days prior to study registration. This exception does not include carcinomatous 
meningitis, which is excluded regardless of clinical stability. 
9. Major surgery within 28 days prior to study registration 
10. Subcutaneous venous access device placement within 7 days prior to study registration. 
11. Elective or planned major surgery to be performed during the course of the clinical trial. 
12. Is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole 
or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is 
permitted. 
13. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: HIV testing is not required. 
14. Known history of testing positive for hepatitis B virus surface antigen (HBV sAg) or 
hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. 
NOTE: Hepatitis B and Hepatitis C testing is not required. 
15. Condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days of study 
drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg 
daily prednisone equivalents are permitted in the absence of active autoimmune disease. 
16. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger. 
NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
17. Received a live vaccine within 30 days prior to the first dose of trial treatment. Examples 
of live vaccines include, but are not limited to: measles, mumps, rubella, chicken pox, 
yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed. 
18. History of interstitial lung disease or active, non-infectious pneumonitis. 
19. Female subject is pregnant or breast-feeding. 


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NOTE: Women of childbearing potential (WOCP) must have a negative pregnancy test 
(either serum β-HCG with a sensitivity of 50 mIU/ml or urine dipstick within 24 hours of 
study registration).  
NOTE: Women are not considered to be of childbearing potential if they meet at least 
one of the following: 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year), or 3) not heterosexually 
active for the duration of the study. See section 5.6.2. 
20. Major blood vessel invasion or significant intratumor cavitation. 
21. If they experience hemoptysis (defined as bright red blood or ≥ ½ teaspoon) within 2 
months prior to first dose of protocol therapy or with radiographic evidence of intratumor 
cavitation or has radiologically documented evidence of major blood vessel invasion or 
encasement by cancer. 
22. Any condition that, in the opinion of the investigator, might jeopardize the safety of the 
subject or interfere with protocol compliance. 
23. Any mental or medical condition that prevents the subject from giving informed consent 
or participating in the trial. 
24. Any pathological condition that carries a high risk of bleeding (for example, tumor 
involving major vessels or known varices.) 
25. Known hypersensitivity to nivolumab or ramucirumab or any of their components. 
26. Known history of active tuberculosis.  
27. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab 
or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). 
28. No prior malignancy is allowed except for adequately treated basal cell or squamous cell 
skin cancer, in situ cervical cancer, localized Gleason ≤ grade 7 prostate cancers. Subjects 
with other solid tumors treated curatively and without evidence of recurrence for at least 
3 years prior to enrollment may be eligible for study after discussion with the sponsor-
investigator 
29. Treatment with any investigational agent within 28 days prior to study registration. The 
subject must have recovered from the acute toxic effects of the regimen. 
 
4. 
SUBJECT REGISTRATION  
All subjects must be registered through the Hoosier Cancer Research Network (HCRN) 
electronic data capture (EDC) system. A subject is considered registered when an “On Study” 
date is entered into the EDC system. Subjects must be registered after signing consent but prior 
to starting protocol therapy.  
 
 
 


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5. 
TREATMENT PLAN   
 
5.1. 
Overall Design and Study Plan  
The primary objective of this open label, non-randomized Phase II trial is to determine the 
activity of nivolumab in combination with ramucirumab in subjects with histologically-
confirmed malignant mesothelioma not amenable to curative surgery and who have received at 
least one pemetrexed-containing chemotherapy regimen. The primary endpoint in this study is 
response rate (RR). Nivolumab and ramucirumab will be given on Day 1 of each 14-day cycle. 
Treatment will continue for up to 24 months (52 cycles) or until disease progression by RECIST 
1.1 criteria, unacceptable toxicity, subject refusal, or subject death. Subjects who voluntarily stop 
the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 
months after initiation of study treatment. 
 
Correlative research analyses include examining the relationship between best clinical response 
overall with tissue PD-L1, and at the end of Cycle 4 (Week 8) with changes in soluble PD-L1,  
cytokine genes expressions and number of CD8+ and Granzyme B+ T cells in tumor tissue from 
before therapy to the end of Cycle 4 (Week 8). Research analyses also include examining the 
relationship between changes in soluble PD-L1 level, during therapy (assessed pre-dose Cycles 1 
and 5 [Days 1 and 57 of treatment period, respectively]) with best clinical response (modified 
RECIST 1.1 criteria) at the end of Cycle 4 (Week 8).  
 
5.2. 
Pre-medication 
No premedication is indicated for nivolumab. However, for subjects who experience a Grade 1 
or Grade 2 infusion reaction, prior to subsequent infusions it is recommended that 
diphenhydramine 50 mg (or equivalent) and/or paracetamol (acetaminophen) 325 to 1000 mg 
should be administered at least 30 minutes before additional nivolumab administrations. If 
necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) 
may be used.  
 
Prior to ramucirumab infusion, IV diphenhydramine (or equivalent) will be given. For subjects 
who experience a Grade 1 or Grade 2 infusion-related reaction (IRR), premedication must be 
given for all subsequent infusions. If a subject has a second Grade 1 or Grade 2 IRR, administer 
dexamethasone 10 mg (or equivalent); for subsequent infusions, premedicate with the following 
(or equivalent): diphenhydramine hydrochloride (IV), acetaminophen, and dexamethasone. 
 
5.3. 
Drug Administration 
 
Drug 
Dose 
Length and route of 
administration 
Frequency of 
administration 
Length 
of cycle 
Nivolumab (1st) 
240 mg 
30 min (-5/+10), IV 
Day 1 
14 days 
Ramucirumab (2nd) 
8 mg/kg 
60 min (-5, +10), IV 
Day 1 
 
NOTE: Infusions may be given ±3 days for reasons such as observed holidays, inclement 
weather, scheduling conflicts, etc. It should be clearly documented in subject’s chart and case 
report forms. NOTE: there must be at least 12 days between each dose of nivolumab. 


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5.3.1. Sequencing of Nivolumab + Ramucirumab Administration 
Dosing will occur in 2-week cycles. On Day 1 of each cycle, the nivolumab intravenous infusion 
is given first followed 60 minutes after the end of the infusion (first two cycles) or 15-30* 
minutes after the end of the infusion (subsequent cycles) by the ramucirumab infusion.  
 
*The interval between infusions for subsequent cycles beyond Cycle 2 will be shortened to 15-30 
minutes provided that subjects in the first two cycles show no untoward effects from nivolumab 
which would require a 60-minute observation period.  
 
5.3.2. Nivolumab Dose and Administration 
Nivolumab will be administered as a 30-minute intravenous infusion dosed at 240 mg. 
Nivolumab is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding polyethersulfone membrane in-line filter. It is not to be administered as an 
IV push or bolus injection. Nivolumab injection can be infused undiluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to protein 
concentrations as low as 1 mg/mL. Care must be taken to assure sterility of the prepared solution 
as the product does not contain any antimicrobial preservative or bacteriostatic agent. 
 
5.3.3. Ramucirumab Dose and Administration 
Ramucirumab will be administered as a 60-minute intravenous infusion dosed at 8 mg/kg.  
 
The dosing calculations should be based on the actual body weight at baseline. If the subject’s 
weight on the day of dosing differs by > 10% from the weight used to calculate the original dose, 
the dose must be recalculated. All doses should be rounded to the nearest milligram. There will 
be no dose modifications allowed. 
 
5.3.4. Monitoring 
• Vital signs including blood pressure, pulse, temperature, respirations, and pulse oximetry, 
will be measured as follows: 
o for the first two cycles of the nivolumab infusion: before, 5 min after start of the 
infusion, and 30 min (±5 min) after the end of the infusion;  
o if vital signs are stable for first two cycles, subsequent cycles: before and 5 min (±5 
min) after the end of the infusion  
o Ramucirumab infusion: before the infusion, 30 min (±5 min) after the start of the 
infusion, and after (±5 min) the end of the infusion 
• Subjects will be closely monitored for toxicities. Toxicity will be assessed using CTCAE 
version 4.  
 
5.3.5 Dose Delay Due to Toxicity 
If both drugs are held on Day 1 due to toxicity, the day treatment is resumed will be considered 
Day 1 of the cycle. If only one drug is held on Day 1 due to toxicity, the dose of that drug will 
not be made up.  
 
 
 
 
 


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5.4. 
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
that are related to ramucirumab and nivolumab are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased. For each disorder, attempts should be made to rule 
out other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to ramucirumab or nivolumab.  
 
5.4.1. Suggested supportive care measures for the management of adverse events that are 
related to ramucirumab 
 
Infusion-Related Reactions 
• Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Proteinuria 
• Treat proteinuria according to established guidelines.  
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Hypertension 
• Treat hypertension according to established guidelines. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Wound Healing  
• Treat wound according to established guidelines. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
• Treat RPLS according to established guidelines. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Arterial Thrombotic Events 
• Initiate anticoagulation therapy. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 


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Pulmonary Embolism (PE) or Venous thromboembolism (VTE) 
• Initiate anticoagulation therapy. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Gastrointestinal Perforation or Fistula Formation 
• Initiate treatment according to established guidelines. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Bleeding 
• Initiate treatment according to established guidelines. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
Hepatic Encephalopathy or Other Serious Signs of Liver Impairment 
• Initiate treatment according to established guidelines. 
• For guidelines on treatment holds, timing for restarting treatment or discontinuing 
treatment permanently, see Section 6.2.1, Table 2. 
 
5.4.2. Suggested supportive care measures for the management of adverse events that are 
related to nivolumab 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology 
agent in this protocol. Early recognition and management of AEs associated with immuno-
oncology agents may mitigate severe toxicity. Management algorithms have been developed to 
assist investigators in assessing and managing the following groups of AEs: Gastrointestinal, 
Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological. 
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the algorithms. 
These algorithms are found in the Nivolumab IB and in Appendix 1. The guidance provided in 
these algorithms should not replace the Investigator’s medical judgment but should complement 
it. 
 
5.5. 
Concomitant Medications 
Although acetaminophen at doses of ≤ 2 grams/day is permitted, it should be used with caution 
in subjects with impaired liver function.  
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the sponsor-investigator by contacting the HCRN Project Manager. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician. 


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5.5.1. Permitted Concomitant Medications and Procedures  
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 including transfusion of blood and blood products, treatment with antibiotics, 
analgesics, erythropoietin, or bisphosphonates, when appropriate. All concomitant medications 
will be recorded on the electronic case report form (eCRF).  
 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered beyond 30 days after the last dose of trial treatment should be recorded for SAEs as 
defined in Section 11.  
 
Myeloid growth factors to treat subjects with neutropenia according to the American Society of 
Clinical Oncology (ASCO) Guidelines are permitted. Myeloid growth factors should be avoided 
(if medically appropriate) in Cycle 1 until subjects have developed a dose-limiting Grade 4 
neutropenia.  
 
Antiemetic agents may be administered at the discretion of the investigator but are not 
commonly required as a prophylactic agent. All other manifestations of the subject’s malignancy 
should be treated at the discretion of the investigator.  
 
Medications with potential central nervous system (CNS) effects are not prohibited in this study, 
but it is recommended that their use be minimized to avoid confusion in the interpretation of 
CNS effects should they occur during the course of treatment with ramucirumab and nivolumab. 
 
In appropriate settings, such as combinations with agents known to produce frequent 
thrombocytopenia, restricted uses of anticoagulants should be considered.  
 
All other medical conditions should be treated at the discretion of the investigator in accordance 
with local community standards of medical care. 
 
5.5.2. Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy not specified in this protocol 
• Immunotherapy not specified in this protocol 
• Concomitant use of chemotherapy  
• Investigational agents other than ramucirumab or nivolumab 
• Radiation therapy  
• 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, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live 
attenuated vaccines, and are not allowed.  


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• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids is allowed.  
 
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. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.6. 
Diet/Activity/Other Considerations 
 
5.6.1. Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 
 
5.6.2. Contraception 
Ramucirumab and nivolumab may have adverse effects on the composition of sperm or on a 
fetus in utero. Investigators shall counsel WOCBP, and male participants who are sexually active 
with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy, the potential of fetal toxicity occurring due to transmission of study drug, present in 
seminal fluid, to a developing fetus, even if the participant has undergone a successful vasectomy 
or if the partner is pregnant.  
 
Women of childbearing potential (WOCBP) must be willing to use two methods of birth control. 
The two birth control methods can be either two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. WOCBP should begin using birth control from the 
screening visit, throughout the study period, and up to 5 months following the last dose of study 
drugs. Total abstinence for the same study period is an acceptable alternative. Women of non 
childbearing potential or considered highly unlikely to conceive are defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥ 45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  
 
Men who are not surgically or medically sterile must agree to use an acceptable method of 
contraception. Male subjects with female sexual partners who are pregnant, possibly pregnant, or 
who could become pregnant during the study must agree to use condoms with spermicide from 
the date of the first dose of study drug, throughout the study period, and through 3 months after 
the last dose of study drug. Total abstinence for the same study period is an acceptable 
alternative. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 


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Subjects should be informed that taking the study medications may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study, they must adhere to the contraception requirements described above. If there is any 
question that a subject will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
 
5.6.3. Use in Pregnancy 
If a subject becomes pregnant while on study treatment, the subject will immediately be removed 
from the study treatment. The site will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated. The outcome of the 
pregnancy will be reported to HCRN and to Eli Lilly and Company Global Patient Safety and 
Bristol-Myers Squibb (BMS) Global Pharmacovigilance & Epidemiology immediately and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). The 
study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to HCRN. If a male subject 
impregnates his female partner, he must immediately inform the site study personnel and the 
pregnancy reported to HCRN and to Eli Lilly and Company and BMS Global Pharmacovigilance 
& Epidemiology, and followed as described above and in Section 11. 
 
5.6.4. Use in Nursing Women 
It is unknown whether ramucirumab or nivolumab is excreted in human milk. Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
6. 
DOSE DELAYS AND MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 will be used to 
grade adverse events. Subjects enrolled in this study will be evaluated clinically and with 
standard laboratory tests before and at regular intervals during their participation in this study as 
specified in Section 7. Subjects will be evaluated for adverse events (all grades), serious adverse 
events, and adverse events requiring protocol therapy interruption or discontinuation at each 
study visit for the duration of their participation in the study.   
 
Subjects discontinued from the treatment phase of the study for any reason will be evaluated 30 
days (± 7) after the last dose of protocol therapy. 
 
6.1 
Discontinuation Information 
If treatment with ramucirumab is unable to restart within 12 weeks of the planned treatment date, 
the subject will be permanently discontinued from ramucirumab.   
 
NOTE: if either agent is permanently discontinued, treatment with the other agent may continue 
at the discretion of the investigator. 
 
 
 


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If treatment with nivolumab is unable to restart within 6 weeks of the planned treatment date, the 
subject will be permanently discontinued from nivolumab with the following exceptions: 
• Dosing delays or interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the Sponsor Investigator must be consulted.  
• Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-related reasons 
may be allowed if approved by the Sponsor Investigator. Prior to re-initiating treatment in 
a subject with a dosing interruption lasting > 6 weeks, the Sponsor Investigator must be 
consulted. 
 
6.2 
Management of Infusion-Related Reaction/ Bronchospasm/ Hypersensitivity 
NOTE: Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, 
hypo- or hypertension, bronchospasm, or other symptoms of allergic-like reactions.  
 
All Grade 3 or 4 infusion reactions from nivolumab should be reported as an SAE if criteria are 
met. Infusion reactions should be graded according to NCI CTCAE v4 guidelines. 
 
Table 1A: Management of Infusion Related Reaction (IRR), Allergic Reaction, 
Hypersensitivity reaction or Bronchospasm from Nivolumab 
Description 
Action 
CTCAE Grade 1 IRR, 
allergic reaction or 
bronchospasm1  
Remain at bedside and monitor subject until recovery from symptoms. 
CTCAE Grade 2 IRR, 
allergic reaction or 
bronchospasm1  
Stop the nivolumab infusion, begin an IV infusion of normal saline, and 
treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and 
monitor subject until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original 
infusion rate. Monitor subject closely. If symptoms recur then no 
further nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the 
subject until resolution of symptoms. The amount of study drug infused 
must be recorded on the electronic case report form (eCRF). 
CTCAE Grade 3 or 4 IRR, 
allergic reaction, 
bronchospasm or 
hypersensitivity reaction2  
Immediately discontinue infusion of nivolumab. Begin an IV infusion 
of normal saline, and treat the subject as follows. Recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg 
IV with methylprednisolone 100 mg IV (or equivalent), as needed. 
Subject should be monitored until the investigator is comfortable that 
the symptoms will not recur. Nivolumab will be permanently 
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Description 
Action 
for the treatment of anaphylaxis. Remain at bedside and monitor subject 
until recovery from symptoms.  
1For any ≤Grade 2 IRR, allergic reaction or bronchospasm, see Section 5.2 for recommended 
premedication for subsequent infusions.  
2Hypersensitivity reactions included in CTCAEv4 include anaphylaxis, Stevens-Johnson syndrome and 
toxic epidermal necrolysis; in the case of late-occurring hypersensitivity symptoms (e.g., appearance of 
a localized or generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine, or corticosteroids). 
 
Table 1B: Management of Infusion Related Reaction (IRR), Allergic Reaction, 
Hypersensitivity Reaction or Bronchospasm from Ramucirumab. 
 
Description 
Action 
CTCAE Grade 1 IRR, allergic 
reaction or bronchospasm1 
Reduce the infusion rate by 50%.  
CTCAE Grade 2 IRR, allergic 
reaction or bronchospasm1 
Reduce the infusion rate by 50%.  
Recurrent CTCAE Grade 2 IRR, 
allergic reaction or 
bronchospasm1 
Stop the infusion. Administer additional doses of 
H1 and H2 blockers intravenously. Administer IV 
steroids and consider epinephrine and 
bronchodilators as clinically indicated. 
CTCAE Grade 3 or 4 IRR, 
allergic reaction, bronchospasm 
or hypersensitivity reaction2 
Will be permanently discontinued from 
ramucirumab. 
1For any ≤Grade 2 IRR, allergic reaction or bronchospasm, see Section 5.2 for recommended 
premedication for subsequent infusions.  
 
2Hypersensitivity reactions included in CTCAEv4 include anaphylaxis, Stevens-Johnson 
syndrome and toxic epidermal necrolysis; in the case of late-occurring hypersensitivity 
symptoms (e.g., appearance of a localized or generalized pruritis within 1 week after treatment), 
symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids). 
 
An appropriate resuscitation plan should in place and a physician readily available during the 
period of drug administration. If treatment delay necessitates a period longer than 12 weeks for 
ramucirumab (or 6 weeks for nivolumab [see exceptions in Section 6]), treatment will be stopped 
and the subject permanently discontinued from the causative agent.  
 
6.3 
Dose Modifications 
 
6.3.1 Ramucirumab Dose Modifications 
Ramucirumab must be withheld for drug-related toxicities and severe or life-threatening AEs as 
per Table 2 below. See Section 5.4 for supportive care guidelines. NOTE: In addition to the 
guidelines below, subjects with intolerable or persistent Grade 2 drug-related AE may hold study 
medication at physician discretion. 
 


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Table 2: Ramucirumab dose modification guidelines for drug-related adverse events 
Toxicity 
Hold 
Treatment For 
Timing for 
Restarting 
Treatment 
Dose/rate 
reductions 
Discontinue 
Subject 
Proteinuria1 
urine protein 
levels ≥2g/24hrs 
once the urine 
protein level 
returns to < 
2g/24hrs 
Reduce dose to 
6 mg/kg per 
dose for the 
first 
occurrence 
 
Reduce dose to 
5 mg/kg for 
the second 
occurrence 
For a third 
occurrence of 
>2g/24hrs, or if 
the protein level 
does not return to 
<2g/24hrs within 
2 weeks 
urine protein 
level >3g/24hrs 
or in the setting 
of nephrotic 
syndrome 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Hypertension 
Grade 3 
Toxicity 
resolves to 
Grade 0-2 with 
medical 
management 
No reduction if 
toxicity 
resolves 
Permanently 
discontinue if 
medically 
significant 
hypertension 
cannot be 
controlled with 
antihypertensive 
therapy. 
Grade 4 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Wound healing 
complications 
≥Grade 1; 
(NOTE: 
interrupt drug 
prior to any 
scheduled 
surgery) 
Restart when 
wound is fully 
healed 
No dose 
reductions 
warranted 
Wound does not 
heal: permanently 
discontinue 
Reversible posterior 
leukoencephalopathy 
syndrome (RPLS)2 
Any occurrence 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Arterial thrombotic 
events3 
Grade 3 or more 
severe 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Pulmonary embolism 
(PE) or Venous 
thromboembolism 
(VTE)3 
Any event that 
occurs OR 
worsens despite 
anticoagulation 
therapy 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Venous 
thromboembolism 
(Subjects with 
unresected primary 
Grade 3-4 
When subject 
has begun 
anticoagulation 
No dose 
reductions 
warranted 
If in the opinion 
of the subject’s 
physician, the 
tumor confers an 


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Toxicity 
Hold 
Treatment For 
Timing for 
Restarting 
Treatment 
Dose/rate 
reductions 
Discontinue 
Subject 
tumors or local 
recurrence)3 
excessive 
bleeding risk 
Gastrointestinal 
perforation or fistula 
formation 
Any occurrence 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Bleeding 
Grade 3-4 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Hepatic 
encephalopathy or 
other serious signs of 
liver impairment 
Any occurrence 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
Infusion-related 
reactions 
Grade 3-4 
Permanently 
discontinue 
Permanently 
discontinue 
Permanently 
discontinue 
All Other Drug-
Related Toxicity 
Grade 3 or 
severe 
Toxicity 
resolves to 
Grade 0-1 
No dose 
reductions 
warranted 
Toxicity does not 
resolve within 12 
weeks of last dose 
Grade 44 
Permanently 
discontinue 
No dose 
reductions 
warranted 
Permanently 
discontinue 
1 Proteinuria will be monitored by urine dipstick and/or urinary protein creatinine ratio for the 
development of worsening of proteinuria during ramucirumab therapy. 
2 All cases of RPLS must be reported via the SAE mechanism. 
3 Any venous or arterial event leading to discontinuation of ramucirumab therapy will be considered 
serious and should be reported via the serious adverse event (SAE) mechanism. 
4 The following events do not require discontinuation: lab alterations or Grade 4 fever. 
NOTE: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event.  
 
6.3.2 Nivolumab Dose Delay Criteria 
Adverse events (both non-serious and serious) associated with nivolumab 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 must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per Table 3 below. See Section 5.4 for supportive care 
guidelines, including use of corticosteroids. NOTE: In addition to information in the table, 
permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. Subjects with intolerable or persistent Grade 2 drug-related AE may have 
study medication held 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 6 weeks of the last dose unless delay beyond 6 weeks allows for prolonged 
steroid taper to manage toxicity. In such cases, the Sponsor Investigator must be consulted prior 
to re-initiating treatment. 
 
 
 


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Table 3: Nivolumab dose modification guidelines for drug-related adverse events 
Toxicity 
Hold 
Treatment 
For 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Colitis 
Grade 2-3 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 
Grade 4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
Grade 2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 
Grade 3-4 
Permanently discontinue 
Permanently discontinue 
Hepatitis 
≥ Grade 2 if 
subject has 
baseline AST, 
ALT or total 
bilirubin that 
is within 
normal limits; 
≥ Grade 3 if 
subject has 
baseline AST, 
ALT or total 
bilirubin 
within the 
Grade 1 
toxicity range  
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 
AST or ALT > 
8 x ULN OR 
total bilirubin 
>5 x ULN OR 
concurrent 
AST or ALT > 
3 x ULN and 
total bilirubin 
> 2 x ULN 
Permanently discontinue 
Permanently discontinue 
Type I diabetes 
mellitus [TIDM] (if 
new onset) or 
Hyperglycemia 
New onset 
T1DM or 
Grade 3 
hyperglycemia 
Toxicity resolves to Grade 
0-1 even if requires 
physiologic hormone 
replacement 
Resume nivolumab when subjects are 
clinically and metabolically stable. 
Grade 4 
May need to permanently 
discontinue; see footnote #4 
May need to permanently discontinue; 
see footnote #4 
Hypophysitis 
Grade 2-3 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 


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Toxicity 
Hold 
Treatment 
For 
Timing for Restarting 
Treatment 
Discontinue Subject 
Grade 4 
Permanently discontinue 
Permanently discontinue 
Nephritis and Renal 
Dysfunction 
Serum 
creatinine 
more than 1.5 
and up to 6 
times the 
upper limit of 
normal 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 
Serum 
creatinine 
more than 6 
times the 
upper limit of 
normal 
Permanently discontinue 
Permanently discontinue 
Skin 
Grade 3 rash 
or suspected 
Stevens-
Johnson 
syndrome 
(SJS) or toxic 
epidermal 
necrolysis 
(TEN) 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 
Grade 4 or 
confirmed SJS 
or TEN 
Permanently discontinue 
Permanently discontinue 
Encephalitis 
New-onset 
moderate or 
severe 
neurologic 
signs or 
symptoms 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 
Immune-
mediated 
encephalitis 
Permanently discontinue 
Permanently discontinue 
Adrenal 
Insufficiency  
Grade 2 
Toxicity resolves to Grade 
0-1 even if requires 
physiologic hormone 
replacement 
Toxicity does not resolve within 12 
weeks of last dose. 
Grade 3-4 
May need to permanently 
discontinue; see footnote #4 
May need to permanently discontinue; 
see footnote #4 
Uveitis1 
≥Grade 2 
Permanently discontinue 
Permanently discontinue 
Thrombocytopenia 
Grade 3 >7 
days or 
associated 
with bleeding 
or Grade 4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity 
Grade 22 
Toxicity resolves to Grade 
0-1 even if requires 
physiologic hormone 
replacement for drug related 
endocrinopathy 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 


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Toxicity 
Hold 
Treatment 
For 
Timing for Restarting 
Treatment 
Discontinue Subject 
prior to re-initiating treatment. 
Grade 3 or 
severe 
Toxicity resolves to Grade 
0-1 even if requires 
physiologic hormone 
replacement for drug related 
endocrinopathy 
Toxicity does not resolve within 6 weeks 
of last dose unless delay beyond 6 weeks 
allows for prolonged steroid taper to 
manage toxicity. In such cases, the 
Sponsor Investigator must be consulted 
prior to re-initiating treatment. 
Grade 44 
Permanently discontinue 
Permanently discontinue 
1 Uveitis or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity 
within the re-treatment period OR requires systemic treatment 
 
2 Exceptions include grade 2 drug-related fatigue or laboratory abnormalities; do not delay for these events.  
 
3 Exceptions include grade 3 lymphopenia or leukopenia; do not delay for these events. In addition, any Grade ≥ 3 
drug-related amylase or lipase abnormality that is not associated with symptoms or clinical manifestations of 
pancreatitis does not require dose delay. The Investigator should be consulted for such Grade ≥ 3 amylase or 
lipase abnormalities. 
 
4 The following events do not require discontinuation: 
• 
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis and decrease to < Grade 4 within 1 week of onset.  
• 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are 
corrected with supplementation/appropriate management within 72 hours of their onset 
• 
Grade 4 lymphopenia or leucopenia 
• 
Grade 4 drug-related endocrinopathy adverse events, such as adrenal insufficiency, ACTH deficiency, 
hyper- or hypothyroidism, or glucose intolerance, which resolve or are adequately controlled with 
physiologic hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the Investigator. 
 
NOTE: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening 
event.  
Subjects 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, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 12 weeks of the 
scheduled interruption, unless otherwise discussed with the HCRN Project Manager. The reason 
for interruption should be documented in the subject's study record. 
 


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7 STUDY CALENDAR & EVALUATIONS  
 
Study Day 
[Cycle = 14 days] 
Screen 
Cycle 1  
Cycle 2 + 
Safety 
Follow up14 
Safety 
Follow up14 
Long Term 
Follow Up15  
-28 days 
Day 1 
(± 3) 
Day 1 
(± 3) 
30 days (±7)  
90 days (±7) 
Q 3 months 
(±14 days) 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
Informed Consent/HIPAA auth. 
X 
 
 
 
 
 
Medical History1  
X 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
 
 
Vital Signs including ECOG PS2 
X 
X 
X 
X 
 
 
AE Assessment and Con Meds 
X 
X 
X 
X 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
Blood Chemistries3 
X 
X13 
X 
X 
 
 
Thyroid Function Testing4 
X 
X13 
X 
X 
 
 
PT/INR and aPTT 
X 
X13 
X 
X 
 
 
Platelets, ANC & Hgb 
X 
X13 
X 
X 
 
 
Urinalysis 
-7d5 
X13 
X 
 
 
 
Pregnancy Test for WOCP6 
X 
-24h 
X6 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
CT or MRI chest, abdomen/pelvis7 
X 
 
X 
 
 
X 
CT or MRI Brain, if indicated7 
[X] 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
Nivolumab 
 
X 
X 
 
 
 
Ramucirumab 
 
X 
X 
 
 
 
CORRELATIVE STUDIES 
 
 
 
 
 
 
CT-guided biopsy8 
X 
 
X8  
 
 
 
Whole Blood for Somatic Baseline9 
 
X 
 
 
 
 
Serum for soluble PD-L1 analysis9 
 
X 
C5D1 
 
 
 
BANKING SAMPLES 
 
 
 
 
 
 
Whole Blood10 - Optional 
 
X 
 
 
 
 
Serum and Plasma11 - Optional 
 
X 
 
X 
 
 
Unstained Slides12 - Optional 
 
X 
X12 
 
 
 
FOLLOW UP 
 
 
 
 
 
 
Survival status, additional cancer therapy 
 
 
 
 
 
X 


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Footnotes: 
1. Medical history to include demographics, prior treatments, radiation and surgical history. Other information obtained during the medical 
history includes: Smoking history to include: amount, frequency, start and stop dates of cigarette, cigar and pipe usage. A question about how 
the patient heard about the study. Prior genetic or biomarker testing results will be required if available. 
2. Vital signs to include BP, HR, weight, height (screening) only. In addition, ECOG performance status should be obtained. 
3. Blood Chemistries to include: sodium, potassium, blood urea nitrogen (BUN), serum creatinine (or GFR; see 3.1.7), calcium, albumin, ALT, 
AST, bilirubin, alkaline phosphatase (ALK), total protein, glucose. 
4. Thyroid studies will be obtained every 3 cycles (about 6 weeks) starting with Cycle 4 (± 7 day window). The type of testing performed (TSH, 
T3 free vs direct, or T4 free vs direct) should be per local standards. 
5. Within 1 week of study registration. If urine dipstick or routine analysis is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1000 
mg of protein in 24 hours to allow participation in this protocol. 
6. A negative serum or urine pregnancy test is required at screening for eligibility and within 24 hours of initiation of study treatment. If the urine 
test cannot be confirmed as negative, a serum pregnancy test will be required. Pregnancy testing will be done every 4 weeks.  
7. Appropriate scans to assess disease status will be obtained within 4 weeks of initiation of study treatment including CT or MRI of the chest, 
abdomen/pelvis. After that time, disease assessment will be performed every 4 cycles (8 weeks) for 6 months, then every 6 cycles (12 weeks) 
until disease progression for a maximum of 2 years from initiation of study treatment. A brain MRI or CT will be performed at screening for 
subjects with a prior history of brain metastasis or if there is suspicion of brain metastatsis. 
8. The subject will need to undergo a CT-guided biopsy (i.e., image-guided percutaneous lung biopsy) to obtain tumor tissue within 28 days 
before initiation of treatment and after 4 cycles (8 weeks) of treatment, for analysis of location and number of tumor infiltrating CD8+ cells 
and Granzyme B+ T cells, and PD-L1 and cytokine expression in different regions of the tumor. Biopsy to include FFPE and snap frozen 
tissue. See Correlative Laboratory Manual (CLM) for collection, labeling and shipping instructions.  
9. Mandatory submission of whole blood for somatic baseline testing prior to treatment on C1D1. Mandatory submission of serum (soluble PD-
L1) will be collected at Pre-Treatment Cycle 1 Day 1 and Pre-Treatment Cycle 5 Day 1. See CLM for collection, processing, labeling and 
shipping instructions.  
10. Optional submission of whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, 
labeling and shipping instructions. 
11. Optional submission of serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the D30 safety follow up 
visit. See CLM for collection, labeling, processing, and shipping instructions. 
12. Optional submission of unstained slides for banking from the biopsy done prior to treatment C1D1 and after 4 cycles of treatment will be 
requested. See CLM for collection, labeling, and shipping instructions. 
13. For Cycle 1 only: labs do not need to be repeated if done within 7 days of Day 1.  
14. Safety Follow Up Visits: 30 days (±7) post last dose of study treatment. For subjects with unresolved treatment related toxicity, follow as 
medically appropriate until resolution or stabilization. Day 90 AE and conmed assessment may be done by phone, email or other avenues as 
appropriate. 
15. Long-term follow up: Every 3 months until 2 years from initiation of study therapy. Follow up may be accomplished by phone call, email, 
local physician’s record. Disease assessment will be performed per physcian’s discretion. Results of all disease assessment should be captured. 
If the patient progresses, they should be followed for survival and/or initiation of anti-cancer therapy. 
 


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8 
CRITERIA FOR DISEASE EVALUATION 
A modified version of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be 
used in this study [35]. For the purposes of this study, subjects will be reevaluated every 4 cycles 
(eight weeks) for 6 months, then every 6 cycles (12 weeks) until disease progression for a 
maximum of 2 years from initiation of study treatment. In addition to a baseline scan, 
confirmatory scans should also be obtained at least four weeks following initial documentation 
of objective response. 
 
8.1 
Target Lesions 
All measurable lesions up to a maximum of 5 lesions representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically). 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension as 10 mm with CT scan. A lymph node must be 15 mm in short axis by CT scan in 
order to be considered pathologically enlarged and measurable. All measurements must be 
recorded in millimeters. A sum of the diameters (long diameter (LD) for all non-nodal target 
lesions and short axis for nodal lesions) will be calculated and reported as the baseline sum LD. 
The baseline sum of all diameters will be used as reference to further characterize the objective 
tumor response of the measurable dimension of the disease. 
 
In subjects with pleural mesothelioma the typical mesothelial “rind” should be measured on 3 
separate levels at least 2 cm apart, perpendicularly from the chest wall on a given cut. Each level 
should be measured in two different places. The three rind thicknesses should be recorded for a 
given level and compared on subsequent scans. Clear anatomic landmarks should be recorded 
carefully to ensure consistency from scan to scan. At least one level should have a measurement 
≥ 1.5 cm. Pleural areas where the initial thickness is less than 1 cm should not be used as 
evaluation measurement. 
 
A sum of the measurements of the pleural rind obtained at 3 different levels should be calculated 
and reported as the baseline sum LD. 
 
These modified RECIST 1.1 criteria have been previously validated in patients with 
mesothelioma [35]. Response assessment using these methods has been found to be a greater 
clinical predictor for survival in patients with mesothelioma than a method of longest diameter to 
assess pleural thickness. 
 
8.1.1 Complete Response (CR) 
Disappearance of all target lesions. Changes in tumor measurements must be confirmed by 
repeat studies performed no less than 4 weeks after the criteria for response are first met. 
 
8.1.2 Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions taking as reference the 
baseline sum LD. Changes in tumor measurements must be confirmed by repeat studies 
performed no less than 4 weeks after the criteria for response are first met. 
 


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8.1.3 Progression 
At least a 20% increase in the sum of the diameters of target lesions taking as reference the 
smallest sum LD recorded since the treatment started or the appearance of one or more new 
lesions. 
 
8.1.4 Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as 
reference the smallest sum of the diameters since the treatment started. Subjects having a 
documented response with no reconfirmation of the response will be listed with stable disease. 
 
8.2 
Non-target Lesions 
All other lesions (or sites of disease) not included in the “target disease” definition should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as “present” or “absent.” 
 
8.2.1 Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level. If tumor 
markers are initially above the upper normal limit, they must normalize for a subject to be 
considered in complete clinical response. 
 
8.2.2 Non-complete Response (non-CR)/ Non-progression (non-PD) 
Persistence of one or more non-target lesion and/or maintenance of tumor marker level above the 
upper limits of normal. 
 
8.2.3 Progression (PD) 
Appearance of one or more new lesions. Unequivocal progression of existing non-target lesions. 
Although a clear progression of non-target lesions is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed 
later on by the study chair. 
 
8.3 
Evaluation of Best Overall Response 
The best overall 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). In general, the subject’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
Target Lesions 
Non-Target 
Lesions 
New Lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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NOTE: 
• Subjects 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. 
• Conditions that may define early death include subjects that have died without 
documentation of disease progression and before it was time to conduct the first tumor 
reassessment. Inevaluable subjects are defined as not having received protocol treatment 
(regardless of how much was received) and no follow-up assessment completed before 
initiation of alternative treatment. 
• In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
8.4 
Guidelines 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 when both methods have been used to assess the 
antitumor effect of a treatment. 
 
• Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). For 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 not acceptable as measurable lesions. A CT scan 
of the chest (with abdomen and pelvis if needed) must be used to evaluate measurable 
disease in this trial. For pelvic and/or abdominal lesions an MRI may be used to evaluate 
measurable disease. The imaging modality used to determine the initial measurement 
should continue to be used consistently for subsequent measurement evaluations. 
 
• Conventional CT of the chest should be performed with contrast if possible and with cuts 
of 2.5 mm in slice thickness contiguously. Spiral CT is preferred. CT scans of the 
abdomen, and pelvis may also be performed using standard slice thickness (5 mm). 
 
• Endoscopy and laparoscopy for objective tumor evaluation has not yet been fully and 
widely validated. Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers. Therefore, the 
utilization of such techniques for objective tumor response should be restricted to 
validation purposes in reference centers. However, such techniques can be useful to 
confirm complete pathological response when biopsies are obtained. 
 


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8.5 
Confirmation Measurement/Duration of Response 
 
8.5.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies that should be performed no less than four weeks after the criteria for response are 
first met. In the case of SD, follow-up measurements must have met the SD criteria at least once 
after initiation of study treatment at a minimum interval of six to eight weeks. 
 
8.5.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 
8.5.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
 
9 
BIOLOGICAL CORRELATIVES  
Any leftover samples after initial testing is complete will be kept for future unspecified cancer 
related research. Permission from the subject will be obtained for storage of these samples via 
informed consent. 
 
9.1 
Correlate PD-L1 expression in tumor tissue (from biopsy before treatment) with 
best clinical response (modified RECIST 1.1 criteria)  in subjects with previously-
treated mesothelioma. (mandatory) 
Expression and localization (central versus peripheral) of PD-L1 in tumor tissue obtained by CT-
guided biopsies (i.e., image-guided percutaneous lung biopsy) will be determined by IHC and 
will be correlated with clinical outcome assessed by imaging. Unstained slides are to be 
submitted; a tumor block is not acceptable. A needle aspirate, frozen sample, plastic embedded 
sample, cell block, clot, bone, bone marrow or cytologic specimen are not acceptable for PD-L1 
analyses. Refer to the CLM for collection, labeling and shipping instructions. 
 
9.2 
Correlate change in PD-L1 expression in tumor tissue from before therapy (assessed 
within 14 days before treatment) to after 4 cycles (8 weeks) of therapy with best 
clinical response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in 
subjects with previously-treated mesothelioma. 
Expression and localization (central versus peripheral) of PD-L1 in tumor tissue obtained by CT-
guided biopsies (i.e., image-guided percutaneous lung biopsy) will be determined by IHC and 
will be correlated with clinical outcome assessed by imaging. Unstained slides are to be 
submitted; a tumor block is not acceptable. A needle aspirate, frozen sample, plastic embedded 
sample, cell block, clot, bone, bone marrow or cytologic specimen are not acceptable for PD-L1 
analyses. Refer to the CLM for collection, labeling and shipping instructions. 


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9.3 
Correlate cytokine genes expressions and change in tumor tissue (such as IL-1, IL-2, 
IL-6, GM-CSF, IL-10, IL-12, T-bet, IRF1, IFNγ, CXCL1, CXCL9, CXCL10, CCL2 
and 5) (from biopsy before and during treatment) with best clinical response 
(modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in subjects with 
previously-treated mesothelioma. (mandatory) 
Expression and localization (central versus peripheral) of cytokines in tumor tissue obtained by 
CT-guided biopsies (i.e., image-guided percutaneous lung biopsy) will be determined by 
nanostring or comparable technology. Biopsy to include FFPE and snap frozen tissue. Refer to 
the CLM for collection, labeling and shipping instructions. 
 
9.4 
Correlate change in soluble PD-L1 level in serum during therapy (assessed pre-dose 
Cycles 1 and 5), to the best clinical response (modified RECIST 1.1 criteria) at the 
end of Cycle 4 (Week 8) in subjects with previously-treated mesothelioma. 
(mandatory) 
Whole blood for serum submission will be collected predose on Cycle 1 Day 1 and Cycle 5 Day 
1 for analysis of soluble PD-L1 levels. Change in soluble PD-L1 levels as a result of treatment 
will be examined in relation to the best clinical response (modified RECIST 1.1 criteria [35]) at 
the end of Week 4 (Cycle 8). This analysis determined by ELISA assay or comparable 
technology will be conducted by a lab such as Martell Diagnostic Laboratory, at Roseville, MN. 
Refer to the CLM for collection, processing, labeling and shipping instructions. 
 
9.5 
Correlate change in number of CD8+ cells and Granzyme B+ T cells in tumor tissue 
from before therapy (assessed within 14 days before treatment) to after 4 cycles (8 
weeks) of therapy to the best clinical response (modified RECIST 1.1 criteria) at the 
end of Cycle 4 (Week 8) in subjects with previously-treated mesothelioma. 
(mandatory) 
Number and localization (central versus peripheral) of CD8+ cells and Granzyme B+ T cells in 
tumor tissue obtained by CT-guided biopsies (i.e., image-guided percutaneous lung biopsy) will 
be determined by IHC by a lab such as Biothera Pharmaceuticals, Inc. (Eagan, MN) and will be 
correlated with clinical outcome assessed by imaging. Changes in number of CD8+ cells and 
Granzyme B+ T cells from before therapy (assessed within 14 days before treatment) to after 4 
cycles (8 weeks ) of therapy will be examined in relation to the best clinical response (modified 
RECIST 1.1 criteria [35]) at the end of Cycle 4 (Week 8). Other markers such as but not limited 
to CD4 FoxP3, PD-L1, Pan-cytokeratin, and DAPI. This analysis determined by ELISA assay or 
comparable technology will be conducted by a lab such as Biothera Pharmaceuticals, Inc. 
(Eagan, MN). Refer to the CLM for collection, processing, labeling and shipping instructions. 
 
9.6 
Samples for future studies (optional) 
Subject consent will be obtained for additional samples collected for future unspecified cancer 
related research. HCRN will manage the banked samples. Samples will be banked indefinitely in 
the HCRN Biorepository. Please refer to the CLM for all sample collection, processing, labeling, 
and shipping instructions. 
 
 


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This includes: 
• Whole blood: Optional - Whole blood will be collected prior to treatment on C1D1.  
• Pre- and Post-treatment plasma: Optional - Whole blood for plasma will be collected 
prior to treatment on Cycle 1 Day 1 and at the D30 safety visit.  
• Pre- and Post-treatment serum: Optional - Whole blood for serum will be collected prior 
to treatment on Cycle 1 Day 1 and at the D30 safety visit.  
• Pre- and Post-treatment biopsies: Optional - Unstained slides will be collected prior to 
treatment on Cycle 1 Day 1 and post Cycle 4.  
 
10 
DRUG INFORMATION 
 
10.1 
Drug Name: Cyramza® (Ramucirumab; IMC-1121B [Anti-VEGFR2 antibody]) 
 
10.1.1 Chemical name and properties 
Disulfide with human monoclonal IMC-1121B κ-chain anti-(human vascular endothelial growth 
factor receptor type VEGFR-2 extracellular domain) (human monoclonal IMC-1121B γ-chain) 
immunoglobulin G1, dimer. Ramucirumab is a recombinant human IgG1 monoclonal antibody 
that specifically binds to vascular endothelial growth factor receptor 2. 
 
10.1.2 Availability 
Eli Lilly and Co. will provide ramucirumab at no charge to subjects participating in this clinical 
trial.  
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
10.1.3 Storage 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Unopened vials of ramucirumab are stable until the expiration date 
indicated on the package when stored at 2° to 8ºC (36° to 46ºF). Keep the vial in the outer carton 
in order to protect from light. Do not freeze or shake. Store diluted infusion for no more than 24 
hours at 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature (below 25°C [77°F]). 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
10.1.4 Dosage and Administration 
Eli Lilly and Company will supply ramucirumab directly to sites at no cost to subjects in this 
clinical trial. Ramucirumab is supplied in a sterile form for intravenous use only. Ramucirumab 
is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution 
for intravenous infusion following dilution and preparation. Ramucirumab is supplied at a 
concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-dose vials. 
CYRAMZA is formulated in glycine (9.98 mg/mL), histidine (0.65 mg/mL), histidine 


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monohydrochloride (1.22 mg/mL), polysorbate 80 (0.1 mg/mL), sodium chloride (4.383 
mg/mL), and Water for Injection, USP, pH 6.0. 
 
Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the vial, if 
particulate matter or discolorations are identified. Store vials in a refrigerator at 2°C to 8°C (36°F 
to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. 
• Calculate the dose and the required volume of ramucirumab needed to prepare the 
infusion solution. The dosing calculations should be based on the actual body weight at 
baseline. If the subject’s weight on the day of dosing differs by > 10% from the weight 
used to calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram. Vials contain either 100 mg/10 mL or 500 mg/50 mL at 
a concentration of 10 mg/mL solution of ramucirumab. 
o Withdraw the required volume of ramucirumab and further dilute with only 0.9% 
Sodium Chloride Injection in an intravenous infusion container to a final volume of 
250 mL. Do not use dextrose containing solutions. 
o Gently invert the container to ensure adequate mixing. 
o DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other 
solutions or co-infuse with other electrolytes or medications. 
o Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 
hours at room temperature (below 25°C [77°F]). 
o Discard vial with any unused portion of ramucirumab. 
 
10.1.5 Side Effects 
Please refer to the current version of the Investigator’s Brochure for a complete list of adverse 
events. 
 
Ramucirumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to traditional chemotherapy. Important identified risks for ramucirumab include, 
but are not limited to hypertension, proteinuria/nephrotic syndrome, arterial thrombotic events, 
impaired wound healing, infusion related reactions, hemorrhage, reversible posterior 
leukoencephalopathy syndrome, thyroid dysfunction, and gastrointestinal disorders 
(perforation/diarrhea). 
 
Further details around frequency, reporting, and management of adverse events can be found in 
the current version of the Investigator’s Brochure. 
 
10.2 
Drug Name: Opdivo® (Nivolumab; [Anti-PD-1 Antibody]) 
 
10.2.1 Other names and properties 
ONO-4538, MDX-1106, BMS-936558-01 or BMS-936558, anti-PD-1, anti-programmed cell 
death-1 monoclonal antibody 
 
10.2.2 Availability 
Bristol-Myers Squibb will supply nivolumab at no charge to subjects participating in this clinical 
trial.  
 


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10.2.3 Product Description and Dosage Form 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL),  
Nivolumab Injection, 100mg/10 mL (10mg/mL) is a clear to opalescent, colorless to pale yellow 
liquid, which may contain light (few) particulates. The drug product is a sterile, non-pyrogenic, 
single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, sodium chloride, 
mannitol, diethylenetriaminepentaacetic 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. The only difference between the two drug product presentations is the vial fill volume. 
 
10.2.4 Storage 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Store nivolumab under refrigeration at 2°C to 8°C (36°F to 46°F). Protect 
nivolumab from light by storing in the original package until time of use. Do not freeze or shake. 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator 
Brochure section for “Recommended Storage and Use Conditions.” 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol.  
 
10.2.5 Dosage and Administration 
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to 3 
mg/kg Q2W dosing regimen. A flat dose of nivolumab 240 mg Q2W was selected since it is 
identical to a dose of 3 mg/kg for subjects weighing 80 kg, the observed median body weight in 
nivolumab treated cancer patients. Using a population pharmacokinetics model, the overall 
distributions of nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable 
after treatment with either 3 mg/kg or 240 mg nivolumab. Given the similarity of nivolumab PK 
across tumor types and the similar exposures predicted following administration of 240 mg flat 
dose compared to 3 mg/kg Q2W regimen, it is expected that the safety and efficacy profile of 
240 mg Q2W nivolumab will be similar to that of 3 mg/kg nivolumab. 
 
Nivolumab is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding polyethersulfone membrane in-line filter at the protocol-specified doses and 
infusion times. It is not to be administered as an IV push or bolus injection. Nivolumab injection 
can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. When the dose is 
fixed (eg, 240 mg, 360 mg or 480 mg flat dose), nivolumab injection can be infused undiluted or 
diluted so as not to exceed a total infusion volume of 120 mL. During drug product preparation 
and handling, vigorous mixing or shaking is to be avoided. Care must be taken to assure sterility 
of the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent. No incompatibilities between nivolumab and polyvinyl chloride (PVC) and 
non-PVC/non-DEHP (di(2-ethylhexyl)phthalate) containers/IV components or glass bottles have 
been observed.  


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10.2.6 Storage and Stability 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL)  
Vials of nivolumab injection must be stored at 2° to 8°C (36° to 46°F) and protected from light 
and freezing.   
 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container.  
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2° to 
8°C, 36° to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20° to 25°C, 68° to 77°F) and room light. The maximum 8 hour period under 
room temperature and room light conditions includes the product administration period. 
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs.  
 
10.2.7 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. 
 
10.2.8 Dispensing 
Nivolumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. The site investigator shall take responsibility for and shall 
take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations. 
 
10.2.9 Side Effects 
Please refer to the nivolumab package insert for a complete list of adverse events. Potential 
safety concerns and recommended management guidelines regarding pulmonary toxicities, GI 
toxicities, hepatotoxicities, endocrinopathies, dermatologic toxicities, and other toxicities of 
concern are summarized below. Management algorithms are found in the Nivolumab IB and in 
Appendix 1.  
 
The overall safety experience with nivolumab is based on experience in approximately 12,300 
subjects as either monotherapy or in combination with other therapeutics. In general, for 
monotherapy, the safety profile is similar across tumor types. The only exception is pulmonary 
inflammation AEs, which may be numerically greater in subjects with NSCLC, possibly because 
in some cases, it can be difficult to distinguish between nivolumab-related and unrelated causes 
of pulmonary symptoms and radiographic changes. The most frequently reported treatment-
related AE is fatigue, which is almost always of low grade. 
 
Most related AEs are thought to be due to the effects of inflammatory cells on specific tissues. A 
variety of preferred terms (PTs) have been used to describe similar kinds of organ-related AEs, 


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with the result being that AE frequency tables organized by PTs can lead to underestimation of 
the frequency of similar kinds of organ-related AEs. Select AE categories group together the 
most common and impactful PTs by organ category. These categories include the following: 
pulmonary, GI, hepatic, skin, endocrine, hypersensitivity/infusion reaction, and renal AEs.  
 
Pulmonary Adverse Events 
Pulmonary AEs have been observed following treatment with nivolumab. The frequency of 
pulmonary AEs may be greater with nivolumab combination therapies than with nivolumab 
monotherapy. The majority of cases reported were Grade 1 or 2, and subjects presented with 
either asymptomatic radiographic changes (e.g., focal ground glass opacities and patchy 
infiltrates) or with symptoms of dyspnea, cough, or fever. Subjects with reported Grade 3 or 4 
pulmonary AEs were noted to have more severe symptoms, more extensive radiographic 
findings, and hypoxia. Pulmonary AEs have been reported in subjects with a variety of tumor 
types; however, there have been numerically more cases in subjects with NSCLC. It is not clear 
whether the underlying NSCLC is a distinct risk factor, or if subjects with NSCLC are more 
likely to develop radiographic changes and symptoms for which it is difficult to distinguish 
between nivolumab-related and unrelated causes. At this time, no other underlying risk factor, 
including prior radiotherapy, presence of lung metastases, or underlying pulmonary medical 
history, has yet to be identified. 
 
Gastrointestinal Adverse Events 
Gastrointestinal AEs have been observed following treatment with nivolumab. Most cases of 
diarrhea were of low grade (Grade 1-2). Colitis occurred less frequently than diarrhea. High-
grade cases of diarrhea and colitis were managed with corticosteroids and, in all cases, the events 
resolved. 
 
Diverticular Perforation 
The prevalence of diverticulosis in the general population is common and increases with age 
from 10% under 40 years of age to approximately 50% over 60 years of age. Approximately 
10% to 25% of subjects with diverticulosis develop diverticulitis. Perforation occurs in 50% to 
70% of instances of complicated diverticulitis [36, 37]. Corticosteroids, non-steroidal anti-
inflammatory drugs (NSAIDs), and opioid analgesics are known risk factors for diverticular 
perforation [38]. Given the high prevalence of diverticulosis and diverticulitis in the general 
population, it is expected that some nivolumab-treated subjects will have these conditions 
concurrently with their malignancy. Cases of diverticular perforation while on concomitant 
corticosteroids (6 cases) or NSAID (1 case) were observed in nivolumab program. While there is 
insufficient evidence to suggest that diverticulosis or diverticulitis is a predisposing factor for GI 
perforation following nivolumab administration, clinical caution should be exercised, as 
appropriate, for subjects on concomitant medications of corticosteroids, NSAID, or opioid 
analgesics. In addition, be vigilant for signs and symptoms of potential perforation, especially in 
subjects with known diverticular disease. 
 
Hepatic Adverse Events 
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, drug-induced liver 
injury (DILI) have been observed following treatment with nivolumab and nivolumab in 
combination with ipilimumab. Most cases were of low or moderate grade. Higher-grade hepatic 


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AEs, including DILI, were managed with corticosteroids (with or without mycophenolate 
mofetil) and, in almost all cases, the events resolved. 
 
Endocrinopathies 
Endocrinopathies have been observed following treatment with nivolumab. Most cases were of 
low or moderate grade. The events have typically been identified through either routine periodic 
monitoring of specific laboratories (e.g., TSH) or as part of a work-up for associated symptoms 
(e.g., fatigue). Events may occur within weeks of beginning treatment, but also have been noted 
to occur after many months (while still on treatment). More than 1 endocrine organ may be 
involved (e.g., hypophysitis [pituitary inflammation] may need to be evaluated at the time 
adrenal insufficiency or thyroid disorder is suspected). Moderate- to high-grade cases were 
managed with hormone replacement therapy and, in some cases, with the addition of 
corticosteroids. In some cases, nivolumab treatment was held until adequate hormone 
replacement was provided. 
 
Skin Adverse Events 
Rash and pruritus were the most common skin AEs observed following treatment with 
nivolumab. The rash was typically focal with a maculopapular appearance occurring on the 
trunk, back, or extremities. Most cases have been of low or moderate grade. In some cases, rash 
and pruritus resolved without intervention. Topical corticosteroids have been used for some 
cases of rash. Anti-histamines have been used for some cases of pruritus. More severe cases 
responded to systemic corticosteroids. 
 
Renal Adverse Events 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic nephritis have 
been infrequently observed following treatment with nivolumab. The frequency of renal AEs 
may be greater with nivolumab combination therapies than with nivolumab monotherapy. Most 
cases were Grade 2 or 3 and based on creatinine elevation. Subjects with a history of renal cell 
carcinoma or prior nephrectomy did not appear to be at higher risk. Events were managed with 
corticosteroids and, in all cases, renal function partially or fully improved. 
 
Neurologic Adverse Events 
Neurologic AEs have been uncommonly observed following treatment with nivolumab. The 
frequency of neurologic AEs may be greater with nivolumab + ipilimumab combination 
therapies than with nivolumab monotherapy or other nivolumab combinations. Neurologic AEs 
can manifest as central abnormalities (e.g., aseptic meningitis, encephalopathy, or encephalitis) 
or peripheral sensory/motor neuropathies (e.g., Guillain-Barre Syndrome, myasthenia gravis 
complicated with sepsis and fatality). The onset has been observed as early as after a single 
treatment with the nivolumab + ipilimumab combination. 
 
Infusion Reactions 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
nivolumab are uncommon. Investigators are advised to monitor for fever, chills, shakes, itching, 
rash, hypertension or hypotension, or difficulty in breathing during and immediately after 
administration of nivolumab. 
 


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Lipase/Amylase Elevations 
Asymptomatic elevations in lipase and amylase have been reported. In monotherapy studies, 
lipase and amylase levels were not systematically monitored, so an estimate of the frequency of 
asymptomatic lipase/amylase elevations is unknown. In studies evaluating the safety of the 
nivolumab + ipilimumab combination in multiple tumor types, lipase and amylase levels were 
systematically monitored, and elevations in any grade of lipase/amylase were consistently noted 
in approximately 10% to 30% of subjects. Very few subjects reported associated symptoms (e.g., 
abdominal pain) or radiographic findings (e.g., stranding) consistent with pancreatitis. Thus, 
there does not seem to be clinical significance to the elevated laboratory values. 
 
Uveitis and Visual Complaints 
Immune therapies have been uncommonly associated with visual complaints. Inflammation of 
components within the eye (e.g., uveitis) is an uncommon, but clinically important, event. 
Uveitis may occur more frequently with nivolumab + ipilimumab combination therapy than with 
nivolumab monotherapy or nivolumab in combination with other therapies. An ophthalmologist 
should evaluate visual complaints with examination of the conjunctiva, anterior and posterior 
chambers, and retina. Topical corticosteroids may be used to manage low-grade events. Low-
grade events that do not resolve and high-grade events should be managed with systemic 
corticosteroids. Consultation with a BMS medical monitor should be sought for all cases of 
ocular inflammatory events. Complaints of double vision should also prompt medical evaluation. 
In addition to ocular inflammatory events, a work-up should also consider pituitary inflammation 
as a cause 
 
Other Immune-mediated Adverse Events 
For suspected immune-related adverse reactions, adequate evaluation should be performed to 
confirm etiology or exclude other causes. Based on the severity of the adverse reaction, 
nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids 
administered. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may 
be resumed after corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab 
must be permanently discontinued for any severe immune-related adverse reaction that recurs 
and for any life-threatening immune-related adverse reaction. 
 
10.3 
Overlapping Toxicities of Ramucirumab and Nivolumab 
Overlapping toxicities of the study medications include: renal failure, infusion reaction, fatigue, 
decreased appetite and headache. 
 
11 
ADVERSE EVENTS  
 
11.1 
Definitions of Adverse Events 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 


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• An intercurrent illness or injury that impairs the well-being of the subject 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
11.1.2 Laboratory Test Abnormalities 
However, the following laboratory abnormalities should be documented and reported 
appropriately: 
• any laboratory test result that is clinically significant or meets the definition of an SAE or 
Drug Induced Liver Injury (DILI) 
• any laboratory abnormality that required the participant to have study drug discontinued 
or interrupted 
• any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
 
Wherever possible, the clinical rather than laboratory term should be used by the reporting 
investigator (e.g., anemia versus low hemoglobin value). 
 
11.1.3 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
• Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
o Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
o Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) 
via the study drug is an SAE.  


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o Although pregnancy is not always serious by regulatory definition, it must be 
handled as an SAE. 
o Ramucirumab and/or nivolumab overdose. For purposes of this trial, an overdose 
will be defined as any dose exceeding the prescribed dose for ramucirumab and/or 
nivolumab by 20%.  
o Any venous or arterial event leading to discontinuation of ramucirumab therapy 
will be considered serious and should be reported per SAE guidelines. 
o Cases of RPLS must be reported per SAE guidelines. 
 
11.1.4 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, package insert, or when it is not included in the 
informed consent document as a potential risk. Unexpected also refers to AEs that are mentioned 
in the IB as occurring with a class of drugs or are anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation.  
 
11.1.5 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 
11.2 
Adverse Event (AE) Recording 
• Adverse events (AEs) will be recorded from the time of consent until 100 days after 
treatment discontinuation of study drugs, or until a new anti-cancer treatment starts, 
whichever occurs first. 
• AEs will be recorded regardless of whether or not the event(s) are considered related to 
the study drugs.  
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
• All AEs considered related to study drugs will be followed until resolution to ≤ Grade 1 
or baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment 
starts, whichever is occurs first. 
 
 
 


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11.3 
Serious Adverse Event (SAE) Reporting 
 
11.3.1 Site Requirements for Reporting SAEs to HCRN 
 
• SAEs will be reported from time of signed informed consent until 100 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• SAEs will be reported on the SAE Submission Form and entered in the SAE tab in the 
EDC system within 1 business day of discovery of the event.   
• SAEs will be reported whether or not they are related to the study drug(s).  
• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
• All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
Additionally, any serious adverse event, considered by an investigator to be related to either 
study drug, which is brought to the attention of the investigator at any time outside of the 100-
day time period specified above, also must be reported immediately to HCRN.  
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be sent electronically to safety@hoosiercancer.org. The 
investigator is responsible for informing the IRB and/or the Regulatory Authority of the SAE as 
per local requirements. The original copy of the SAE Submission Form and the email 
correspondence must be kept within the study file at the study site. 
 
Once the SAE has resolved, sites must submit a follow up SAE Submission Form within a 
reasonable timeframe to HCRN electronically to safety@hoosiercancer.org.  
 
11.3.2 HCRN Requirements for Reporting SAEs to Eli Lilly  
HCRN will submit all at least possibly related SAEs (including DILI, overdose, pregnancy, etc.) 
received from sites to Eli Lilly within 7 business day of receipt of the SAE Reporting Form and 
to regulatory authorities (FDA) per federal guidelines.   
 
HCRN will fax or email a SAE Submission Form for all SAE reports and any other relevant safety 
information to Eli Lilly and Company (Attn: Global Patient Safety; FAX 866-644-1697 or 317-
453-3402)  
 
HCRN will provide follow-up information to Eli Lilly and Company Global Patient Safety as 
reasonably requested. 
 
11.3.3 HCRN Requirements for Reporting SAEs to BMS 
HCRN will submit all SAEs (including DILI, overdose, pregnancy, etc.) received from sites to 
BMS within 1 business day of receipt of the SAE Reporting Form and to regulatory authorities 
(FDA) per federal guidelines.   
 


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HCRN will fax or email a SAE Submission Form for all SAE reports and any other relevant 
safety information to BMS (Attn: Global Pharmacovigilance & Epidemiology; email: 
Worldwide.Safety@BMS.com; FAX: 609-818-3804). 
 
HCRN will provide follow-up information to BMS Global Pharmacovigilance & Epidemiology 
as reasonably requested. 
 
11.3.4 Reporting of Pregnancy 
It is the responsibility of site investigators or their designees to report any pregnancy in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner that 
occurs during the trial or within 5 months)following the last dose of study drugs for females, and 
7 months following the last dose of study drugs for males.. All subjects and female partners of 
male subjects who become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
 
Such events must be reported within 1 business day to HCRN. HCRN will report the event 
within 1 business day to Eli Lilly and Company (Attn: Global Patient Safety; FAX 866-644-
1697 or 317-453-3402) and BMS (Attn: Global Pharmacovigilance & Epidemiology; 
Worldwide.Safety@BMS.com; FAX: 609-818-3804). 
 
11.3.5 Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs. 
 
Potential drug induced liver injury is defined as: 
1. An elevated AST or ALT lab value that is greater than 3 × the upper limit of normal,  
and,  
2. an elevated total bilirubin lab value that is greater than 2 × the upper limit of normal 
without initial findings of cholestasis (elevated serum alkaline phosphatase),  
     
and,  
3. No other immediately apparent possible causes of aminotransferase (ALT or AST) 
elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-
existing chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
 
DILIs that occur in any subject from the date of first dose through 100 days following 
discontinuation of dosing, whether or not related to Eli Lilly and Company’s product and/or 
BMS’s product, must be reported within 1 business day to HCRN. The site will submit a 
completed SAE Submission Form to HCRN within 1 business day of discovery of the event. 
The form may be sent electronically to safety@hoosiercancer.org. 
 


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HCRN will report the event within 1 business day to Eli Lilly and Company (Attn: Global 
Patient Safety; FAX 866-644-1697 or 317-453-3402) and BMS (Attn: Global Pharmacovigilance 
& Epidemiology; Worldwide.Safety@BMS.com; FAX: 609-818-3804). 
 
11.3 Sponsor-Investigator Responsibilities 
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
 
11.4 HCRN Responsibilities for Reporting SAEs to the FDA  
 
11.4.1 Protocols Conducted Under an IND 
HCRN has been designated to manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of the sponsor-investigator.  HCRN will cross-reference 
this submission to Eli Lilly’s and BMS’s parent INDs at the time of submission.  Additionally, 
HCRN will submit a copy of these documents to Eli Lilly and BMS at the time of submission to 
FDA. 
 
HCRN will be responsible for all communication with the FDA in accordance with 21CFR312 
which includes but is not limited to the 7- and 15-Day Reports, as well as an Annual Progress 
Report. Additionally, HCRN will submit a copy of these reports to Eli Lilly and BMS at the time 
of submission to FDA. 
 
11.5 
IND Safety Reports Unrelated to This Trial 
Eli Lilly and Company and BMS will provide HCRN with IND safety reports from external 
studies that involve the study drugs to HCRN (safety@hoosiercancer.org) per their guidelines. 
HCRN will forward the safety reports to the sponsor-investigator who will review these reports 
and determine if revisions are needed to the protocol or consent. HCRN will forward these 
reports to participating sites within 1 business day of receiving the sponsor-investigator’s 
review. Based on the sponsor-investigator’s review, applicable changes will be made to the 
protocol and informed consent document (if required). All IND safety reports will also be made 
available to sites via the EDC system. 
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
 
 


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12 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design 
The primary objective of this study is to evaluate the response rate of checkpoint inhibitor with 
combination of the anti PD-1 agent, nivolumab and the anti VEGFR2 antibody, ramucirumab in 
subjects with previously-treated mesothelioma. The primary study endpoint is the response rate 
[complete response (CR) + partial response (PR)] of patients to this treatment. Nivolumab and 
ramucirumab will be given on Day 1 of each 14-day cycle. Treatment will continue up to 24 
months (52 cycles) or until disease progression, unacceptable toxicity, subject refusal, or subject 
death. Subjects who voluntarily stop the study, have progressive disease, or unacceptable 
toxicities will be followed for a total of 24 months after initiation of study treatment. 
 
Correlative research analyses include examining the relationship between best clinical response 
overall with tissue PD-L1, and at the end of Cycle 4 (Week 8) with changes in PD-L1 and 
cytokine genes expressions and number of CD8+ and Granzyme B+ T cells in tumor tissue from 
before therapy to the end of Cycle 4 (Week 8). Research analyses also include examining the 
relationship between changes in soluble PD-L1 level, during therapy (assessed pre-dose Cycles 1 
and 5 [(Days 1 and 57 of treatment period, respectively]) relative to baseline to the best clinical 
response (modified RECIST 1.1 criteria) and to treatment outcome. 
 
12.2 
Criteria for Stopping Study 
The study will be stopped for safety reasons if ≥ 2 subjects in first 20 or ≥ 3 in first 30 subjects 
develop grade 5 therapy related toxicity during first 4 cycles of therapy.  
 
12.3 
Sample Size 
This is a non-randomized one arm study of nivolumab and ramucirumab. The primary study 
endpoint is the response rate [complete response (CR) + partial response (PR)] of patients for the 
therapy. Previous studies identified such response rate of 20% [Alley’s Lancet Oncology paper 
2017]. We hypothesize a response rate of 40%. Controlling for a probability of Type I error at 
0.05 (one-sided), our sample size is estimated to be 33 to ensure 80% statistical power in 
successfully detecting an alternative response rate of 0.40, compared to a null rate of 0.2. With 
estimated up to 5% of patients that are not evaluable for primary endpoint, sample size will be 
increased to 35. Sample size analyses were conducted using the PASS software (NCSS, 
Kaysville, Utah, USA). 
 
12.4 
Analysis of Primary Objectives/Aims 
The primary endpoint is determination of the response rate [complete response (CR) + partial 
response (PR)] with the combination of the anti PD-1 agent, nivolumab and the anti VEGFR2 
antibody, ramucirumab in subjects with previously-treated mesothelioma; it will be calculated 
with associated 95% confidence interval using. 
 
12.5 
Analysis of Secondary Endpoints 
Characterize adverse effects (AE) of nivolumab in combination with ramucirumab in subjects 
with previously-treated mesothelioma. 
 


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Proportion of subjects with each grade of adverse events as defined by CTCAE v4 will be 
computed along with 95% confidence intervals, and reported in a tabular and descriptive manner. 
 
Median progression free survival (PFS) and overall survival (OS) times will be computed, and 
PFS rates at 3, 6, and 12 months and OS rates at 2 years +/- 2 months will be calculated with 
associated 95% confidence intervals.  Kaplan-Meier curves for reach survival rate will be 
plotted.  
 
12.6 
Analysis of Correlative Endpoints 
• PD-L1 expression in tumor tissue (categorical based on 5% threshold) from before 
therapy (assessed within 14 days before treatment) will be correlated with the best 
clinical response (modified version of RECIST 1.1) and treatment outcome. Chi-square 
statistics will be computed. 
 
• Change in PD-L1 expression in tumor tissue from before therapy (assessed within 14 
days before treatment) to after 4 cycles (8 weeks) of therapy will be correlated with the 
best clinical response (modified version of RECIST 1.1) and treatment outcome. Chis-
square statistics will be computed. 
 
• Change in cytokine expression in tumor tissue from before therapy (assessed within 14 
days before treatment) to after 4 cycles (8 weeks) of therapy will be correlated with the 
best clinical response (modified version of RECIST 1.1) and treatment outcome. Chi-
square statistics will be computed. 
 
• Change in soluble PD-L1 level during therapy (assessed pre-dose Cycles 1 and 5 [(Days 
1 and 57 of treatment period, respectively]) relative to baseline will be examined in 
relation to the best clinical response (modified version of RECIST 1.1) and treatment 
outcome. Correlation-statistics will be computed.  
 
• Change in number of CD8+ cells (rich vs. poor) and Granzyme B+ T cells (rich vs. poor) 
from before therapy (assessed within 14 days before treatment) to after 4 cycles (8 
weeks) of therapy will be examined in relation to the best clinical response (modified 
version of RECIST 1.1) and treatment outcome. Chi-square statistics will be computed. 
 
 
 


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13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Board (DSMB) 
This study will have a Data and Safety Monitoring Board (DSMB). The DSMB is chaired by an 
independent medical oncologist external to this trial. The DSMB will provide a recommendation 
to the sponsor-investigator after all information is reviewed. This information will also be 
provided to HCRN who will distribute to the site investigator/participating sites for submission 
to their respective IRB, according to the local IRB’s policies and procedures. 
 
The DSMB review will include but is not limited to: 
• Adverse event summary report 
• Audit results, if applicable 
• Data related to stopping/decision rules described in study design 
• Study accrual patterns  
• Protocol deviations 
 
The DSMB will review data a minimum of twice per year during the active study drug 
administration phase of the study. 
 
13.2 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study.  Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel. 
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause visits may occur as necessary. Source documents will be 
reviewed for verification of agreement with data entered into the EDC system.  It is important for 
the site investigator and their relevant personnel to be available for a sufficient amount of time 
during the monitoring visits or audit, if applicable. The site investigator and institution guarantee 
access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Eli Lilly, BMS, or their designees 
as well as inspection by appropriate regulatory agencies. 
 
13.3 
Compliance with Trial Registration and Results Posting Requirements  
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion. The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information. 


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14 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through the web-based clinical research platform, a system compliant with Good Clinical 
Practices and Federal Rules and Regulations. HCRN personnel will coordinate and manage data 
for quality control assurance and integrity. All data will be collected and entered into the EDC 
system by study site personnel from participating institutions. 
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is housed at HCRN and is the sole property of the sponsor-investigator’s 
institution. It should not be made available in any form to third parties, except for authorized 
representatives of appropriate Health/Regulatory Authorities, without written permission from 
the sponsor-investigator and HCRN. After the initial publication, the complete data set will be 
available to all HCRN institutions. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the investigator agrees to 
keep records, including the identity of all participating subjects (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, 
the records should be retained by the investigator in compliance with regulations. No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subject will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study team. Samples that are 
collected will be identified by a subject study number assigned at the time of registration to the 
trial.  
 
Subjects will be informed in writing that some organizations, including the sponsor-investigator 
and his/her research associates, HCRN, Eli Lilly and Company, Bristol-Myers Squibb, IRB, or 
government agencies, like the FDA, may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws. 
 


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If the results of the study are published, the subject’s identity will remain confidential. 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol, including the final version of the informed consent form must be 
approved in writing by an IRB. The investigator must submit written approval to the HCRN 
office before he or she can enroll any subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided 
to the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki. Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The investigator will ensure the subject is given full and adequate oral and written information 
about the nature, purpose, possible risks and benefits of the study. Subjects must also be notified 
they are free to discontinue from the study at any time. The subject should be given the 
opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The investigator must store the original, signed informed 
consent form. A copy of the signed informed consent form must be given to the subject. 


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16 
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17 
APPENDIX 1: Nivolumab Management Algorithms 
 
These general guidelines constitute guidance to the site Investigator and may be supplemented 
through discussions with the Sponsor-Investigator by contacting the HCRN project manager. The 
guidance applies to all immuno-oncology agents and regimens. 
 
As general principle, differential diagnoses should be diligently evaluated according to standard 
medical practice. Non-inflammatory etiologies should be considered and appropriately treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 


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