An Investigator-Sponsored Phase 2 Single Arm Trial of Ramucirumab and Pembrolizumab in Patients With EGFR Mutant Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: Ohio State University Comprehensive Cancer Center

IRB Protocol Number: 
2019C0145 
IRB Approval date: 
06/10/2022 
Version: 
05/06/2022 
 
PROTOCOL NUMBER: OSU-19132 
 
 
 
 
 
 
 
 
  
 
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CLINICAL STUDY PROTOCOL 
 
AN INVESTIGATOR-SPONSORED PHASE 2 SINGLE ARM TRIAL OF 
RAMUCIRUMAB AND PEMBROLIZUMAB IN PATIENTS WITH EGFR MUTANT 
NON-SMALL CELL LUNG CANCER 
 
PROTOCOL NUMBER: 
 
 
OSU-19132 
PROTOCOL VERSION:  
1.9 
PROTOCOL VERSION DATE: 
05/06/2022 
INVESTIGATIONAL PRODUCT:  
RAMUCIRUMAB 
PEMBROLIZUMAB 
SPONSORING PRINCIPAL 
INVESTIGATOR:  
ASRAR ALAHMADI, MBBS 
 
DRUG PRODUCT SUPPLIER:  
LILLY 
MERCK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICIAN: 
SARAH JANSE, PHD 
 
 

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Version: 
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PROTOCOL NUMBER: OSU-19132 
 
 
 
 
 
 
 
 
  
 
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Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by federal 
or state law or regulations. In any event, persons to whom the information is disclosed must be 
informed that the information is privileged or confidential and may not be disclosed by them. 
These restrictions on disclosure will apply equally to all future information supplied to you, 
which is indicated as privileged or confidential. 
 
 

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TABLE OF CONTENTS 
Synopsis ......................................................................................................................................... vi 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ xiv 
1. 
Introduction ........................................................................................................................... 1 
1.1 
Overview ......................................................................................................................... 1 
1.2 
Ramucirumab:  Mechanism of Action ......................................................................... 1 
1.3 
Pembrolizumab:  Mechanism of Action ....................................................................... 2 
1.3.1 
Clinical Experience ................................................................................................... 2 
1.4 
Clinical Safety ................................................................................................................. 3 
1.5 
Phase II Single Arm Trial of Ramucirumab and Pembrolizumab in EGFR mutant 
Non-Small Cell Lung Cancer ................................................................................................... 3 
2. 
Objectives and Endpoints ..................................................................................................... 8 
2.1 
Primary Objective .......................................................................................................... 8 
Primary Endpoint: .................................................................................................................... 8 
2.2 
Secondary Objectives ..................................................................................................... 8 
Secondary Endpoints ................................................................................................................ 8 
2.3 
Exploratory objectives ................................................................................................... 9 
3. 
Investigational Plan ............................................................................................................... 9 
3.1 
Overview of Study Design and Dosing Regimen ......................................................... 9 
3.1.1 
Definition of Treatment Cycle and Duration .......................................................... 10 
3.1.3 
Treatment Phase ...................................................................................................... 10 
3.1.4 
End of Treatment Visit............................................................................................ 10 
3.2 
Study Duration ............................................................................................................. 10 
3.3 Study Schema .................................................................................................................... 12 
4. 
Patient Selection ................................................................................................................... 13 
4.1 
Study Population and Sample Size ............................................................................. 13 
4.2 
Inclusion Criteria ......................................................................................................... 13 
4.3 
Exclusion Criteria ........................................................................................................ 15 
4.4 
Lifestyle Restrictions .................................................................................................... 17 
Pregnancy .............................................................................................................................. 17 
Use in Nursing Women ......................................................................................................... 18 
4.5 
Patient Removal from Study ....................................................................................... 18 
5. 
Investigational Medicinal Products and treatment plan .................................................. 19 
5.1 
Ramucirumab Formulation and Administration ...................................................... 19 
5.2 
Ramucirumab Storage and Stability .......................................................................... 19 
5.3 
Ramucirumab Labelling .............................................................................................. 19 
5.4 
Ramucirumab Dosing Information ............................................................................ 19 
5.5 
Pembrolizumab Formulation and Administration ................................................... 20 
5.6 
Pembrolizumab Storage and Stability ....................................................................... 20 
5.7 
Pembrolizumab Labelling ........................................................................................... 20 

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5.8 
Pembrolizumab Dosing Information .......................................................................... 20 
5.9 
Handling – Ramucirumab and Pembrolizumab ....................................................... 21 
5.10 
Drug Product Accountability .................................................................................. 21 
6. 
Study Procedures ................................................................................................................. 22 
6.1 
Study Assessments ........................................................................................................ 22 
6.1.1 
Efficacy Assessments.............................................................................................. 22 
6.1.2 
Laboratory Assessments ......................................................................................... 22 
6.1.3 Sample Collection for translational analyses................................................................ 23 
6.2 
Data Safety and Monitoring Plan ............................................................................... 25 
6.3 
Schedule of Study Events ............................................................................................. 25 
6.4 
End of Study ................................................................................................................. 32 
6.5 
Planned Treatment of the Patients after End of Treatment Phase ......................... 32 
6.6 
Removal of Patients from Treatment ......................................................................... 32 
6.7 
Study Discontinuation .................................................................................................. 33 
7. 
Toxicities, Risks and AE-Related Dose Modifications ..................................................... 33 
7.1 
Ramucirumab Toxicity Overview............................................................................... 33 
7.2 
Pembrolizumab Toxicity Overview ............................................................................ 35 
8. 
Supportive Care Guidelines ................................................................................................ 43 
8.1 
Concomitant Medications ............................................................................................ 43 
8.2 
Permitted Concomitant Medication ........................................................................... 43 
8.3 
Glucocorticoid therapy ................................................................................................ 43 
8.4 
Prohibited Medication ................................................................................................. 43 
8.5 
Rescue Medications & Supportive Care .................................................................... 44 
8.6 
Dose Adjustments for Weight ..................................................................................... 44 
9. 
Statistical Considerations.................................................................................................... 45 
9.1 
Endpoints ...................................................................................................................... 45 
9.1.1 
Primary Endpoint .................................................................................................... 45 
9.1.2 
Secondary Endpoints .............................................................................................. 45 
9.2 
Sample Size Justification ............................................................................................. 45 
9.3 
Planned Interim Analysis ............................................................................................ 45 
9.4 
Analysis Plan ................................................................................................................. 45 
9.4.1 
Primary endpoint analysis: ...................................................................................... 45 
9.4.2 
Analysis of secondary endpoints: ........................................................................... 46 
9.5 
Analysis of Exploratory Endpoints - Correlative studies: ........................................ 48 
10. 
Data Management ............................................................................................................ 49 
10.1 
Clinical Data .............................................................................................................. 49 
10.2 
Quality Assurance..................................................................................................... 49 
11. 
Protection of Human Subjects ........................................................................................ 49 
11.1 
Human Subjects Involvement and Characteristics: .............................................. 49 
11.2 
Consent process: ....................................................................................................... 50 
11.3 
Possible Toxicities/Side-Effects: .............................................................................. 50 
11.3.1 
Benefits ................................................................................................................... 50 

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11.3.2 
Costs ........................................................................................................................ 50 
11.3.3 
Alternatives ............................................................................................................. 50 
11.3.4 
Confidentiality ........................................................................................................ 50 
11.3.5 
Patient safety ........................................................................................................... 50 
11.3.6 
Monitoring of data to ensure safety ........................................................................ 51 
11.3.7 
Privacy .................................................................................................................... 51 
12. 
Informed Consent ............................................................................................................ 51 
13. 
Reporting Requirements ................................................................................................. 51 
13.1 
Adverse Drug Reaction Reporting .......................................................................... 51 
13.2 
Serious Adverse Event Reporting (SAE) ................................................................ 52 
13.3 
Reporting to FDA: .................................................................................................... 53 
13.4 
Reporting to the Drug Provider (Lilly) ................................................................... 53 
13.5 
Reporting to the Drug Provider (Merk) ................................................................. 54 
13.6 
Sponsor Responsibility for Reporting Adverse Events ......................................... 57 
14. 
References ......................................................................................................................... 58 
Contraception Requirements ................................................................................................. 68 
Pregnancy Testing ................................................................................................................. 70 
 
 

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Version: 
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SYNOPSIS 
 
Study Title 
A Phase II Single Arm Trial of Ramucirumab with 
Pembrolizumab in EGFR Mutant Non-Small Cell Lung 
Cancer 
Study Rationale 
Non-small cell lung cancer (NSCLC) is one of the most 
common and lethal cancers in the United States. Fifteen 
percent of these NSCLC patients have epidermal growth 
factor receptor (EGFR) driver mutations, which are 
associated with high response rates (>70%) to tyrosine 
kinase inhibitors (TKI) but low response rates (10%) to 
single agent immune checkpoint inhibitors (ICI) such as 
pembrolizumab (anti-PD1 monoclonal antibody (mAb)).[1-
5] In addition, responses to TKIs are not durable due to 
acquired resistance.[6] Vascular endothelial growth factor 
(VEGF) has emerged as a potential pathway of interest for 
treatment in this patient population because EGFR mutant 
NSCLC is associated with increased VEGF expression.[7] 
Notably, VEGF induces tumor related angiogenesis and also 
has immune dysregulatory effects that impact dendritic cell 
(DC) maturation, myeloid derived suppressor cells (MDSC) 
proliferation, and T cell PD-1 expression.[8-11] In clinical 
and preclinical studies, VEGFR inhibitors reverse this 
immune dysregulation and may work in synergy with ICI to 
enhance immune response.[12-14]  
Given the lack of durable responses to first line therapy in 
EGFR mutant NSCLC, development of tolerable and 
effective second line therapies is imperative. Two phase 3 
trials demonstrated potential clinical importance of VEGF 
inhibitors for EGFR mutant patients receiving ICI. 
IMPower150 
demonstrated 
progression-free 
survival 
advantage for carboplatin and paclitaxel with bevacizumab 
(anti-VEGF mAb) and atezolizumab (anti-PDL1 mAb) 
whereas IMPower130 demonstrated no survival difference 
for carboplatin, nab-paclitaxel, and atezolizumab without 
the addition of bevacizumab.[15-17] These results suggest a 
key role of anti-VEGF in combination with ICI in the EGFR 
mutant population and this combination may obviate the 
need for chemotherapy. Chemotherapy toxicity was 
significant in both IMPower trials – up to 55% of patients 
experienced grade 3-4 toxicity, most of which was 
attributable to carboplatin and paclitaxel (neuropathy, 
nausea, and pancytopenia).[16] 

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To evaluate the clinical efficacy of this combination, we 
propose a phase II single arm trial of ramucirumab (anti-
VEGFR mAb) and pembrolizumab (anti-PD1 mAb) for 
EGFR mutant NSCLC patients who have progressed on at 
least one EGFR TKI. The primary endpoint will be response 
rate and the secondary endpoints will be safety, tolerability, 
and survival. We anticipate that the combination of 
ramucirumab and pembrolizumab will be associated with a 
higher response rate (≥ 25%) than observed responses with 
single agent ICI (~ 10%). We will perform exploratory 
correlative studies to evaluate the immune cell activation 
profiles with combination therapy. 
Primary Objective 
To evaluate response rate of the combination of 
ramucirumab and pembrolizumab in EGFR mutant 
NSCLC. 
Secondary 
Objectives 
 
Correlative Studies 
 
 
To evaluate safety, tolerability, and survival for patients 
receiving ramucirumab and pembrolizumab.  
 
Exploratory 
objectives: 
To 
characterize 
predictive 
immunologic biomarkers of response in tissue and 
peripheral blood of patients receiving R+P combination 
therapy 
 
Exploratory Correlative Endpoints: 
1) Baseline tumor immunoprofile by IHC, including tumor 
infiltrating lymphocytes and T cell receptor (TCR) 
immunosequencing (immunoSEQ) and relationship to 
clinical outcomes, including response rate.  
2)  Circulating immune cell profiles in response to treatment 
and in relation to clinical response using 10-color 65 marker 
multiplex CyTOF profile on peripheral blood samples. 
3) Circulating VEGF at baseline, after treatment and at 
progression to evaluate correlation with clinical response. 
 
Sample Size 
Minimum 13 patients, maximum 34 patients 
Study Design 
Agents: Ramucirumab, Pembrolizumab 

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Version: 
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Tumor type: EGFR mutation positive NSCLC 
The proposed study will be an open-label single arm phase 
II trial of ramucirumab and pembrolizumab (R+P) in EGFR 
mutant NSCLC after progression on tyrosine kinase 
inhibitors (TKIs). Patients are required to receive at least one 
TKI (erlotinib, gefitinib, afatinib or osimertinib). Post-TKI 
chemotherapy is also permitted.  
Each treatment cycle will be 21 days; patients will receive 
ramucirumab 10 mg/kg IV and pembrolizumab 200 mg IV 
and on day 1. Dosing of ramucirumab and pembrolizumab 
is based on prior phase 1 testing of the combination. A two-
stage design will be utilized to minimize exposure to 
combination therapy if there is limited efficacy. The initial 
stage will enroll 13 patients; if  ≥ 1 patient has a confirmed 
response, the study will continue and enroll an additional 21 
patients for a total of 34 patients.  
Response will be assessed using RECIST (RECIST 1.1 and 
iRECIST). Imaging will be performed every 6 weeks/2 
cycles to assess response. Patients with clinical benefit may 
continue therapy beyond progression for up to 2 cycles – if 
progressive disease confirmed on repeat imaging, therapy 
would be discontinued. Toxicity will be assessed using 
CTCAE v5.0. Progression free survival will be assessed 
using RECIST and will be assessed starting from date of 
study enrollment. 
Blood samples tissue will be collected at baseline (day 1, 
cycle 1), cycle 3 day1 (approx. 6 weeks), and at study 
discontinuation (or progression). Archival tissue will be 
requested at enrollment for correlative studies.  
Duration of 
Treatment 
Patients may continue to receive study treatment (R+P)  
until radiographic documentation of disease progression, 
the occurrence of unacceptable toxicity or of the 
occurrence of other withdrawal criteria.  
 
If either drug is discontinued due to toxicity, the other drug 
may be continued.  
 
Inclusion /Exclusion 
Criteria 
Inclusion Criteria: 
1. Adult patients aged ≥18 years 

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2. Histologically confirmed recurrent or metastatic non-
small cell carcinoma of the lung with sensitizing EGFR 
mutations. Exon 20 resistance mutations will not be 
permitted but uncommon sensitizing mutations are 
allowed. 
3. Prior Systemic Anticancer Therapy: Neo/adjuvant 
therapy or prior therapy for locally advanced disease 
will be permitted. Patients with prior exposure to 
PD/PD-L1 inhibitors will be excluded. No limit on prior 
EGFR TKIs (erlotinib, gefitinib, afatinib, dacomitinib 
or osimertinib). Prior chemotherapy for metastatic 
disease is permitted only. A 7 day washout period or 
four half-lives after the last treatment dose, whichever 
is longer, is required for TKI. A 4 week washout is 
required for cytotoxic chemotherapy.  
4. Measurable disease per RECIST criteria 
5. ECOG performance status of 0-1 
6. Adequate organ function, hematologic, hepatic, renal 
and coagulation parameters as defined in the protocol.  
7. Because the teratogenicity of ramucirumab is not 
known, the patient, if sexually active, must be 
postmenopausal, surgically sterile, or using effective 
contraception (hormonal or barrier methods).  
8. Female patients of childbearing potential must have a 
negative serum pregnancy test within 72 hours prior to 
first dose of protocol therapy. 
 
Exclusion Criteria 
1. 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). Replacement therapy (eg., 
thyroxine, insulin, or physiologic corticosteroid 
replacement 
therapy 
for 
adrenal 
or 
pituitary 
insufficiency, etc.) is not considered a form of systemic 
treatment.  
2. Known active chronic infections – HIV/AIDS, known 
active Hepatitis B or C. Known history of Hepatitis B 
(defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as 
HCV RNA [qualitative] is detected) infection. Note: no 

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testing for Hepatitis B and Hepatitis C is required unless 
mandated by local health authority.  
3. Cirrhosis (Child-Pugh B or worse) or cirrhosis with 
history of hepatic encephalopathy or clinically 
meaningful ascites resulting from cirrhosis.  
4. Prior exposure to ramucirumab. 
5. Has received prior therapy with an anti-PD-1, anti-PD-
L1, or anti-PD-L2 agent or with an agent directed to 
another stimulatory or co-inhibitory T-cell receptor 
(eg, CTLA-4, OX-40, CD137). 
6. Any Grade 3-4 GI bleeding within 3 months prior to 
first dose of protocol therapy. 
7. History of deep vein thrombosis (DVT), pulmonary 
embolism (PE), or any other significant 
thromboembolism (venous port or catheter thrombosis 
or superficial venous thrombosis are not considered 
“significant”) during the 3 months prior to first dose of 
protocol therapy. 
8. Patients receiving dipyridamole, clopidogrel, or 
similar agents. Once-daily aspirin use (maximum dose 
325 mg/day) is permitted.  
9. Uncontrolled CNS metastases. Patients with treated 
brain metastases are eligible if they were clinically 
stable with regard to neurologic function, off steroids 
after cranial irradiation (whole brain radiation therapy, 
focal radiation therapy, and stereotactic radiosurgery) 
ending at least 2 weeks prior to first dose of study 
treatment, or after surgical resection performed at least 
28 days prior to first dose of study treatment. The 
patient must have no evidence of Grade ≥1 CNS 
hemorrhage based on pretreatment MRI or IV contrast 
CT scan (performed within 28 days before first dose of 
study treatment). Note: Patients who received systemic 
therapy that adequately and appropriately treated CNS 
metastases, including tyrosine kinase inhibitors, are 
eligible provided that CNS disease control is 
confirmed by pretreatment MRI within 28 days of 
receiving first dose of study treatment. 
10. Hemoptysis (defined as bright red blood or 
≥ 1/2 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. 

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11. Uncontrolled or poorly-controlled hypertension (>160 
mmHg systolic or > 100 mmHg diastolic for >4 
weeks) despite standard medical management. 
12. Any arterial thromboembolic events, including but not 
limited to myocardial infarction, transient ischemic 
attack, cerebrovascular accident, or unstable angina, 
within 6 months prior to first dose of protocol therapy. 
13. Major surgery within 28 days or device placement 
within 7 days prior to the first dose of protocol 
therapy.  Patient has elective or planned major surgery 
to be performed during the course of the clinical trial. 
14. Serious or non-healing wound, ulcer, or bone fracture 
within 28 days of study treatment.  
15. Prior history of GI perforation/fistula (within 6 months 
of first dose of protocol therapy) or risk factors for 
perforation. 
16. Small cell or mixed (small cell/non-small cell) lung 
cancer 
17. Pregnancy or breastfeeding.  
18. Has received a live vaccine within 30 days prior to the 
first dose of study drug.  Examples of live vaccines 
include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow 
fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines 
(eg, FluMist®) are live attenuated vaccines and are not 
allowed. 
19. History of (non-infectious) pneumonitis that required 
steroids or has current pneumonitis. 
20. History or current evidence of any condition, therapy, 
or laboratory abnormality that might confound the 
results of the study, interfere with the subject’s 
participation for the full duration of the study, or is not 
in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
21. Known psychiatric or substance abuse disorders that 
would interfere with cooperation with the requirements 
of the trial. 
22. Severe hypersensitivity (≥Grade 3) to pembrolizumab 
and/or any of its excipients. 
23. Active infection requiring systemic therapy. 
24. Known history of active TB   (Bacillus Tuberculosis).   
 

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Screening 
Assessments 
Signed written informed consent  
Inclusion/Exclusion Criteria  
Demographics and medical history  
Pregnancy test (if applicable)  
Physical examination, ECOG, and vital signs  
Urine analysis  
Hematology (CBC, coagulation studies) 
Complete serum chemistry 
Assessment of disease status  
Concomitant medication  
Treatment and Post-
Treatment 
Assessments 
Cycle 1 , Day 1 
Physical examination and vital signs 
Complete blood count with differential 
Complete clinical chemistry (including liver function tests) 
TSH  - free T3 and T4 if abnormal 
Adverse events and concomitant medication 
 
Cycle 1, Day 8 
Physical examination and vital signs  
Complete clinical chemistry (including liver function tests) 
Urinalysis  
 
Cycle 2 and Beyond 
Physical examination and vital signs 
Complete blood count with differential 
Complete clinical chemistry (including liver function tests) 
TSH  - free T3 and T4 if abnormal – repeat every 3rd cycle 
Urine analysis  
Pregnancy test (if applicable)  
 
Assessment of disease status: 
• CT scans (disease evaluation will be done 
according to irRECIST and RECIST 1.1)  
 
Adverse events and concomitant medication 

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Final Visit 
Physical examination and vital signs 
Complete blood count with differential 
Complete clinical chemistry (including liver function tests) 
Assessment of disease status 
Adverse events and concomitant medication 
Response 
CT scans will be used for tumor assessment, at 
baseline and then at 6 week intervals. Patients who achieve 
stable disease, partial response (PR), or complete response 
(CR) per RECIST v.1.1 criteria will continue therapy until 
disease progression.  Patients with confirmed disease 
progression by RECIST will be discontinued.  
Safety Variables & 
Analysis 
The safety and tolerability of ramucirumab and 
pembrolizumab will be evaluated by assessment of drug 
related toxicities, adverse event (AE) reports, physical 
examinations, and laboratory safety evaluations. Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 
will be used for grading of AEs.  Investigators will provide 
their assessment of causality as 1) unrelated, 2) possibly 
related, or 3) probably or definitely related for all AEs.   
Statistical Analysis
 
 
The primary study objective is to assess the overall response 
rate (ORR) of ramucirumab and pembrolizumab. The study 
will use Simon’s two-stage design. Response rate with 
single agent IO is around 10% and we would consider a 
response rate of at least 25% to be interesting for further 
study. The initial stage will include 13 patients; the trial will 
be terminated if there are no responses. If the trial goes on 
to the second stage, an additional 21 patients will be 
included for a total of 34 patients studied. 
Secondary objectives involve evaluating safety and 
tolerability and estimating PFS and overall survival. 
Descriptive statistics will be calculated for these outcomes 
and Kaplan-Meier curves will be calculated to estimate PFS 
and OS. Patients who have reached the end of the study but 
not progressed will be considered censored at the last 
documented date of contact. Estimates from this analysis 
will be used as preliminary data to inform future research. 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APC 
Adenomatous polyposis coli 
API 
Active pharmaceutical ingredient 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
BW 
Body weight 
CBC 
Complete blood count 
CI 
Confidence interval 
CK 
Creatine kinase 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract research organisation 
CTCAE 
Common terminology criteria for adverse events 
CT Scan 
Computed Tomography Scan 
CYP450 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Desoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
h 
Hour 
HR 
Hazard ratio 
IA 
Interim analysis 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intent to treat 
i.v. 
Intravenous 
KRAS 
Kirsten Rat sarcoma 
LDH 
Lactate dehydrogenase 
m² 
Square metre (body surface area) 

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mg 
Milligram 
min 
Minute 
mL 
Millilitre 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute  
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PO 
Per oral  
PR 
Partial response 
PTT 
Partial thromboplastin time 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
SADR 
Serious adverse drug reaction 
SUSAR 
Suspected unexpected serious adverse reaction 
TSH 
Thyroid Stimulating Hormone 
TTP 
Time to progression 
UNL 
Upper normal limit 
WBC 
White blood cell count 
 

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1. INTRODUCTION 
1.1 
Overview  
Non-small cell lung cancer (NSCLC) is one of the most common and lethal cancers in the United 
States. Fifteen percent of these NSCLC patients have epidermal growth factor receptor (EGFR) 
driver mutations, which are associated with high response rates (>70%) to tyrosine kinase 
inhibitors (TKI) but low response rates (10%) to single agent immune checkpoint inhibitors (ICI) 
such as pembrolizumab (anti-PD1 monoclonal antibody (mAb)).[1-5] In addition, responses to 
TKIs are not durable due to acquired resistance.[6] Vascular endothelial growth factor (VEGF) 
has emerged as a potential pathway of interest for treatment in this patient population because 
EGFR mutant NSCLC is associated with increased VEGF expression.[7] Notably, VEGF induces 
tumor related angiogenesis and also has immune dysregulatory effects that impact dendritic cell 
(DC) maturation, myeloid derived suppressor cells (MDSC) proliferation, and T cell PD-1 
expression.[8-11] In clinical and preclinical studies, VEGFR inhibitors reverse this immune 
dysregulation and may work in synergy with ICI to enhance immune response.[12-14]  
Given the lack of durable responses to first line therapy in EGFR mutant NSCLC, development of 
tolerable and effective second line therapies is imperative. Two phase 3 trials demonstrated 
potential clinical importance of VEGF inhibitors for EGFR mutant patients receiving ICI. 
IMPower150 demonstrated progression-free survival advantage for carboplatin and paclitaxel with 
bevacizumab (anti-VEGF mAb) and atezolizumab (anti-PDL1 mAb) whereas IMPower130 
demonstrated no survival difference for carboplatin, nab-paclitaxel, and atezolizumab without the 
addition of bevacizumab.[15-17] These results suggest a key role of anti-VEGF in combination 
with ICI in the EGFR mutant population and this combination may obviate the need for 
chemotherapy. Chemotherapy toxicity was significant in both IMPower trials – up to 55% of 
patients experienced grade 3-4 toxicity, most of which was attributable to carboplatin and 
paclitaxel (neuropathy, nausea, and pancytopenia).[16] 
To evaluate the clinical efficacy of this combination, we propose a phase II single arm trial of 
ramucirumab (anti-VEGFR mAb) and pembrolizumab (anti-PD1 mAb) for EGFR mutant NSCLC 
patients who have progressed on at least one EGFR TKI. The primary endpoint will be response 
rate and the secondary endpoints will be safety, tolerability, and survival. We anticipate that the 
combination of ramucirumab and pembrolizumab will be associated with a higher response rate (≥ 
25%) than observed responses with single agent ICI (~ 10%). We will perform exploratory 
correlative studies to evaluate the immune cell activation profiles with combination therapy. 
1.2 
Ramucirumab:  Mechanism of Action  
Ramucirumab is an anti-VEGFR-2 monoclonal antibody (mAb); it inhibits angiogenesis by 
binding specifically to the extracellular domain of VEGFR-2 inhibiting binding of VEGF receptor 
ligands VEGF-A, VEGF-C, and VEGF-D. Clinical studies support the activity of ramucirumab in 
altering the tumor microenvironment; among other changes, PD-L1 expression and CD8+ T cell 
infiltration was increased with ramucirumab.[14] The relationship between tumor VEGF and PD-
1 presents a critical therapeutic opportunity to target both pathways to enhance clinical response. 

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1.3 
Pembrolizumab:  Mechanism of Action  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Pembrolizumab (Keytruda®) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades.[18]  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma.[19, 20] 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2).[21, 22] 
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade.[22-25]  The mechanism by which PD-1 down-modulates T-cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins.[26, 27]  As a consequence, the PD-1/PD-L1 pathway is an attractive target 
for therapeutic intervention in NSCLC.  
1.3.1 
Clinical Experience  
Ramucirumab and pembrolizumab both have clinical activity in NSCLC.  

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Ramucirumab is approved in combination with docetaxel for NSCLC. The phase III REVEL trial 
evaluated second line docetaxel + ramucirumab/placebo, including EGFR mutant patients (n=33, 
5%). The addition of ramucirumab improved median OS (10.5 months vs 9.1 months, p=0.023) as 
well as RR (23% vs 14%, p<0.0001) for the overall NSCLC population. [28, 29]  
Pembrolizumab, an anti-PD-1 mAb, is approved for treatment of patients with metastatic non-
mutant NSCLC both as first line and second line therapy. [30-32] In non-mutated NSCLC, 
pembrolizumab – as a single agent or with chemotherapy - is associated with response rates ≥ 
20%.[30] The use of checkpoint inhibitors in patients with EGFR mutations has been more 
nuanced. A recent phase II study of pembrolizumab in TKI-naïve EGFR mutant lung cancer was 
stopped early (only 11 patients were enrolled) due to futility.  A retrospective cohort study 
confirmed these findings; the cohort included 110 EGFR mutant patients with response rate of 
12% to ICI.[5] These results suggest low efficacy for single agent checkpoint inhibitors but do 
not exclude potential synergy of combination therapies. [20, 21]  
A recent phase I study evaluated ramucirumab (R) and pembrolizumab (P) in multiple tumor types, 
including EGFR wild type NSCLC (n=22). The primary objective of the study was to assess safety 
and tolerability of R+P (R 10 mg/kg and P 200 mg on day 1 of 21 day cycle). The study concluded 
that there were no new concerning safety signals at full doses of each mAb; it also demonstrated 
encouraging antitumor activity in previously treated EGFR wild type NSCLC (RR – 18-45% when 
stratified by PDL1).  
1.4 
Clinical Safety 
Pembrolizumab and ramucirumab are both approved by the Food and Drug Administration 
(FDA) for commercial use in NSCLC but have not been approved in combination.  Measures 
will be taken to ensure the safety of the patients participating in this trial including the use of 
stringent inclusion and exclusion criteria and close monitoring.  Toxicity grading will be 
performed in accordance with NCI CTCAE, Version 5.0.  If more than one different type of 
toxicity occurs concurrently, the most severe grade will determine the modification. 
If toxicities are encountered, adjustments will be made to the study treatment as detailed in the 
sections below.  All AEs and SAEs will be recorded during the trial and for up to 30 days after 
the last dose of study treatment or until the initiation of another anti-cancer therapy, whichever 
occurs first. 
1.5 
Phase II Single Arm Trial of Ramucirumab and Pembrolizumab in EGFR mutant 
Non-Small Cell Lung Cancer 
1.5.1 
Rationale for the Study  
Non-small cell lung cancer (NSCLC) is among the most common and most lethal cancer in the 
United States. Of these patients, approximately 15% have tumors with sensitizing EGFR driver 
mutations. Sensitizing mutations, in particular exon 19 and exon 21, are associated with first line 
response rates of > 70% with tyrosine kinase inhibitors (TKI).[3] Although these drugs are highly 
effective, responses are not durable and most patients will develop progressive disease. After first 
or second generation TKI, osimertinib is available for patients with T790M mutation. Current 
therapies after TKI are limited primarily to cytotoxic chemotherapy. Immunotherapy appears to 

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have an evolving role in this population. Single agent immunotherapy (PDL1 inhibitors) have been 
associated with low response rates in these patients. Given the synergistic activity of 
pembrolizumab (P) and ramuciramab (R) in phase 1 trials, we propose a single arm phase II trial 
of R+P in EGFR mutant NSCLC patients who have progressed on EGFR TKI. 
EGFR Mutations in NSCLC 
EGFR driver mutations are associated with sensitivity to EGFR inhibition with tyrosine kinase 
inhibitors. The first and second generation EGFR inhibitors – gefitinib, erlotinib, and afatinib – 
demonstrated dramatic improvements in response rates and progression free survival (PFS) in 
EGFR mutant patients when compared to first line chemotherapy.[2, 33-35] Despite these 
successes, patients ultimately progress. Up to 60% of patients receiving erlotinib, afatinib, or 
gefitinib develop T790M resistance mutation and can be salvaged with osimertinib, a third 
generation EGFR inhibitor.[36] The FLAURA trial then compared first line osimertinib to 
erlotinib and demonstrated a significant improvement in PFS, moving osimertinib into first line as 
the preferred agent.[4] 
When osimertinib is used in the first line setting, the mechanisms of resistance are yet to be fully 
characterized and no cases of T790M mutation were reported in the phase 1 study in nine patients 
with 
previously 
untreated EGFR mutation–positive 
advanced 
NSCLC 
who 
received 
osimertinib.[37] Some reported mechanisms in patients with T790M-positive NSCLC after 
EGFR-TKI treatment include acquired EGFR mutations (C797S), MET and HER2 amplification, 
and small-cell transformation.[38-41] Second line options after osimertinib currently include 
cytotoxic chemotherapy, immunotherapy, or chemoimmunotherapy. 
Immunotherapy in NSCLC 
Immunotherapy (IO), specifically PD/PDL1 inhibition, has emerged as an important option for 
management of NSCLC. The immune system plays a role in prevention/treatment of 
cancer through surveillance and cytotoxic killing of tumor cells. Tumor growth may occur due to 
immune dysregulation; immunotherapy by checkpoint inhibition helps restore the immune system 
to recognize, stimulate immune response and eliminate tumor cells by overcoming mechanisms 
used for immune evasion. Pembrolizumab is a selective humanized IgG4 kappa monoclonal 
antibody that inhibits the pPD-1 receptor, an integral component of immune checkpoint regulation 
in the tumor microenvironment. In lung cancer, pembrolizumab is approved for treatment of 
patients with metastatic NSCLC both as first line and second line therapy. For first line therapy, it 
is utilized either in patients with tumor PD-L1 expression ≥ 50 % as a single agent or in 
combination with chemotherapy (regardless of PD-L1 expression).[30, 31] For second line (or 
later), pembrolizumab is approved for patients with tumor PD-L1 ≥1.[32] Across these trials, 
pembrolizumab – as a single agent or with chemotherapy - is safe and effective in NSCLC with 
response rates ≥ 20%. Specifically in patients with high PD-L1 expression (≥ 50 %), response rate 
to single agent pembrolizumab is 44.8% (compared to 27.8% with chemotherapy doublet).[30] 
The use of checkpoint inhibitors in patients with EGFR mutations has been more nuanced. Many 
of the early trials either excluded EGFR mutant patients or included limited numbers of EGFR 
patients. BIRCH (phase II trial of single agent atezolizumab) included 45 EGFR mutant patients 

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who progressed or did not tolerate TKI therapy. Response rates were similar for “first line” EGFR 
mutant (compared to wild-type) but lower for patients in second/third line.[42] Two other single 
agent atezolizumab trials also included EGFR mutant patients (POPLAR and OAK).[43, 44] OAK 
included 85 EGFR mutant patients; a subgroup analysis of EGFR-mutant patients favored 
chemotherapy over atezolizumab (HR, 1.24; 95% CI, 0.21- 2.18), suggesting a lack of benefit for 
these patients.[44] The phase 3 IMpower150 trial (carboplatin, paclitaxel, bevacizumab and 
atezolizumab) also included EGFR mutant patients. As in the BIRCH trial, “first line” EGFR 
mutant patients were required to have received at least 1 TKI prior to enrollment. A total of 80 
EGFR mutant patients were included – 35 received atezolizumab, 45 received chemotherapy 
alone. There was a benefit with the addition of atezolizumab in PFS (9.7 months vs 6.1 months). 
[16] Notably, EGFR mutants have been excluded from most trials with pembrolizumab. A recent 
phase II study of pembrolizumab in TKI-naïve EGFR mutant lung cancer was stopped early (only 
11 patients were enrolled) due to futility.  These results suggest low efficacy for single agent 
checkpoint inhibitors but do not exclude potential synergy of combination therapies.  
Anti-Angiogenic Agents in NSCLC 
Anti-angiogenic agents, particularly VEGF inhibitors, have demonstrated activity in EGFR mutant 
NSCLC. Ramucirumab is a human monoclonal antibody that targets the VEGF receptor-2, an 
important key receptor implicated in angiogenesis and for tumor growth.  It inhibits angiogenesis 
by binding specifically to the extracellular domain of VEGFR-2 inhibiting binding of VEGF 
receptor ligands VEGF-A, VEGF-C, and VEGF-D. The phase III REVEL trial evaluated second 
line docetaxel + ramucirumab or placebo. It has been approved as second-line for patients with 
advanced or metastatic non-small cell lung cancer (NSCLC) in combination with docetaxel. EGFR 
mutant patients were permitted if they had received both TKI and platinum-based chemotherapy, 
although there were only 33 EGFR mutant patients on the trial (≤ 3% of overall study population). 
The addition of ramucirumab improved median OS (10.5 months vs 9.1 months, p=0.023) as well 
as RR (23% vs 14%, p<0.0001). Primary toxicities related to ramucirumab included hypertension 
and bleeding. Results were similar across histologic subgroups.[28, 29] Ramucirumab is currently 
approved as second-line therapy for patients with advanced/metastatic NSCLC in combination 
with docetaxel. 
Based on these findings of activity of anti-VEGF therapy in EGFR mutant NSCLC and  synergy 
between P+R, we propose a phase II single arm trial to evaluate the efficacy of R+P in EGFR 
mutant NSCLC patients. 
1.5.2 
Rationale for Starting Dose and Dosing Schedule 
A phase I study evaluated ramucirumab (R) plus pembrolizumab (P) in patients with multiple 
tumor types, including a NSCLC cohort (n=27). One dosing regimen was evaluated in a phase 1a 
for NSCLC: R 10 mg/kg and P 200 mg on day 1 of 21 day cycle. The primary objective of the 
study was to assess safety and tolerability of R+P. The study concluded that there were no new 
concerning safety signals; it also demonstrated encouraging antitumor activity in previously 
treated NSCLC - RR 30%, median PFS 9.7 months.[45]  
Based on this phase 1 data, our study will use the same dose and doing schedule. 

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1.5.3 
Assessment for Response  
CT scan will be used for objective tumor assessment at baseline and then at 6 week/2 cycle 
intervals. Patients who achieve stable disease, PR, or CR per RECIST v.1.1 criteria will continue 
therapy until disease progression. Immune RECIST criteria will also be assessed (Table 1). For 
patients with progressive disease by RECIST, treatment may be continued for up to 2 additional 
cycles if the primary physician feels there is clinical benefit (Figure 1). If progression is 
confirmed on second scan, treatment will be discontinued.  
1.5.4 
RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study treatment).  Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 5 
per organ, if clinically relevant to enable a broader sampling of tumor burden. 
1.5.5 
iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs.  When clinically stable, participants should not be discontinued 
until progression is confirmed by the Investigator, working with local radiology, according to the 
rules below.  This allowance to continue treatment despite initial radiologic PD takes into 
account the observation that some participants can have a transient tumor flare in the first few 
months after the start of immunotherapy, and then experience subsequent disease response. 
A description of the adaptations and iRECIST process is provided in Appendix 2, with additional 
detail in the iRECIST publication.[46]  iRECIST will be used by the Investigator to assess tumor 
response and progression, and make treatment decisions.   
Table 1: Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD 
by RECIST 1.1  
Repeat 
imaging at 4 to 
8 weeks to 
confirm PD. 
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging by 
site by iRECIST. 
Repeat 
imaging at 4 to 
8 weeks to 
confirm PD 
per 
Investigator’s 
discretion 
only. 
Discontinue 
treatment 

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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
Repeat tumor 
imaging 
confirms PD 
(iCPD) by 
iRECIST per 
Investigator 
assessment 
No additional 
imaging 
required. 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor). 
No additional 
imaging 
required. 
Not applicable 
Repeat tumor 
imaging shows 
iUPD by 
iRECIST per 
Investigator 
assessment 
Repeat 
imaging at 4 to 
8 weeks to 
confirm PD.  
May occur at 
next regularly 
scheduled 
imaging visit. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Repeat 
imaging at 4 to 
8 weeks to 
confirm PD 
per 
Investigator’s 
discretion 
only. 
Discontinue 
treatment 
Repeat tumor 
imaging shows 
iSD, iPR, or 
iCR by 
iRECIST per 
Investigator 
assessment. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
Investigator’s 
discretion.  Next 
tumor image should 
occur according to 
the regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; 
iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive 
disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1.. 
 
 
 
 

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Figure 1: Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
2. OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
To evaluate response rate of the combination of ramucirumab and pembrolizumab in 
EGFR mutant NSCLC. 
Primary Endpoint: Overall response rate (ORR): Response rate will be evaluated with 
CT scans every 2 cycles and tumor measurements using RECIST 1.1 criteria. Immune 
RECIST (iRECIST) will also be assessed (see Appendices 1 and 2 for details).  
2.2 
Secondary Objectives 
To evaluate safety, tolerability, and survival for patients receiving pembrolizumab and 
ramucirumab. 
Secondary Endpoints: Safety, tolerability, clinical benefit rate (responses + stable 
disease), progression-free and overall survival. 

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2.3 
Exploratory objectives  
To characterize predictive immunologic biomarkers of response in tissue and peripheral 
blood of patients receiving ramucirumab and pembrolizumab combination therapy  
Exploratory Endpoints: 1) Baseline tumor immunoprofile by IHC, including tumor 
infiltrating lymphocytes and T cell receptor (TCR) immunosequencing (immunoSEQ) and 
relationship to clinical outcomes, including response rate. 2)  Circulating immune cell 
profiles in response to treatment and in relation to clinical response using  CyTOF profile 
on peripheral blood samples. 3) Circulating VEGF at baseline, after treatment and at 
progression to evaluate correlation with clinical response 
 
3. INVESTIGATIONAL PLAN 
3.1 
Overview of Study Design and Dosing Regimen 
The clinical trial will be an open-label, two-stage, single arm phase II trial of ramucirumab and 
pembrolizumab in EGFR mutant NSCLC after progression on at least one EGFR TKI.  
 
Each treatment cycle will be 21 days. Patients will receive ramucirumab 10 mg/kg and 
pembrolizumab 200 mg IV on day 1. Dosing of pembrolizumab and ramucirumab is based on prior 
phase 1 testing of the combination.  
 
All trial treatments will be administered on an outpatient basis. 
 
The treatment to be used in this trial is outlined below in Table 2 
Table 2:  Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Freque
ncy 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
Ramucirumab 
10 mg/kg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
 
 
Tumor tissue will be collected at baseline. Peripheral blood samples will be collected at baseline, 
cycle 3 day 1, and at progression (or study discontinuation).  
During the treatment period, patients will undergo physical examination monthly and CT scans 
at baseline and then approximately every 6 weeks (2 cycles) thereafter. The disease status will be 
assessed per RECIST v.1.1 and iRECIST (immune RECIST) criteria (Appendices 1 and 2). 

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Patients will be treated for up to 35 cycles or until confirmed progression of disease or the 
development of unacceptable toxicities. All patients will then undergo a final visit (end of 
treatment visit). 
3.1.1 
Definition of Treatment Cycle and Duration 
Ramucirumab and pembrolizumab will be administered on day 1 of each cycle. One cycle is 
defined as 21 days. 
3.1.2 
Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.3).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. Ramucirumab will be 
administered first followed by pembrolizumab.  
Ramucirumab 10 mg/kg will be administered as an IV infusion every 3 weeks.  Administer 
initial infusion over 60 minutes; if tolerated, may administer subsequent infusions over 30 
minutes starting with cycle 2. Given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
3.1.3 
Treatment Phase  
Treatment will be continued for up to 35 cycles until confirmed progression of disease is 
demonstrated by CT scan, unacceptable toxicities occur in individual subjects, or consent is 
withdrawn.  
3.1.4 
End of Treatment Visit  
Patients that discontinue from treatment will undergo an end of treatment visit, regardless of the 
reason of discontinuation, 30 (+/- 14) days after the last dose of study medication. 
This study to be conducted at The Ohio State University Wexner Medical Center. If the protocol 
meets criteria to proceed with enrollment after initial futility analysis, we will consider expansion 
to include additional sites.    
3.2 
Study Duration 
Patients will receive pembrolizumab and ramucirumab day 1 during each 21-day cycle.  Patient 
may continue on study drugs until disease progression or for up to 35 cycles.  Objective 
assessment of disease progression will be performed every six weeks.  

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The study enrolled first patient in Summer 2020 with respect to first patient in (FPI). With an 
expected accrual rate of 1 patients every 2months, and a total number of 34 patients planned (if 
trial proceeds to second stage), the anticipated enrollment period is 60 months with the last 
patient enrolled by Summer2025. The anticipated length of treatment period will be 
approximately 3-6 months, leading to the last patient off study treatment in November-December 
2025. The primary endpoint analysis will be done after the last accrued patient has been followed 
for at least 6 weeks. 
 

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3.3 Study Schema 
Figure 2: Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Phase 
Screening Phase 
Post Treatment 
Follow-Up 
Eligibility Assessment –  
• NSCLC EGFR mutant (sensitizing mutations - exon 19 or exon 21) 
• Prior TKI therapy (first or second line, including 2nd line osimertinib 
for T790M positive patients) 
• ECOG performance status 0-1 
Treatment Plan 
Ramucirumab 10 mg/kg + Pembrolizumab 200 mg IV  
Day 1 of 21 day cycle 
Response assessment: CT scan every 2 cycles 
Progressive Disease (PD) 
May continue beyond progression if 
clinical benefit 
Confirm PD with repeat CT scan at 
least 3 weeks apart  
Discontinue therapy if PD 
confirmed on second CT scan 
Stable Disease (SD) 
 Partial Response (PR) 
 Complete Response (CR) 
Treatment will be continued for up 
to 35 cycles 
Patient follow-up by phone and/or chart review (if patient unavailable) for 
survival 

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Figure 3: Correlative Study Schedule 
 
4. PATIENT SELECTION 
This Investigator Initiated Trial will be conducted in compliance with the protocol, GCP and all 
applicable regulations.   
4.1 
Study Population and Sample Size 
This trial will be open to non-small cell lung cancer (NSCLC) patients with sensitizing EGFR 
mutations who have received first or second line therapy with tyrosine kinase inhibitor (TKI). 
These are most commonly lung adenocarcinoma but there are no restrictions for histology.  
Planned enrollment is up to 34 patients. There will be a 2 stage design with a planned interim 
analysis for futility planned after the initial 13 patients (stage 1) have been followed for at least 6 
weeks.  
4.2 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent in accordance with federal, local, and institutional guidelines 
2. Histologically confirmed recurrent or metastatic non-small cell carcinoma of the lung with 
sensitizing EGFR mutations. Exon 20 resistance mutations will not be permitted but 
uncommon sensitizing mutations are allowed. 
3. Prior Systemic Anticancer Therapy: Neo/adjuvant therapy or prior therapy for locally 
advanced disease will be permitted. Patients with prior exposure to PD/PD-L1 inhibitors 
will be excluded. No limit on prior EGFR TKIs (erlotinib, gefitinib, afatinib, dacomitinib 
or osimertinib). Patients who develop progressive disease after erlotinib, gefitinib, afatinib, 
or dacomitinib must either receive osimerintib (T790M positive) or be T790M negative. 
Prior chemotherapy for metastatic disease is permitted. A 7 day washout period or four 
half-lives after the last treatment dose, whichever is longer, is required after TKI therapy. 
A 4 week washout period is required for cytotoxic chemotherapy.  
4. Measurable disease per RECIST criteria.  

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5. ECOG performance status of 0-1. Evaluation of ECOG is to be performed within 7 days 
prior to the date of first dose of study treatment.   
6. Have adequate organ function as defined in the following table (Table 3).  Specimens must 
be collected within 10 days prior to the start of study treatment 
Table 3:  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 × ULN OR 
≥40 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Urine protein 
≤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 
protocol). 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants 
with liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or 
aPTT is within therapeutic range of 
intended use of anticoagulantsc 

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7. Because the teratogenicity of ramucirumab is not known, patients who are sexually 
active, must be either postmenopausal, surgically sterile, or using effective contraception 
(hormonal or barrier methods).  
• A male participant must agree to use a contraception as detailed in Appendix 5 of 
this protocol during the treatment period and for at least 3 months after the last 
dose of study treatment and refrain from donating sperm during this period. 
• A female participant is eligible to participate if she is not pregnant (see Appendix 
5), not breastfeeding, and at least one of the following conditions applies:  
a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5  
OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 
during the treatment period and for at least 3 months after the last dose of study 
treatment. 
8. For female patients of childbearing potential, a negative serum pregnancy test within 72 
hours prior to first dose of protocol therapy is required. 
 
4.3 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study. 
1. 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). Replacement 
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood 
cell (pRBC) transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
c Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14 
days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving 
warfarin, the patient must have an INR ≤3.0. 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). 
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and 
guidelines for the administration of specific chemotherapies. 

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2. Known active chronic infections – HIV/AIDS, known active Hepatitis B or C. Known history 
of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing 
for Hepatitis B and Hepatitis C is required unless mandated by local health authority.  
3. Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or 
clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined 
as ascites from cirrhosis requiring diuretics or paracentesis. 
4. Prior exposure to ramucirumab. 
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137). 
6. Any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy. 
7. History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are 
not considered “significant”) during the 3 months prior to first dose of protocol therapy. 
8. Patients receiving dipyridamole, clopidogrel, or similar agents.  Once-daily aspirin use 
(maximum dose 325 mg/day) is permitted.  
9. Uncontrolled CNS metastases. Patients with treated brain metastases are eligible if they were 
clinically stable with regard to neurologic function, off steroids after cranial irradiation 
(whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending 
at least 2 weeks prior to first dose of study treatment, or after surgical resection performed at 
least 28 days prior to first dose of study treatment. The patient must have no evidence of 
Grade ≥1 CNS hemorrhage based on pretreatment MRI or IV contrast CT scan (performed 
within 28 days before first dose of study treatment). Note: Patients who received systemic 
therapy that adequately and appropriately treated CNS metastases, including tyrosine kinase 
inhibitors, are eligible provided that CNS disease control is confirmed by pretreatment MRI 
within 28 days of receiving first dose of study treatment. 
10. Hemoptysis (defined as bright red blood or ≥ 1/2 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. 
11. Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg 
diastolic for >4 weeks) despite standard medical management. 
12. Any arterial thromboembolic events, including but not limited to myocardial infarction, 
transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior 
to first dose of protocol therapy. 
13. Major surgery within 28 days or device placement within 7 days prior to the first dose of 
protocol therapy.  Patient has elective or planned major surgery to be performed during the 
course of the clinical trial. 
14. Serious or non-healing wound, ulcer, or bone fracture within 28 days of study treatment.  
15. Prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or 
risk factors for perforation. 
16. Small cell or mixed (small cell/non-small cell) lung cancer 
17. Pregnancy or breastfeeding.  

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18. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of 
live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed. 
19. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 
20. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the subject’s participation for the full 
duration of the study, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
21. Known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
22. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
23. Active infection requiring systemic therapy. 
24. Known history of active TB   (Bacillus Tuberculosis).   
 
4.4 
Lifestyle Restrictions 
4.4.1.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
4.4.1.2 Contraception 
Ramuricumab and/or Pembrolizumab may have adverse effects on a fetus in utero.  Refer to 
Appendix 5 for approved methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, 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 Merck.  If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately and 
the pregnancy must be reported to Merck and followed as described in Section 7.2.2. 

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Use in Nursing Women 
It is unknown whether ramucirumab or pembrolizumab 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, participants who are breast-feeding are not eligible for enrollment. 
4.5 
Patient Removal from Study Treatment 
Patients may be removed from the study treatment at any time for the following reasons: 
• Disease progression 
• Noncompliance with study procedures 
• Need of treatment with medications not allowed by the study protocol 
• The participant  or participant’s legally acceptable representative requests to discontinue 
study treatment 
• Intercurrent illness that interferes with study assessments 
• Incidence or severity of AEs in this study indicates a potential health hazard to the patient 
(Investigator discretion) 
• Pregnancy 
• At the discretion of the treating investigator after discussion with principal investigator 
• Termination of the study by the Investigator or pharmaceutical company 
• Ramucirumab specific criteria for end of study treatment: 
o Grade 3 and 4 arterial thromboembolic events, or any PE/DVT occurring or 
worsening during anticoagulant therapy, require permanent discontinuation of 
ramucirumab therapy. 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. 
o Any patient who experiences signs of hepatic encephalopathy or other serious 
signs of liver impairment such as hepatorenal syndrome must be permanently 
discontinued from ramucirumab therapy. 
o The patient will have ramucirumab permanently discontinued if the protein level 
is >3 g/24 hours, if there is a third occurrence of >2 g/24 hours, or if the protein 
level does not return to <2 g/24 hours within 2 weeks. 
o Patients with grade 4 hypertension must not receive further treatment with 
Ramucirumab. Patients with grade 3 or 4 infusion-related reactions must not 
receive further treatment with ramucirumab. 
o Ramucirumab should be permanently discontinued in the event of a 
gastrointestinal perforation or fistula formation. 
o If Reversible Posterior Leukoencephalopathy (RPLS) is diagnosed, ramucirumab 
must be permanently discontinued. All cases of RPLS must be reported via the 
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o Completion of 35 treatments (approximately 2 years) with ramucirumab. 
• Pembrolizumab specific criteria for end of study treatment (detailed in Table 5): 
o Recurrent grade 3 toxicity 
o Recurrent Grade 2 pneumonitis 
o Grade 4 toxicity, except for endocrinopathies (as detailed in Table 5) 
o Completion of 35 treatments (approximately 2 years) with pembrolizumab 
• 
Patients who complete 35 cycles of either pembrolizumab or ramucirumab will 
discontinue study treatment but will continue to be followed for survival and toxicity 
unless the patient withdraws consent. Likewise, patients who are removed for other 
reasons listed above may still be followed for survival and toxicity unless study consent 
is withdrawn. 
5. INVESTIGATIONAL MEDICINAL PRODUCTS AND TREATMENT PLAN 
5.1 
Ramucirumab Formulation and Administration 
The 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. 
Product Name & Potency 
Dosage Form 
Ramucirumab 10 mg/1 ml 
Solution for Injection 
 
Premedication: Diphenhydramine 50 mg intravenous (IV) 30 minutes prior to infusion. 
For patients with infusion reaction (grade 1 or 2), premedication should also include 
dexamethasone 10 mg IV and acetaminophen 650 mg oral (PO). 
5.2 
Ramucirumab Storage and Stability 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
5.3 
Ramucirumab Labelling 
Supplies will be labeled in accordance with regulatory requirements. 
5.4 
Ramucirumab Dosing Information 
The planned dose of ramucirumab is 10 mg/kg IV every 3 weeks (Q3W). This is the FDA 
approved dose for non-small cell lung cancer. This is also the dose that was utilized in phase 1 
combination testing of ramucirumab and pembrolizumab.[45] 

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5.5    Pembrolizumab Formulation and Administration 
The 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. 
Pembrolizumab will be provided by Merck as summarized below. 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
5.6 
Pembrolizumab Storage and Stability 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
5.7 
Pembrolizumab Labelling 
Supplies will be labeled in accordance with regulatory requirements. 
5.8 
Pembrolizumab Dosing Information 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.   
 
As outlined below, this dose is justified by: 
• 
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• 
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 
• 
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W 
 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5 fold 
difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied.  Subsequently, flat dose-exposure-response relationships were also 

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observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols.  
5.9 
Handling – Ramucirumab and Pembrolizumab 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
5.10 Drug Product Accountability 
Study drug for the study are provided by Lilly and Merck and will be labeled as per the 
applicable regulations.  Sites must request study drug by submitting an order form directly to the 
drug depot in order for the study drug to be shipped to the site pharmacy.  The Investigator (or 
designee) will verify and acknowledge receipt of all study drug shipments by signing and 
returning all required forms.  
Study drug accountability records will be maintained at the site pharmacy and will be available 
for review by the study monitor during each monitoring visit and at the close out visit.  
All medication must be stored in a secure area under the proper storage requirements with access 
restricted to the site staff pharmacist or designee(s). 
The Investigational medicinal product should not be used for any purpose outside the scope of 
this protocol, nor can Investigational medicinal product be transferred or licensed to any party 
not participating in the clinical study. Data for Investigational medicinal product are confidential 
and proprietary and shall be maintained as such by the Investigators. 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful 
record of the inventory and disposition of unused material.  
All clinical drug supplies must be kept in an appropriate, limited access, secure place until used 
or returned to Lilly or Merck or designee for destruction. After study drug is reconciled, drug 

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may be destroyed as per Institutional Policy, or returned to Lilly or Merck respectively. The 
Investigator, or a responsible party designated by the Investigator, must maintain a careful record 
of the inventory and disposition of all agents. 
 
6. STUDY PROCEDURES  
Data will be collected via the completion of a Case Report Form (CRF) for each eligible patient. 
The investigator should confirm eligibility of the patient according to the inclusion and exclusion 
criteria of the study. All patients have to provide written Informed Consent before any study 
specific assessment is performed. A study specific assessment is defined as a procedure that is 
not part of the routine assessments performed for diagnostic purposes or standard care. Screening 
assessments should occur within 10 days of the first administration of study drug. 
Patients not meeting the eligibility criteria will not be enrolled into the study. Patients should 
receive their first dose of study treatment as soon as possible after registration, but not later than 
7 days after registration. 
6.1 
Study Assessments 
6.1.1 
Efficacy Assessments  
Primary Endpoint: The response rate of R+P will be evaluated using RECIST 1.1 as well as 
iRECIST.  Disease status will be measured by CT scan at baseline and then once every two 
cycles and as clinically indicated. Radiographic response per RECIST v.1.1 and iRECIST 
criteria (Appendices 1 and 2) will be determined by comparison to the tumor measurement 
obtained at baseline. Tumor progression will be determined by comparison to the smallest tumor 
measurement at either baseline or after initiation of therapy.  The baseline disease assessment 
must be recorded and measured within 28 days prior to treatment start. During the treatment 
period, disease assessments will be performed every 6 weeks, i.e. once every two cycles, and as 
clinically indicated.  
 
Secondary Endpoints: Safety and tolerability will be assessed with adverse event (AE) 
assessments at each study visit. CTCAE v5.0 will be used for adverse event grading. Attributions 
of causality will be assessed by the primary treating physician. Clinical benefit rate (stable 
disease + responses) will be assessed using the same criteria as response rate and on the same 
schedule. Survival will be measured from the date of study registration to the date of event (i.e., 
death or progressive disease) or the date of last follow-up if no event has occurred at their last 
evaluation. 
6.1.2 
Laboratory Assessments 
Safety blood samples include complete blood count, clinical chemistry, including liver function 
test, and coagulation. 
 

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6.1.3 
Summary Table for Specimen Collection 
Biomarker Name 
Collection Time 
Point 
Specimen and 
Quantity 
Send Specimens to: 
Baseline 
TCR 
immunoSEQ/multiplex 
IHC 
 
 
Formalin-Fixed-
Paraffin-Embedded 
(FFPE) tumor tissue 
(archival or fresh 
biopsy), 5-10 slides 
per patient  
Ohio State 
University – Carbone 
lab 
Cycle 1, Day 1 
CyTOF panel 
Pre-treatment 
Blood (1x heparin 
tubes, 10 ml) 
Ohio State 
University Carbone 
Lab/Li lab (PIIO) 
TCR immunoSEQ 
Pre-treatment 
Blood (1x heparin 
tubes, 10 mla) 
Ohio State 
University Carbone 
lab/Li lab (PIIO) 
VEGF Elisa 
Pre-treatment 
Blood (1x heparin 
tubes, 10 mla) 
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
Cycle 3, Day 1 
CyTOF panel 
Pre-treatment 
Blood ((1x heparin 
tubes, 10 ml*) 
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
TCR immunoSEQ 
Pre-treatment 
Blood (1x heparin 
tubes, 10 mla) 
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
VEGF Elisa 
Pre-treatment 
Blood (1x heparin 
tubes, 10 mla) 
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
End of Treatment or Progressive Disease 

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CyTOF panel 
 
Blood ((1x heparin 
tubes, 10 ml) 
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
TCR immunoSEQ 
 
Blood (1x heparin 
tubes, 10 mla) 
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
VEGF Elisa 
 
Blood (1x heparin 
tubes, 10 mla) 
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
TCR immunoSEQ 
Molecular 
testing/multiplex IHC 
 
Optional at 
progression 
Formalin-Fixed 
Paraffin-Embedded 
(FFPE) tumor tissue 
(archival or fresh 
biopsy), 5-10 slides 
per patient  
Ohio State 
University – Carbone 
lab/Li lab (PIIO) 
a – Same tube will be used for TCR and VEGF 
Sample Collection for translational/correlative analyses 
 
Correlative study assessments will be included:  
Tumor biopsies: Archival or fresh biopsy will be utilized. For archival tissue, we will request a 
minimum of 5 slides (FFPE). Tissue will be tested for expression of biomarkers of response 
including TCR immunoSEQ and cancer specific markers to the tumor by immunohistochemistry. 
Tumor tissue will be kept with the intention to perform tests as new techniques, research tools, 
and biomarkers become available. 
Blood (2 tubes x 10 ML): BD Vacutainer (heparin tubes) will be used for blood collection. 
Peripheral blood will be analyzed for circulating immune cell profiles in relation to clinical 
response using CyTOF profile at baseline and prior to cycle 3. Peripheral blood analysis will also 
include TCR immunosequencing (immunoSEQ) and VEGF (ELISA) at baseline, during 
treatment and at progression. 
Peripheral blood for CyTOF profile will be collected at 3 time points (baseline and cycle 2, day 1  
at progression/end of treatment) for the initial 13 patients (stage 1). If a patient discontinues 
treatment after cycle 2, EOT samples will be collected at that time.  Peripheral blood 
mononuclear cells (PBMC) and plasma for remaining correlative studies (TCR immunoSEQ and 
VEGF) will be preserved from collected blood samples at 3 time points: baseline (pre-treatment 
day 1), prior to cycle 3, and at study discontinuation or disease progression. Correlative studies 
will be collected as scheduled even if one of the two drugs is held/discontinued.  
Samples will be stored for batching of correlative studies (TCR immunoSEQ and VEGF). 

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6.2 
Data Safety and Monitoring Plan 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at 
their regular disease group meetings (at least monthly) and the discussion will be documented in 
the minutes. The PI of the trial will review toxicities and responses of the trial where applicable 
at these disease group meetings and determine if the risk/benefit ratio of the trial changes. 
Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
known about the agent/device from other sources; including published literature, scientific 
meetings and discussions with the investigators, to determine if the trial should be terminated 
before completion. Serious adverse events and responses will also be reviewed by the OSUCCC 
Data and Safety Monitoring Committee (DSMC). The PI will also submit a progress report 
(biannually for Phase II and quarterly for Phase I) that will be reviewed by the committee per the 
DSMC plan. All reportable Serious Adverse Events (SAE) will also be reported to the IRB of 
record as per the policies of the IRB. 
Throughout the treatment period until one month after the last dose of study medication, patients 
will be assessed for all adverse events. National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE v 5.0) will be used for grading. If necessary, the patient may be 
withdrawn from the study treatment.  
6.3 
Schedule of Study Events  
The Schedule of Study Events is shown in Table 4Table 4.     

 
 
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Table 4.  Schedule of Study Events 
Assessments 
Screening/ 
Baseline 
 
Cycle 1*  Cycle 1 
Cycle 2  
Cycle 
2 
Cycle 
3 + 
End of 
Treatment 
Visit window [days] 
Within 
28 days 
Within 
10 days 
Within  
7 days 
Day 1  
Day 8 
Day 1 
Day 8 
Day 1 
30 days 
 
+/- 3 
days 
 
+/- 3 
days 
± 14 days 
Informed consent1 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical History2 
 
X 
 
 
 
 
 
 
X 
Pregnancy test (if applicable)3 
 
X 
 
 
 
 
 
X 
 
Vital signs and weight5 
 
X 
 
X 
X 
X 
X 
X 
X 
Physical examination and 
ECOG 
 
 
X 
X 
X 
X 
X 
X 
X 
Urine analysis6 
 
X 
 
X 
X 
X 
X 
X 
X 
Hematology7 
 
X 
 
X 
 
 
 
X 
X 
Coagulation studies8 
 
X 
 
 
 
 
 
X7 
 
Complete Serum chemistry9 
 
X 
 
X 
X 
X 
X 
X 
X 
TSH 10 
 
X 
 
 
 
 
 
X9 
 
Peripheral blood correlative 
studies11 
 
 
 
X 
 
 
 
X11 
X 
Tumor biopsy11 
X 
 
 
 
 
 
 
 
X 
Assessment of disease 
status12 
X 
 
 
 
 
 
 
X 
X 
Ramucirumab dosing 
 
 
 
X 
 
X 
 
X 
 
Pembrolizumab dosing 
 
 
 
X 
 
X 
 
X 
 
Adverse event assessment 
 
 
 
X 
 
X 
 
X 
X 
Concomitant Medication 
 
X 
 
X 
 
X 
 
X 
X 
Study Assessment Footnotes 

 
 
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Page 27
* Each treatment cycle is 21 days 
1 Prior to the first study-specific assessments 
2 Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, 
disease progression during or after therapy, as well as discontinuations due to intolerability or any other serious illness. 
3 Applicable for women of childbearing potential. Serum β-HCG test within 14 days before the first dose of study drug.  
4 Urine pregnancy test on day 1 of cycle 1 to confirm pregnancy status prior to treatment. Repeat urine pregnancy testing for women 
of childbearing potential every 9 weeks or if pregnancy is suspected. Positive urine pregnancy testing will require confirmation with 
serum pregnancy testing. 
5 Vital signs: Weight, blood pressure, pulse and temperature 
6 Urine analysis will include appearance, color, glucose, hemoglobin, ketones, pH, and protein. Microscopy will only be performed if 
clinically indicated. Urine dipstick protein > 1+ will require 24 hour urine collection for urine protein assessment. 24 urine collection 
will include measurement of both protein and creatinine. 
7 Hematology: Complete blood count including differential is required.  WBC differential may be automated or manual as per 
institutional standards.  
8 Coagulation studies will include PT/INR and PTT. These studies will be repeated every 3rd cycle or as needed (for patients on active 
anti-coagulation). 
9 Complete Serum Chemistry includes: sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphate, 
magnesium, ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin. 
10 TSH will be performed at baseline - free T3/free T4 to be checked if TSH is out of the normal range.  
11  Correlative studies (peripheral blood) will be drawn pre-treatment on cycle 1 day 1; cycle 3 day 1, and at final study visit. Tumor 
biopsy sample (archival) will be collected at study enrollment. Optional tumor biopsy at progression if clinically indicated. 
12 Disease status will be measured by CT scan every 6 weeks (+/- 7 days) for the first 6 months and then every 12 weeks and as 
clinically indicated. Baseline imaging within 28 days of study initiation. 

 
 
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Page 28
 
6.3.1 
Screening Assessments  
All patients will be screened and screening procedures performed within 10 days (unless 
otherwise noted) prior to the start of induction treatment. These include the following:  
 
Signed written informed consent 
Obtained prior to any study specific assessments 
Inclusion/Exclusion Criteria 
(Day -28 to 1) 
 
• Age 
• Tumor diagnosis 
• Prior therapies 
• Comorbid conditions 
Demographics and Medical 
History 
• Age, gender, ethnic background 
• Previous and concurrent relevant diseases 
• Current symptoms and/ or residual toxicities from 
prior therapies 
• Details on prior cancer therapy, including start 
and stop dates, disease progression during or after 
therapy, as well as discontinuation due to 
toxicities 
Concomitant medication 
Concomitant medication currently used will be 
documented. 
Pregnancy test (if applicable)  
A serum pregnancy test will be performed in women 
of child-bearing potential: pre-menopausal women 
and women who are post-menopausal for < 2 years.  
Physical examination and vital 
signs  
(Day -7 to 1) 
• Body height and weight 
• Vital signs: Blood pressure, pulse, temperature 
• Physical examination 
• ECOG performance status (Appendix 3) 
Urine analysis  
Appearance, color, urine bilirubin, glucose, 
hemoglobin, ketones, pH, protein, specific gravity, 
urobilinogen. 
Hematology (CBC) 
 
Hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell (WBC) 
count, WBC differential, red blood cell count, 
lymphocytes, monocytes, neutrophils, band 
neutrophils, eosinophils, basophils, platelets.  WBC 
differential may be automated or manual as per 
institutional standards.  

 
 
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Page 29
Complete Serum Chemistry 
 
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, total 
protein, albumin 
Assessment of disease status (Day -
28 to 1) 
The disease status will be measured by CT scan 
(Chest/Abdomen/Pelvis). MRI brain will be done as 
clinically indicated.  
Tumor biopsy - archival 
Archival tumor biopsy material (paraffin embedded 
and formalin fixed) will be collected, if available. If 
standard of care biopsy is performed, fresh tumor 
cells will be collected for study.  
 
 
6.3.2 
Treatment Phase 
During the treatment phase the following assessments are to be performed (see Schedule of 
Study Events in Table 4 for timing of assessments in each cycle). 
Physical examination and vital 
signs 
• Body weight 
• Blood pressure, pulse, temperature 
• Physical examination (symptom directed) 
 
Urine analysis  
(every other cycle) 
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology  
Hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell (WBC) 
count, WBC differential, red blood cell count, 
lymphocytes, monocytes, neutrophils, band 
neutrophils, eosinophils, basophils, platelets.  WBC 
differential may be automated or manual as per 
institutional standards.  
Complete clinical chemistry  
 
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, 
total protein, albumin 
TSH  
If TSH is abnormal, free T3 and free T4 will also be 
measured. Repeat TSH every 3rd cycle 
 
Pregnancy test (if applicable)  
A urine pregnancy test will be performed on cycle 1 
day 1 and every 3rd cycle or if pregnancy is 
suspected in women of child-bearing potential: pre-

 
 
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Page 30
menopausal women and women who are post-
menopausal for < 2 years.  
Adverse events and concomitant 
medication 
Assessed on an ongoing basis 
 
6.3.3 
Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For the 
abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when 
CT with iodinated contrast is contraindicated, or when local practice mandates it.  MRI is the 
strongly preferred modality for imaging the brain.  The same imaging technique regarding 
modality, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new tumor 
burden and improve the accuracy of the assessment of response or progression based on imaging. 
Expedited confirmation of measurable disease based on RECIST 1.1 at Screening should be used 
to determine participant eligibility.  Confirmation that the participant’s imaging shows at least 1 
lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly recommended 
prior to participant enrollment.   
6.3.4 
Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the start of study 
treatment The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1 prior to first dose of study treatment.  
Brain imaging, if performed to document the stability of existing metastases, should be by MRI 
if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable alternative. 
 
6.3.5 
Tumor Imaging on Study 
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days]) from 
the date of allocation.  Subsequent tumor imaging should be performed every 6 weeks (42 days 
±7 days) or more frequently if clinically indicated.  After 6 months, participants who remain on 
treatment will have imaging performed every 12 weeks (84 days ±7 days).  Imaging timing 
should follow calendar days and should not be adjusted for delays in cycle starts.  Imaging 
should continue to be performed until disease progression is identified by the Investigator.  
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a response is 
observed.  Participants will then return to regular scheduled imaging every 6 weeks, starting with 
the next scheduled imaging time point.  Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point.   

 
 
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Page 31
Per iRECIST (Appendix 2), disease progression should be confirmed by the site 4 to 8 weeks 
after first radiologic evidence of PD in clinically stable participants as defined by Appendix 2 
(Note- if patient is receiving clinical benefit, oligoprogressive CNS disease that can be controlled 
with local therapy such as stereotactic radiation, may continue on treatment beyond progression 
with PI approval. Ramucirumab should be held for 2 weeks prior to radiation. Patient can have 
radiation for CNS oligoprogression as long as ramucirumab is held for 4-6 weeks afterwards. 
Ramucirumab can be restarted after this time if the patient is asymptomatic, clinically stable and 
this is considered appropriate by the investigator.).  Participants who have unconfirmed disease 
progression may continue on treatment at the discretion of the Investigator until progression is 
confirmed by the site provided they have met the conditions detailed in Section 9.2.1.6.  
Participants who receive confirmatory imaging do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent scheduled 
imaging time point, if clinically stable.  Participants who have confirmed disease progression by 
iRECIST, as assessed by the site, will discontinue study treatment.   
  
6.3.6 
End of Treatment and Follow-up Tumor Imaging 
Patients who discontinue therapy for any reason must have and end of treatment (EOT) visit 
completed 30 days (± 14 days) after the last application of study drug. 
At the EOT visit, the patients will undergo the following assessments: 
Physical examination and vital 
signs 
• Body weight 
• Blood pressure, pulse, temperature 
• Physical examination 
Urine analysis  
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology  
Hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell (WBC) 
count, WBC differential, red blood cell count, 
lymphocytes, monocytes, neutrophils, band 
neutrophils, eosinophils, basophils, platelets. WBC 
differential may be automated or manual as per 
institutional standards.  
Complete serum chemistry  
Sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, glucose, calcium, phosphate, magnesium, 
ALT, AST, alkaline phosphatase, total bilirubin, 
total protein, albumin 
Assessment of disease status 
CT scan (if not performed within the last 28 days) 
Adverse events and concomitant 
medication 
Assessed on an ongoing basis 
 

 
 
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Page 32
In participants who discontinue study treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 week window).  If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory.  In participants who discontinue study treatment due to documented disease 
progression and the Investigator elects not to implement iRECIST, this is the final required 
tumor imaging. 
In participants who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (every 12 weeks in Year 1 or every 24 weeks 
after Year 1) to monitor disease status until the start of a new anticancer treatment, disease 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
6.3.7 
Post-treatment follow-up 
Patient status will continue to be evaluated post-study. Patients will be contacted via telephone 
every 3 months for the first year after study completion. Beyond 1 year post-treatment, patients 
will be contacted every 6 months to obtain information for post-study survival data.  Patients will 
be asked to supply the name and addresses of two contact people who the site may contact to 
assist with phone follow-up. Post-study survival data may alternatively be obtained during 
patient visits to site or source documents from other medical visits.  
6.4 
End of Study 
The primary statistical analysis will be performed when 80% of the events for the secondary 
analysis of PFS have occurred.  This will ensure appropriate follow-up time for the primary 
endpoint of ORR and for the secondary endpoints of PFS and OS. 
6.5 
Planned Treatment of the Patients after End of Treatment Phase 
After completion of the study at routine follow-up (EOT), patients will generally be treated at the 
discretion of the investigator according to medical routine. 
6.6 
Removal of Patients from Treatment 
Subjects will be free to discontinue treatment or withdraw from the study at any time, for any 
reason, or they may be withdrawn/ removed if necessary in order to protect their health (see 
reasons for withdrawal below). It is understood by all concerned that an excessive rate of 
withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of subjects 
should be avoided.  
If there is a medical reason for withdrawal of treatment, the patient will remain under the 
supervision of the investigator until the AEs have been resolved or declined to baseline values. 
If a patient has failed to attend scheduled assessments in the study, the investigator must 
determine the reasons and circumstances as completely and accurately as possible.  
In case of premature discontinuation of the study treatment, the investigations scheduled for the 
EOT should be performed, if possible. The CRF section entitled “End of Treatment” must be 
completed in all cases. Should a patient decide to withdraw, every effort will be made to 
complete and report the observations as thoroughly as possible. The investigator should contact 

 
 
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Page 33
the patient to determine as completely as possible the reason for the withdrawal. A complete 
final evaluation at the time of the patient’s withdrawal should be made, with an explanation of 
why the patient is withdrawing from the study. If the reason for removal of a patient from the 
study is an adverse event or an abnormal laboratory test result, the principal specific event or test 
will be recorded on the case report form. 
6.7 
Study Discontinuation 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of decision by drug sponsor (Merck or Lilly) to no longer supply study drug, ample 
notification will be provided so that appropriate adjustments to participant treatment can be 
made. 
7. TOXICITIES, RISKS AND AE-RELATED DOSE MODIFICATIONS  
7.1 
Ramucirumab Toxicity Overview 
Ramucirumab is currently approved by the Food and Drug Administration (FDA) for 
commercial use in combination with docetaxel in non-small cell lung cancer. The combination of 
pembrolizumab with ramucirumab is investigational. The entire safety profile of the combination 
therapy is not known at this time. Measures will be taken to ensure the safety of the patients 
participating in this trial, including the use of stringent inclusion and exclusion criteria and close 
monitoring. Toxicity grading will be performed in accordance with NCI CTCAE version 5.0. If 
more than one different type of toxicity occurs concurrently, the most severe grade will 
determine the modification. 
7.1.1 
Risks Associated with Ramucirumab 
Potential risks and toxicities of ramucirumab are detailed in the manufacturer’s package insert 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s002lbl.pdf).  
7.1.2 
Dose Modification for Ramucirumab 
Infusion-Related Reactions (IRR): 
• Reduce infusion rate by 50% of grade 1 or 2 IRR. 
• Grade 1 or 2 IRR should receive pre-medication with dexamethasone and acetaminophen 
prior to subsequent infusions. 
• Grade 3 or 4 IRR: Discontinue ramucirumab. 
Hypertension 

 
 
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Page 34
• Hold ramucirumab for severe hypertension (Uncontrolled or poorly-controlled 
hypertension (>160 mmHg systolic or > 100 mmHg diastolic) until controlled with 
medical management.  
• Discontinue ramucirumab for severe hypertension (>160 mmHg systolic or > 100 mmHg 
diastolic for >4 weeks) that cannot be controlled with antihypertensive therapy. 
Proteinuria: 
• If a patient has proteinuria with 24 hour urine protein ≥ 2 g, ramucirumab should be held. 
When level returns to less than 2 g/24 hr, may resume at a reduced dose of 8 mg/kg every 
3 weeks. If level 2 g/24 hr or greater recurs, interrupt therapy again, and when level 
returns to less than 2 g/24 hr, resume at a reduced dose of 6 mg/kg every 3 weeks. 
• For nephrotic syndrome or urine protein > 3 g/24 hr, ramucirumab should be permanently 
discontinued.  
Wound Healing: 
• Hold ramucirumab prior to surgery and until the wound is fully healed.  
Indications for permanent discontinuation of Ramucirumab 
• IRR: Patients with grade 3 or 4 infusion-related reactions must not receive further treatment 
with ramucirumab. 
• Hypertension: Patients with grade 4 hypertension must not receive further treatment with 
Ramucirumab. 
• Proteinuria: The patient will have ramucirumab permanently discontinued if the protein level 
is >3 g/24 hours, if there is a third occurrence of >2 g/24 hours, or if the protein level does 
not return to <2 g/24 hours within 2 weeks. 
• Thromboembolism: Grade 3 and 4 arterial thromboembolic events, or any PE/DVT occurring 
or worsening during anticoagulant therapy, require permanent discontinuation of 
ramucirumab therapy. 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. 
• Hepatic disease: Any patient who experiences signs of hepatic encephalopathy or other 
serious signs of liver impairment such as hepatorenal syndrome must be permanently 
discontinued from ramucirumab therapy. 
• Ramucirumab should be permanently discontinued in the event of a gastrointestinal 
perforation or fistula formation. 
• If Reversible Posterior Leukoencephalopathy (RPLS) is diagnosed, ramucirumab must be 
permanently discontinued. All cases of RPLS must be reported via the SAE mechanism. 
  
For all other toxicities, ramucirumab may be held for up to 42 days. If toxicity does not improve 
to grade 1 or better within 21 days, discontinue ramucirumab.  
7.1.3 
Reproductive risks  
Because the teratogenicity of ramucirumab and pembrolizumab is not known, the patient, if 
sexually active, must be postmenopausal, surgically sterile, or using effective contraception 
(hormonal or barrier methods).  
 

 
 
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Page 35
Patients should not become pregnant or father a baby while on this study because the drugs in this 
study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  It is 
important patients understand the need to use birth control while on this study.  Female patients 
of child-bearing potential must agree to use dual methods of contraception and have a negative 
serum pregnancy test at screening (< 14 days prior to first dose) and negative urine pregnancy 
test on day 1 of study drug. Male patients must use an effective barrier method of contraception 
if sexually active with a female of child-bearing potential.  Acceptable methods of contraception 
are condoms with contraceptive foam, oral, implantable or injectable contraceptives, 
contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who 
is surgically sterilized or post-menopausal. Total (true) abstinence (when this is in line with the 
preferred and usual lifestyle of the patient), is an acceptable method of contraception.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal 
are not acceptable methods of contraception.  For both male and female patients, effective 
methods of contraception must be used throughout the study and for three months following the 
last dose. 
7.2 
Pembrolizumab Toxicity Overview 
Pembrolizumab is currently approved by the Food and Drug Administration (FDA) for 
commercial use as a single agent and in combination with cytotoxic chemotherapy for non-small 
cell lung cancer. The combination of pembrolizumab with ramucirumab is investigational. The 
entire safety profile of the combination therapy is not known at this time. Measures will be taken 
to ensure the safety of the patients participating in this trial, including the use of stringent 
inclusion and exclusion criteria and close monitoring. Toxicity grading will be performed in 
accordance with NCI CTCAE version 5.0. If more than one different type of toxicity occurs 
concurrently, the most severe grade will determine the modification. 
If toxicities are encountered, adjustments will be made to the study treatment as detailed in the 
sections below. All AEs and SAEs will be recorded during the trial and for up to 30 days after 
the last dose of study treatment or until the initiation of another anti-cancer therapy, whichever 
occurs first. 
 
7.2.1 
Risks Associated with Pembrolizumab 
Potential risks and toxicities associated with Pembrolizumab are detailed in the Investigator’s 
Brochure.  
7.2.2 
Dose Modifications for Pembrolizumab 
Pembrolizumab may be held up to 12 weeks for immune-related toxicity. If a patient has an 
immune-related toxicity that does not resolve within 12 weeks, pembrolizumab will be 
discontinued  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 

 
 
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Page 36
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided below in Table 5.   
 
7.3 
Study Drug Discontinuation 
If either ramucirumab or pembrolizumab is held or discontinued for toxicity, the remaining 
drug may be continued as maintenance therapy for up to 35 cycles or disease progression 
or unacceptable toxicity.  
 

PROTOCOL NUMBER: OSU-19132 
 
 
CONFIDENTIAL 
 
Table 5. Dose modifications and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial 
dose 
of 
1-2 
mg/kg 
prednisone or equivalent) 
followed by taper 
 
• Monitor participants for signs and symptoms of pneumonitis 
• Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid treatment 
• Add prophylactic antibiotics for opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial 
dose 
of 
1-2 
mg/kg 
prednisone or equivalent) 
followed by taper 
 
• Monitor participants for signs and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, blood or mucus in stool with or 
without fever) and of bowel perforation (ie, peritoneal signs 
and ileus). 
• Participants with ≥ Grade 2 diarrhea suspecting colitis should 
consider GI consultation and performing endoscopy to rule 
out colitis.  
• Participants with diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake 
is not feasible, fluid and electrolytes should be substituted via 
IV infusion. 
Recurrent 
Grade 3  
or 
Grade 4 
Permanently 
discontinue 

PROTOCOL NUMBER: OSU-19132 
 
 
CONFIDENTIAL 
 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial 
dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• Monitor with liver function tests (consider weekly or more 
frequently until liver enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial 
dose 
of 
1-2 
mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate 
insulin 
replacement therapy for 
participants with T1DM  
• Administer 
anti-
hyperglycemic 
in 
participants 
with 
hyperglycemia  
 
• Monitor participants for hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and 
initiate 
hormonal 
replacements as clinically 
indicated.   
 
• Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidis
m  
Grade 2 
Continue  
• Treat with non-selective 
beta-blockers 
(eg, 
propranolol) 
or 
thionamides 
as 
appropriate  
• Monitor for signs and symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 

PROTOCOL NUMBER: OSU-19132 
 
 
CONFIDENTIAL 
 
Hypothyroidis
m 
Grade 2-4 
Continue  
• Initiate 
thyroid 
replacement 
hormones 
(eg, 
levothyroxine 
or 
liothyroinine) 
per 
standard of care 
• Monitor for signs and symptoms of thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
• Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based 
on 
type 
and 
severity of AE administer 
corticosteroids  
• Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 

PROTOCOL NUMBER: OSU-19132 
 
 
CONFIDENTIAL 
 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be 
resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
Table 6. Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 

PROTOCOL NUMBER: OSU-19132 
 
 
CONFIDENTIAL 
 
NCI CTCAE 
Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for ≤24 
hrs 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held 
until symptoms resolve and the 
participant should be premedicated for 
the next scheduled dose. 
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of _____ with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive 
to symptomatic 
medication and/or 
brief interruption of 
infusion); 
recurrence of 
symptoms following 
initial improvement; 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
No subsequent dosing 

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7.3.1 
Dose modification and toxicity management of infusion-reactions related 
to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6. 
 
 
 
 
hospitalization 
indicated for other 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; 
pressor or 
ventilatory support 
indicated 
Corticosteroids 
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine 
should be used immediately. 
Participant is permanently 
discontinued from further study 
drug treatment. 
Appropriate resuscitation equipment should be available at the bedside and a physician 
readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse 
Events v5.0 (CTCAE) at http://ctep.cancer.gov 

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7.3.2 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record. 
8. SUPPORTIVE CARE GUIDELINES  
8.1 
Concomitant Medications  
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 final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participants's primary physician.  
8.2 
Permitted Concomitant Medication  
Patients will receive concomitant medications to treat symptoms, AEs and intercurrent illnesses 
that are medically necessary as standard care.  Medications to treat concomitant diseases like 
diabetes, hypertension, etc., are allowed. 
8.3 
Glucocorticoid therapy 
Glucocorticoids (≤ 20 mg oral prednisone or equivalent) per day are permitted at baseline and 
during the study for non-malignant conditions (i.e., asthma, irritable bowel disease, etc.,) as 
needed, but patients should preferably have been on a stable dose for at least two weeks before 
study entry. 
8.4 
Prohibited Medication 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs 
(NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or 
similar agents is not permitted. Once-daily aspirin use (maximum dose 325 mg/day) is 
permitted. 
• Radiation therapy  
o Note:  Radiation therapy to the brain may be allowed after consultation with the PI 
for patients receiving clinical benefit. See section 6.3.5. .  Ramucirumab therapy 
should be temporarily discontinued for 2 weeks prior to starting radiation.  However, 

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starting radiation sooner is permissible if the investigator considers that the benefits 
outweigh the risks for the patient.  Patient can have radiation for CNS 
oligoprogression as long as ramucirumab is held for 4-6 weeks afterwards. 
Ramucirumab can be restarted after this time if the patient is asymptomatic, 
clinically stable and this is considered appropriate by the investigator.  
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.  
• 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 may be approved after consultation with the Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor and 
the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
8.5 
Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.2.2 [Table 5].  Where appropriate, these guidelines include the use of oral or IV 
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 pembrolizumab.  
8.6 
Dose Adjustments for Weight 
Ramucirumab dose will be adjusted if patient has > 10% change in weight from weight used to 
calculate previous dose. No weight based dose adjustment is required for pembrolizumab. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1 
Endpoints 
9.1.1 
Primary Endpoint  
Overall response rate will be evaluated using both RECIST and iRECIST criteria. Patients will 
have repeat imaging every 6 weeks to assess response. 
9.1.2 
Secondary Endpoints 
• Safety and tolerability as measured by adverse events 
• Clinical benefit rate – CR+PR+SD 
• Survival – progression-free and overall  
9.1.3 
Exploratory Endpoints (Correlative Studies) 
To characterize predictive immunologic biomarkers of response in tissue and peripheral blood  
• T cell receptor (TCR) immunosequencing in peripheral blood (before and after treatment) 
and tumor tissue (at baseline) with clinical response. 
• CyTOF from peripheral blood and infiltrating immune cells in tissue at baseline and after 
treatment  
• Circulating VEGF in peripheral blood at baseline and after treatment with clinical response 
9.2 
Sample Size Justification   
Response rate with single agent IO is around 10% and we would consider a response rate of at 
least 25% to be interesting for further study. The optimal two-stage design to test the null 
hypothesis that P ≤ 0.10 versus the alternative that P ≥ 0.25 will include 13 patients in the first 
stage. After testing the drug on 13 patients in the first stage, the trial will be terminated if 1 or 
fewer respond. If the trial goes on to the second stage, an additional 21 patients will be included 
for a total of 34 patients studied. 
9.3 
Planned Interim Analysis 
After testing the drug on 13 patients in the first stage, the trial will be terminated if no patients 
respond. If the trial goes on to the second stage, an additional 21 patients will be included for a 
total of 34 patients studied. 
9.4 
Analysis Plan 
9.4.1 
 Primary endpoint analysis:  
The primary study objective is to assess the overall response rate (ORR) of ramucirumab plus 
pembrolizumab. To do so, we will use Simon’s two-stage design.20 This design is implemented by 
first enrolling a small group of patients and then enrolling a second group of patients in the second 
stage conditional on an adequate number of responses in the first group. Response rate with single 
agent IO is around 10% and we would consider a response rate of at least 25% to be interesting 
for further study. The optimal two-stage design to test the null hypothesis that P ≤ 0.10 versus the 
alternative that P ≥ 0.25 will include 13 patients in the first stage. After testing the drug on 13 
patients in the first stage, the trial will be terminated if 1 or fewer respond. If the trial goes on to 
the second stage, an additional 21 patients will be included for a total of 34 patients studied. If the 

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total number responding is less than or equal to 5, the drug is rejected. This design has an expected 
sample size of 20.95 and a probability of early termination of 0.621.The sample size was calculated 
using PASS 16 and assuming α = 0.10 with a desired power of 80%.  
Overall survival and progression-free survival as continuous time-to-event outcomes: All 
evaluable patients will be used for this analysis.  Kaplan-Meier curves will be used to estimate 
overall survival, measured from the date of study registration to the date of event (i.e., death) or 
the date of last follow-up if no event has occurred at their last evaluation. We will further 
consider Cox proportional hazards models to explore a limited set of confounding factors. 
 
9.4.2 
Analysis of secondary endpoints:  
Secondary objectives involve evaluating safety and tolerability and estimating PFS and overall 
survival. Descriptive statistics will be calculated for these outcomes and Kaplan-Meier curves will 
be calculated to estimate PFS and OS. Patients who have reached the end of the study but not 
progressed will be considered censored at the last documented date of contact. Estimates from this 
analysis will be used as preliminary data to inform future research. 
Overall response. All evaluable patients (i.e. eligible patients who have received at least one dose 
of the treatment) will be assessed in terms of their best response to therapy. Those who achieve a 
partial response (PR) or complete response (CR) will be considered responses and the overall 
response rate will be calculated as the number of PRs and CRs divided by the total number of 
evaluable patients. We will also perform analysis of disease control rate (CR + PR + SD). These 
estimates will be accompanied by exact binomial confidence intervals as well.  
 
Safety and Tolerability. Frequency and severity of adverse events and tolerability of the regimen 
will be collected and summarized by descriptive statistics for each of the disease cohorts.  As per 
NCI CTCAE v 5.0, the term toxicity is defined as adverse events that are classified as either 
possibly, probably, or definitely related to study treatments. The maximum grade for each type 
of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine 
toxicity patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and 
classified as either “unrelated” or “unlikely to be related” to study treatment in the event of an 
actual relationship developing. The incidence of severe (grade 3+) adverse events or toxicities 
will be described. We will also assess tolerability of the regimens through assessing the number 
of patients who required dose modifications and/or dose delays. In addition, we will also capture 
the proportion of patients who go off treatment due to adverse reactions or even those who refuse 
further treatment for lesser toxicities that inhibit their willingness to continue participation on the 
trial. All patients who have received at least one dose of the therapeutic agent in this study will 
be evaluable for toxicity and tolerability. This is detailed in Table 7. 
 
 

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Table 7: Evaluating Adverse Events 
V5.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of 
investigational product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate 
risk of death from the event as it occurred (Note: This does not include an adverse event that, 
had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s 
ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as 
an inpatient admission, regardless of length of stay, even if the hospitalization is a 
precautionary measure for continued observation. (Note: Hospitalization for an elective 
procedure to treat a pre-existing condition that has not worsened is not a serious adverse 
event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of the 
investigational products and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product 
regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH 
definition, is reportable to the Sponsor within 24 hours, to Merck within 2 working days and 
to Lilly within 15 days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an 
overdose is considered a serious adverse event for collection purposes. An overdose that is 
not associated with an adverse event is considered a non-serious event of clinical interest and 
must be reported within 24 hours to the Sponsor and to Merck within 2 working days and to 
Lilly within 15 days. 
 
Other important medical events that may not result in death, not be life threatening, or not 
require hospitalization may be considered a serious adverse event when, based upon 

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appropriate medical judgment, the event may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed previously (designated 
above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the 
appropriate length of time and units 
Action taken  
Did the adverse event cause investigational agent to be discontinued? 
Relationship 
to 
Investigational 
Product  
Did investigational agent cause the adverse event? The determination of the likelihood that 
investigational agent caused the adverse event will be provided by an investigator who is a 
qualified physician. The investigator’s signed/dated initials on the source document or 
worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the test drug and 
the adverse event based upon the available information. 
The following components are to be used to assess the relationship between 
investigational agent and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely investigational agent caused 
the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to investigational 
agent such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of 
investigational agent?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to 
trials with investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors 
 
9.5 
Analysis of Exploratory Endpoints - Correlative studies:  
Several correlative markers will be explored in this trial in relation to clinical outcomes of 
interest, and in particular in relation to the primary endpoint of response rate. Statistical analysis 
corresponding to the correlative studies will be descriptive and exploratory in nature.  
For immune cell subpopulation data by flow cytometry, we will identify differences between the 
paired PBMC samples from the same patients.  TCR immunoSEQ data will be summarized for 
each patient for T-cell clonality difference, descriptive statistics and confidence interval will be 
obtained across patients. 

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 To study the association of immune cell subpopulations among blood and the tumor 
microenvironment, we will use linear mixed-effects models for repeated measurements within 
patients. A bivariate plot will be used to describe the relationship between response rate and peak 
VEGF via ELISA over time. Results will be summarized using descriptive statistics (i.e. means, 
medians, standard deviations, 95% confidence intervals for continuous variables, and frequencies 
for discrete data). The limited sample will not provide sufficient power for formal hypothesis 
testing (except to detect very large differences in these markers), but the preliminary data will be 
used to explore potential relationships and differences using graphical analyses and quantitative 
summaries of these markers. These results and exploratory analyses will also be used in planning 
a future randomized study of this combination treatment regimen in this patient population. 
10. DATA MANAGEMENT 
10.1 Clinical Data 
A Research Study Manager will be assigned to the study. The responsibilities of the RSA include 
project compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, 
problem resolution and prioritization, and coordinate the activities of the protocol study team and 
coordination with the study statistician. The data collected for this study will be entered into a 
secure database (Clinical Research Database (CRDB). Source documentation will be available to 
support the computerized patient record. The principal investigator will maintain ultimate 
responsibility for the clinical trial. 
10.2 Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action.  Random-sample data quality and protocol 
compliance audits will be conducted by the study team, at a minimum of two times per year, 
more frequently if indicated. 
11. PROTECTION OF HUMAN SUBJECTS 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side effects. 
Alternative, non-protocol, treatment options will be discussed with the patient. It will be 
reviewed that participation in this clinical trial is voluntary and that the patient may withdraw 
consent at any time. The study is designed with careful safety monitoring for toxicity including 
physician visits and serial cardiac monitoring. Specific guidelines for symptom management are 
in place to protect the study participant.  
11.1 Human Subjects Involvement and Characteristics:  
All patients who meet the all of the inclusion and none of the exclusion criteria will be eligible. 
Eligible patients will be 18 years of age or older with a ECOG performance status ≤ 1 and a 
diagnosis of EGFR mutant NSCLC. Both men and women and members of all ethnic groups are 
eligible for this trial. Pregnant and breast-feeding women are excluded from this study. This 

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protocol does not include children because the number of children is expected to be limited for 
the patient population expected to be accrued onto this study. Also, the majority of children are 
already accessed by a nationwide pediatric cancer research network. This statement is based on 
exclusion 4b of the NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects. 
11.2 Consent process:  
All patients at the OSU Thoracic Oncology clinic who meet the inclusion criteria will be eligible. 
Participation in the trial is voluntary. All patients will be required to sign a statement of informed 
consent, which must conform to IRB guidelines.  
11.3 Possible Toxicities/Side-Effects:  
There are risks associated with treatment as described in Section 7; however, patients screened 
for enrollment will be deemed appropriate for treatment independent of this study.  
11.3.1 
Benefits 
It is unknown if the combination of ramucirumab and pembrolizumab can benefit patients with 
EGFR mutant lung cancers. The goal of this study is to assess if combination therapy has the 
potential to demonstrate objective response in patients with lung cancer.   
11.3.2 
Costs 
Patients will be charged for physician visits, routine laboratory tests, and radiologic studies 
required for monitoring their condition.  
The cost of research only biopsies, research related testing/screening, study drugs, as well as 
correlative analyses will be covered by research funds.   
11.3.3 
Alternatives  
For patients considering this trial as second or third-line therapy or beyond, standard 
chemotherapy or chemo-immunotherapy may be treatment alternatives.  
11.3.4 
Confidentiality  
Every effort will be made to maintain patient confidentiality. Research and hospital records are 
confidential. Patients’ names and any other identifying information will not be used in reports or 
publications resulting from this study. Other authorized agencies and appropriate internal 
personnel (eg. qualified monitors) and external personnel (e.g. qualified monitors from Lilly or 
Merck), its authorized agents, the FDA, and/or other governmental agencies) may review patient 
records as required.  
11.3.5 
Patient safety 
Patients are monitored by physicians and oncology nurses who are very familiar with clinical 
trials. In the case of an adverse reaction, immediate medical attention is available. In the 
evenings and weekends, we have a 24-hour urgent care facility for outpatients. The PI or co-PI 
will also be available at all times to organize any necessary intervention.  

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11.3.6 
Monitoring of data to ensure safety 
This study is to be monitored by the institutional IRB and Ohio State University Comprehensive 
Cancer Center Data and Safety Monitoring Committee (DSMC). This incorporates an 
independent data and safety monitoring board established by arrangement with the National 
Cancer Institute. The analysis of safety will include all patients. Adverse events, including all 
toxic effects of treatment, will be tabulated individually, and summarized by severity and 
causality.  
11.3.7 
Privacy  
The use and disclosure of protected health information pursuant to a completed and signed 
Research Authorization form may be allowed. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A 
Research Authorization form must be completed by the Principal Investigator and approved by 
the IRB and Privacy Board (IRB/PB).  
12. INFORMED CONSENT 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available that 
may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent form 
or addendum to the original consent form that captures the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
 
13. REPORTING REQUIREMENTS 
13.1 Adverse Drug Reaction Reporting 
Toxicity will be scored using CTCAE Version 5.0 for toxicity and adverse event reporting.  A 
copy of the CTC Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  All appropriate treatment areas have access to a copy of the CTC 
Version 4.0.  

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13.2 Serious Adverse Event Reporting (SAE)  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that had it occurred in 
a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB within 10 days of the investigator’s or research staff member’s learning of 
the event. Events resulting in temporary or permanent interruption of study activities by the 
investigator, sponsor, or DSMB to avoid potential harm to subjects should be reported within 48 
hours. Events that may represent unanticipated problems involving risks to subjects or others 
should be promptly reported, regardless of whether they occur during or after the study, or 
involve a subject who has withdrawn from or completed study participation.  If changes to the 
research or consent process are proposed as a result of the event, or if additional information will 
be provided to current and/or past participants, an amendment request must also be submitted for 
IRB review 
Serious adverse events will be captured from the time the patient signs consent until 30 days 
after the last dose of drug. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
The following detailed information must be recorded for each serious adverse event in the SAE 
report form: 
• A description of the AE in medical terms  
• The severity grade as assessed by the investigator according to the definitions in NCI- 
CTCAE Version 5.0 

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• The date of becoming serious and the date of becoming known (if different) 
• The reason for seriousness 
• The outcome of the SAE at the time of the report 
• Information on administration of the study drug and chemotherapy and any action taken 
• Information on any treatment procedures necessary for the SAE, concomitant medications, 
relevant lab tests and relevant medical history 
If in any one subject the same SAE occurs on several occasions, then the SAE in question must 
be documented and assessed anew each time. 
The investigator is required to submit SAE Follow-up reports until the SAE has resolved or 
stabilized and all queries have been answered. 
 
13.3 Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the Investigator according to 21 CFR 
312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the Investigator’s guidelines, and Institutional Review Board policy. 
13.4 Reporting to the Drug Provider (Lilly) 
Responsibilities of the Principal Investigator and Institution also include: 
 
• to comply with applicable laws, regulations and standards regarding Investigator’s and 
Institution’s obligations, as the sponsor of the Study, to collect and report adverse events 
to regulatory authorities, IRBs, Ethics Committees or other third parties.  In addition to 
the obligations set forth below, Investigator and Institution agree to provide Lilly with a 
copy of all information Investigator and/or Institution submit to regulators related to any 
adverse events for the Study Drug that occur during the Study that Investigator and/or 
Institution have not otherwise provided Lilly; 
 
• to notify Lilly, sub-investigators, and the IRB of any problems involving risk to Study 
patients and report new safety information to IRBs in accordance with applicable 
requirements; 
 
• to notify Lilly within fifteen (15) business days of Investigator and/or Institution receiving 
notification of any “serious” and/or “unexpected” adverse event experienced by a patient 
participating in the Study and receiving Study Drug that is possibly related, based on 
Investigator’s assessment, to the Study Drug.  For purposes of this requirement, “serious” 
means:  (1) death; (2) in-patient hospitalization or prolonged hospitalization; (3) life-
threatening; (4) persistent or significant disability or incapacity; (5) congenital anomaly or 
birth defect; or (6) other serious events that may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other five listed outcomes.  Serious 
adverse events should be reported to Lilly using a CIOMS Form or other form acceptable 
to Lilly.  Investigator and Institution further agree to make available promptly to Lilly such 

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records as may be necessary and pertinent for Lilly to further investigate an adverse event 
in the Study that is possibly associated with the Study Drug; 
  
Lilly Adverse Event Reporting:  
• 
Local fax number: 866-644-1697 
Local telephone number:  317-453-3402 
 
13.5 Reporting to the Drug Provider (Merck) 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal. 
 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed but 
before treatment allocation/randomization must be reported by the investigator if the participant 
is receiving placebo run-in or other run-in treatment, if the event cause the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure.  
 
• All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator.  
• All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 

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study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator.  
• All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 
days following cessation of study treatment if the participant initiates new anticancer 
therapy must be reported by the investigator.  
• Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately by the investigator if the 
event is considered to be drug-related. 
 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study treatment or study participation, the investigator must 
promptly notify Merck. 
 
13.5.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215-661-6229) 
 
13.5.2 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if they cause 
the participant to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment 
or a procedure.   

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Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.  All reported pregnancies 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 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
13.5.3 
Immediate Reporting of Adverse Events to the Sponsor and to Merck 
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
investigational product that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is another important medical event  
• 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose. 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety if it causes the participant to 
be excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to the Merck product, 
must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to Merck Global Safety. 

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All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
 
13.5.4 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must be 
reported within 2 working days to Merck Global Safety if it causes the participant to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 2 working days to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 13.5.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit 
of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
 
13.6 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
 
 

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14. REFERENCES  
 
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16. 
Socinski, M.A., et al., Atezolizumab for First-Line Treatment of Metastatic Nonsquamous 
NSCLC. N Engl J Med, 2018. 378(24): p. 2288-2301. 
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lymphodepleting chemotherapy for the treatment of patients with refractory metastatic 
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Hunder, N.N., et al., Treatment of metastatic melanoma with autologous CD4+ T cells 
against NY-ESO-1. N Engl J Med, 2008. 358(25): p. 2698-703. 
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Chemnitz, J.M., et al., SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based 
switch motif of programmed death 1 upon primary human T cell stimulation, but only 
receptor ligation prevents T cell activation. J Immunol, 2004. 173(2): p. 945-54. 
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Sheppard, K.A., et al., PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett, 2004. 
574(1-3): p. 37-41. 
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Riley, J.L., PD-1 signaling in primary T cells. Immunol Rev, 2009. 229(1): p. 114-25. 
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Parry, R.V., et al., CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol, 2005. 25(21): p. 9543-53. 
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Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev, 2010. 236: p. 219-42. 
28. 
Garon, E.B., et al., Ramucirumab plus docetaxel versus placebo plus docetaxel for 
second-line treatment of stage IV non-small-cell lung cancer after disease progression on 
platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. 
Lancet, 2014. 384(9944): p. 665-73. 
29. 
Paz-Ares, L.G., et al., Treatment outcomes by histology in REVEL: A randomized phase 
III trial of Ramucirumab plus docetaxel for advanced non-small cell lung cancer. Lung 
Cancer, 2017. 112: p. 126-133. 
30. 
Reck, M., et al., Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-
Cell Lung Cancer. N Engl J Med, 2016. 375(19): p. 1823-1833. 
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Gandhi, L., et al., Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung 
Cancer. N Engl J Med, 2018. 
32. 
Garon, E.B., et al., Pembrolizumab for the treatment of non-small-cell lung cancer. N 
Engl J Med, 2015. 372(21): p. 2018-28. 
33. 
Wu, Y.L., et al., First-line erlotinib versus gemcitabine/cisplatin in patients with 
advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase 
III, randomized, open-label, ENSURE study. Ann Oncol, 2015. 26(9): p. 1883-9. 
34. 
Sequist, L.V., et al., First-line gefitinib in patients with advanced non-small-cell lung 
cancer harboring somatic EGFR mutations. J Clin Oncol, 2008. 26(15): p. 2442-9. 

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35. 
Sequist, L.V., et al., Phase III study of afatinib or cisplatin plus pemetrexed in patients 
with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol, 2013. 31(27): 
p. 3327-34. 
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Yu, H.A., et al., Analysis of tumor specimens at the time of acquired resistance to EGFR-
TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res, 2013. 
19(8): p. 2240-7. 
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Ramalingam, S.S., et al., Osimertinib As First-Line Treatment of EGFR Mutation-
Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol, 2018. 36(9): p. 841-849. 
38. 
Thress, K.S., et al., Acquired EGFR C797S mutation mediates resistance to AZD9291 in 
non-small cell lung cancer harboring EGFR T790M. Nat Med, 2015. 21(6): p. 560-2. 
39. 
Chen, K., et al., Novel Mutations on EGFR Leu792 Potentially Correlate to Acquired 
Resistance to Osimertinib in Advanced NSCLC. J Thorac Oncol, 2017. 12(6): p. e65-e68. 
40. 
Kim, T.M., et al., Mechanisms of Acquired Resistance to AZD9291: A Mutation-
Selective, Irreversible EGFR Inhibitor. J Thorac Oncol, 2015. 10(12): p. 1736-44. 
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Planchard, D., et al., EGFR-independent mechanisms of acquired resistance to AZD9291 
in EGFR T790M-positive NSCLC patients. Ann Oncol, 2015. 26(10): p. 2073-8. 
42. 
Peters, S., et al., Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for 
Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung 
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Fehrenbacher, L., et al., Atezolizumab versus docetaxel for patients with previously 
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Rittmeyer, A., et al., Atezolizumab versus docetaxel in patients with previously treated 
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45. 
Herbst, R.S., et al., A phase 1 study of ramucirumab (R) plus pembrolizumab (P) in 
patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) 
adenocarcinoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC): 
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Seymour, L., et al., iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol, 2017. 18(3): p. e143-e152. 
 
 
 

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APPENDIX 1 
 RECIST 1.1 CRITERIA  
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (eg, discontinuation 
of study treatment).  Although RECIST 1.1 references a maximum of 5 target lesions in total and 
2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if 
clinically relevant to enable a broader sampling of tumor burden. All patients will have their BEST 
RESPONSE on study classified as outlined below: 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) 
must have reduction in the short axis to <10mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline 
sum LD. 
Stable Disease (SD) 
Steady state of disease.  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of measured lesions taking as references the 
smallest sum of diameters recorded since the treatment started.  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  Appearance of one 
or more new lesions will also constitute progressive disease.  
Response Duration 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded since the treatment started. 
Stable Disease Duration 
Stable disease duration will be measured from the time of start of therapy until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment 
started. 

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APPENDIX 2: DESCRIPTION OF THE IRECIST PROCESS FOR ASSESSMENT OF 
DISEASE PROGRESSION 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
(using iRECIST for participant management (see Table 1 and Figure 1).  This decision by the 
Investigator should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of 
iUPD, regardless of which factors caused the progression. 

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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 
5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for 
target lesions at baseline.  All other new lesions will be followed qualitatively as New Lesions – 
Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared 
to a prior iUPD time point; this does not have to meet the “unequivocal” standard of 
RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time 
point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The 

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assessment of the subsequent confirmation scan proceeds in an identical manner, with possible 
outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”.  This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule.  If PD is confirmed, participants will be discontinued from study treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment 
may be considered.  In this case, if study treatment is continued, tumor imaging should continue 
to be performed following the intervals as outlined above. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression.  The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD. 

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o If non-target lesions had shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any significant further growth of non-target lesions, 
taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion 
sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression 
must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in 
one respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the 
burden of new lesions has increased from its smallest value (for new target lesions, their sum of 
diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication.[46] 
 

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APPENDIX 3: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE ASSESSMENT 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-
disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically 
strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory and capable of all 
self-care, but unable to carry out any work activities.  Up 
and about more than 50% of waking hr. 
3 
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hr. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of 
the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-
655 
 
 
 

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APPENDIX 4: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.0 
(CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 

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APPENDIX 5: CONTRACEPTIVE GUIDANCE AND PREGNANCY TESTING 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame:  
• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
• Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per 
year when having penile-vaginal intercourse with a woman of childbearing potential who is 
not currently pregnant. 
o Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration. 
 
Female participants: 
 

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Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 8 
during the protocol-defined time frame.  
 
Table 8 
: Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
• Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
• Oral  
• Intravaginal  
• Transdermal  
• Injectable 
Progestogen-only hormonal contraception b, c 
• Oral  
• Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
• Progestogen- only contraceptive implant b, c  
• Intrauterine hormone-releasing system (IUS) b  
• Intrauterine device (IUD) 
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
  Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently 
and correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 3 months after the last dose of study treatment. 

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c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points specified 
in the Schedule of Activities, and as required locally. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
 

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