Clinical trial NCT03689855
Conditions: Non-small Cell Lung Cancer Non Small Cell Lung Cancer NSCLC
Sponsor: Washington University School of Medicine
Start date: 2019-06-05; Completion date: 2024-04-22
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Data suggests that combining ramucirumab with immunotherapy in non-small cell lung cancer (NSCLC) patients who have previously received immune checkpoint blockers (ICBs) may be more effective than traditional therapy. The investigators propose a pilot study to test the combination of ramucirumab and atezolizumab in patients with advanced-stage NSCLC patients previously treated with ICB.

Detailed description:

Arms: arm 1: * Ramucirumab will be given intravenously over the course of an hour on an outpatient basis on Day 1 of each 21-day cycle at a dose of 10 mg/kg.
* Atezolizumab will be given intravenously on an outpatient basis on Day 1 of each 21-day cycle at a dose of 1200 mg.
Interventions: intervention 1: Ramucirumab intervention 2: Atezolizumab intervention 3: Peripheral blood draw intervention 4: Biopsy
Intervention descriptions: intervention 1: Ramucirumab is an investigational agent for this trial and will be supplied by Lilly Oncology, free of charge to the patient. intervention 2: The initial dose will be administered over 60 minutes (+/- 15 minutes). If the first infusion is tolerated without infusion-associated events, the second infusion may be delivered over 30 minutes (+/- 10 minutes). intervention 3: -Baseline and Cycle 2 Day 1 intervention 4: * If archival biopsy tissue not available, participant will undergo biopsy at baseline
* When feasible, a repeated tumor biopsy will be obtained between Cycles 2 and 3 after the scheduled CT scan.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Ramucirumab and atezolizumab after progression on any immune checkpoint blocker in 
NSCLC (RamAtezo-1) 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201810163 
Version Date: 04/27/20 
 
Principal Investigator: 
Daniel Morgensztern, M.D. 
Phone:  (314) 747-7948 
E-mail:  danielmorgensztern@wustl.edu  
 
Sub-Investigators 
 
 
 
 
Modality 
Brett Herzog, M.D., Ph.D. 
 
 
 
Medical Oncology 
Maria Baggstrom, M.D. 
 
 
 
Medical Oncology 
Siddhartha Devarakonda, M.D. 
 
 
Medical Oncology 
Ramaswamy Govindan, M.D. 
 
 
Medical Oncology 
Peter Oppelt, M.D. 
 
 
 
 
Medical Oncology 
Timothy Rearden, M.D. 
 
 
 
Medical Oncology 
Caron Rigden, M.D.  
 
 
 
Medical Oncology 
Anna Roshal, M.D. 
 
 
 
 
Medical Oncology 
Saiama Waqar, MBBS 
 
 
 
Medical Oncology 
Jeff Ward, M.D., Ph.D. 
 
 
 
Medical Oncology 
Feng Gao, Ph.D. 
 
 
 
 
Biostatistics 
 
 
Study Drug(s): 
 
Ramucirumab (Cyramza) 
Atezolizumab (Tecentriq) 
 
IND #: 
141458 EXEMPT 
ClinicalTrials.gov #: 
NCT03689855 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 


Page 2 of 41 
 
Ramucirumab and atezolizumab after progression on any immune checkpoint blocker in 
NSCLC (RamAtezo-1) 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
09/20/18 
Amendment #1 Version 
 
 
 
 
 
 
12/26/18 
Amendment #2 Version 
 
 
 
 
 
 
06/07/19 
Amendment #3 Version 
 
 
 
 
 
 
04/27/20 
 
 
 


Page 3 of 41 
 
Ramucirumab and atezolizumab after progression on any immune checkpoint blocker in 
NSCLC (RamAtezo-1) 
 
SCHEMA 
  


Page 4 of 41 
 
Table of Contents 
SCHEMA ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ....................................................................... 6 
1.1 
Non-Small Cell Lung Cancer (NSCLC) .............................................................. 6 
1.2 
Atezolizumab ...................................................................................................... 6 
1.3 
Ramucirumab ..................................................................................................... 6 
1.4 
Rationale ............................................................................................................ 7 
1.5 
Correlative Studies Background ......................................................................... 7 
1.6 
Amendment #3 Study Continuation .................................................................... 8 
2.0 
OBJECTIVES ........................................................................................................ 9 
2.1 
Primary Objective ............................................................................................... 9 
2.2 
Secondary Objectives ........................................................................................ 9 
2.3 
Exploratory Objectives ....................................................................................... 9 
3.0 
PATIENT SELECTION .......................................................................................... 9 
3.1 
Inclusion Criteria ................................................................................................ 9 
3.2 
Exclusion Criteria ............................................................................................. 11 
3.3 
Inclusion of Women and Minorities .................................................................. 13 
4.0 
REGISTRATION PROCEDURES ....................................................................... 13 
4.1 
Confirmation of Patient Eligibility ...................................................................... 13 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ............ 14 
4.3 
Assignment of UPN .......................................................................................... 14 
5.0 
TREATMENT PLAN ............................................................................................ 14 
5.1 
Agent Administration ........................................................................................ 14 
5.2 
Toxicity and Response Evaluations ................................................................. 14 
5.3 
General Concomitant Medication and Supportive Care Guidelines ................. 14 
5.4 
Women of Childbearing Potential ..................................................................... 16 
5.5 
Duration of Therapy ......................................................................................... 16 
5.6 
Duration of Follow-up ....................................................................................... 17 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ........................................................... 17 
6.1 
Dose Modifications for Ramucirumab .............................................................. 17 
6.2 
Dose Modifications for Atezolizumab ............................................................... 18 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ....................................... 20 
7.1 
Definitions .......................................................... Error! Bookmark not defined. 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University ................................................................................................................... 20 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) 
at Washington University ........................................................................................... 20 
7.4 
Reporting to Eli Lilly ......................................................................................... 21 
7.5 
Timeframe for Reporting Required Events ....................................................... 21 
8.0 
PHARMACEUTICAL INFORMATION ................................................................. 21 
8.1 
Ramucirumab (Cyramza) ................................................................................. 21 
8.2 
Atezolizumab (Tecentriq) ................................................................................. 23 
9.0 
CORRELATIVE STUDIES ................................................................................... 24 
9.1 
Peripheral Blood ............................................................................................... 24 
9.2 
Biopsy Samples ............................................................................................... 24 
9.3 
Processing and Storage ................................................................................... 24 


Page 5 of 41 
 
10.0 STUDY CALENDAR ............................................................................................ 25 
11.0 DATA SUBMISSION SCHEDULE ....................................................................... 25 
12.0 MEASUREMENT OF EFFECT ............................................................................ 26 
12.1 Antitumor Effect – Solid Tumors ....................................................................... 26 
12.2 Disease Parameters ......................................................................................... 26 
12.3 Methods for Evaluation of Measurable Disease ............................................... 27 
12.4 Response Criteria ............................................................................................ 29 
13.0 DATA AND SAFETY MONITORING ................................................................... 32 
14.0 STATISTICAL CONSIDERATIONS .................................................................... 32 
14.1 Objectives and Endpoints ................................................................................ 32 
14.2 Study Design .................................................................................................... 33 
14.3 Data Analysis ................................................................................................... 33 
15.0 REFERENCES .................................................................................................... 34 
APPENDIX A: ECOG Performance Status Scale .......................................................... 37 
APPENDIX B: Definition for Adverse Event Reporting ......................................................  
APPENDIX C: Reporting Timelines ...................................................................................  
 
 
 


Page 6 of 41 
 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Non-Small Cell Lung Cancer (NSCLC) 
 
Lung cancer remains the leading cause of cancer-related death, with an estimated 1.6 
million deaths per year 1. In the United States, the American Cancer Society estimates that 
there will be approximately 250,000 new cases of lung cancer and 158,000 deaths in 2018 
2. Approximately 85% of patients with lung cancer have a group of histological subtypes, 
collectively known as non-small cell lung cancer (NSCLC) 3. The majority of patients with 
NSCLC present with stage IV disease due to distant metastases or malignant pleural 
effusion and are treated with palliative intent 4. Even among patients undergoing surgery 
with curative intent, a high percentage of tumors recur, with 5-year overall survival (OS) 
ranging from 83% in stage IA to 36% in stage IIIA 5. Patients with metastatic NSCLC and 
no targetable oncogenic alterations usually have a poor prognosis, with low responses to 
the initial platinum-based chemotherapy and virtually universal relapse 6.  Immune 
checkpoint blockers (ICBs) have revolutionized the treatment of NSCLC, with the three 
approved drugs (nivolumab, pembrolizumab and atezolizumab) being more effective than 
docetaxel in randomized clinical trials 7-10.  Nevertheless, the benefit is restricted to a small 
percentage of patients, with objective response rates of less than 20% and median 
progression-free survival (PFS) ranging from 2.3 to 3.9 months.  
 
1.2 
Atezolizumab 
 
Under normal physiologic conditions, the immune checkpoint molecules maintain self-
tolerance preventing autoimmunity and limiting collateral damage to the normal tissues 
during response to infections 11,12. Cancer cells however, may co-opt these molecules to 
evade immune destruction. Programmed death 1 (PD-1), one of the key checkpoint 
molecules, may bind to two ligands, PD-L1/PD-L2. PD-L1 is an extracellular protein that 
downregulates immune responses primarily in peripheral tissues through binding to its two 
receptors PD-1 and B7.1. PD-1 is an inhibitory receptor expressed on T cells following T-
cell activation, which is sustained in states of chronic stimulation such as in chronic 
infection or cancer 13,14. Binding of PD-L1 with PD-1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of T 
cells. B7.1 is a molecule expressed on antigen-presenting cells and activated T cells. PD-
L1 binding to B7.1 on T cells and antigen-presenting cells can mediate downregulation of 
immune responses, including inhibition of T-cell activation and cytokine production 15,16. 
Overexpression of PD-L1 on tumor cells and the tumor microenvironment has been 
reported to prevent anti-tumor immunity, resulting in immune evasion 17. Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumor-specific T-cell immunity. Atezolizumab is a humanized IgG1 monoclonal antibody 
against PD-L1 18. Direct targeting of PD-L1 leaves the PD-L2-PD-1 interaction intact, 
potentially avoiding effects on immune homoeostasis. Atezolizumab is approved in the 
United States metastatic NSCLC that has progressed during or following treatment with a 
platinum-containing regimen. 
 
1.3 
Ramucirumab 


Page 7 of 41 
 
 
Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated 
signaling and angiogenesis contribute to the pathogenesis of lung cancer. In patients with 
lung cancer, circulating VEGF levels are associated with increased tumor aggressiveness 
and reduced survival 19. Furthermore, high levels of VEGF in preclinical models reduced 
the T cell progenitors in the thymus 20, and exposure to VEGF led to decreased number, 
activity and cytotoxic activity of T cells ex vivo in a VEGFR-2 dependent mechanism 21. 
Blocking VEGF receptor-mediated signaling abrogated VEGF’s suppressive effects on T-
cells in preclinical models and VEGFR-2 inhibition reduced tumor growth in lung 
adenocarcinoma animal studies 22,23. Ramucirumab, a human IgG1 monoclonal antibody 
against VEGFR-2, prevents ligand binding and receptor-mediated pathway activation in 
endothelial cells and is currently indicated for the treatment of multiple malignancies 
including gastric and gastric-esophageal adenocarcinomas progressing after platinum-
containing therapy and in combination with docetaxel in metastatic NSCLC with disease 
progression on or after platinum-based chemotherapy 24. Ramucirumab in combination 
with docetaxel has demonstrated improved response rates and PFS in NSCLC patients 
compared to docetaxel alone 25. In early phase studies, ramucirumab in combination with 
ICBs has shown promising results in ICB-naïve patients 26. 
 
1.4 
Rationale 
 
Although ICBs have changed advanced NSCLC treatment, only a small percentage achieve 
a sustained benefit. Furthermore, efficacy from additional therapy is limited 27. While the 
lack of response to ICBs is likely multifactorial, an important factor in achieving a response 
with anti-PD-1/PD-L1 blockade is the presence of T cells entering the tumor to kill the 
tumor cells once their defense is removed. Unfortunately, tumors often inhibit T-cell 
trafficking to the tumor via vascular endothelial growth factor (VEGF)-mediated down-
regulation of important adhesion molecules on tumor-associated blood vessels and failure 
to respond to ICBs has been associated with decreased tumor-infiltrating immune cells 28 
29. Inhibition of VEGF-VEGFR-2 signaling results in increased T-cell invasion into the 
tumor 28,30,31, and preclinical models have demonstrated a synergistic effect of blocking 
both tumor-associated immunosuppression and angiogenesis 30,32,33.  Furthermore, 
inhibition of VEGF receptor mediated signaling decreased PD-1 expression on cytotoxic 
T-cells, suggesting that inhibition of this pathway may enhance T-cell function in the tumor 
microenvironment 34. Indeed, use of immunotherapy and anti-angiogenesis therapy in 
melanoma also increased CD8+ T-cell infiltration in tumors 31. Together, this data suggests 
that combining ramucirumab with immunotherapy in NSCLC patients who have 
previously received ICBs may be more effective than traditional therapy. We propose a 
pilot study to test the combination of ramucirumab and atezolizumab in patients with 
advanced-stage NSCLC patients previously treated with ICB. 
 
1.5 
Correlative Studies Background 
 
Despite the widespread use of PD-1/PD-L1 antagonists for patients with NSCLC, the exact 
molecular mechanisms that mediate disease response remain poorly understood 35.  It is 
clear that PD-1-directed therapies induce proliferation and increase the functional activity 


Page 8 of 41 
 
of CD8+ T-cells in the periphery of patients 36-38, but despite this, the majority of patients 
will not derive meaningful benefit from this class of agents, and responses are often not 
durable.  Blunting tumor angiogenesis in order to remodel the tumor microenvironment is 
an attractive combinatorial approach to synergize with standard immunoncology agents 39.  
Increased VEGF expression is known to suppress the maturation of antigen-presenting 
dendritic cells and inhibit lymphocyte tracking into tumor tissues, which can limit the 
effectiveness of an antitumor adaptive immune response 40.  We hypothesize that the 
addition of ramucirumab will augment the clinical activity of atezolizumab, and in order 
to evaluate the exact mechanism of action of the combination, we propose a comprehensive 
analysis of paired peripheral blood samples collected longitudinally during this study.  We 
will evaluate whether the combination of atezolizumab and ramucirumab (a) alters 
populations of circulating monocytes and myeloid derived suppressor cells, (b) increases 
the number and affects the phenotype of circulating NK cells, effector CD8+ and effector 
CD4+ T-cell subsets, (c) results in the generation of durable populations of memory CD8+ 
and CD4+ T-cells and (d) alters the ratio of circulating regulatory T-cells to effector CD8+ 
cells.  We will utilize mass cytometry (CyTOF) for these analyses, a high dimensional 
technique that allows the assessment of ~40 individual markers using metal labeled 
antibodies to enable deep profiling of selected phenotypic and functional makers on 
individual cells as well as unique statistical analyses to simplify the interpretation of 
complex relationships of large numbers of cells 41-43.  We will collect and cryopreserve 
peripheral blood mononuclear cells prior to combination atezolizumab/ramucirumab 
therapy and again at the time of first radiographic assessment. Analyses will be completed 
in a batched fashion using an established mass cytometry panel at the The Andrew M. and 
Jane M. Bursky Center for Human Immunology & Immunotherapy Programs (CHiiPs) at 
Washington University School of Medicine at the conclusion of study procedures to 
correlate immune profiles with clinical response. Patients will also undergo repeated 
biopsy to evaluate the differences in immune cell infiltrates between baseline and after two 
cycles of treatment.   
 
1.6 
Amendment #3 Study Continuation 
 
1.6.1 Synopsis 
 
The primary objective of the RamAtezo trial is to determine the overall response 
rate for the combination of ramucirumab and atezolizumab in patients with NSCLC 
previously treated with immune checkpoint blocker. This is an unmet need where 
there are few treatment options for patients after tumor progression on immune 
checkpoint blockers, particularly when used in combination with platinum-based 
doublet in the first-line setting. 
  
The study design uses a Simon’s two-stager MiniMax design where 12 patients are 
enrolled into the stage I. In case of one or more responses, the study will accrue 9 
more patients, with a total of 4 responders indicating the preliminary evidence of 
efficacy.  
  


Page 9 of 41 
 
Although there were no responses among the initial 12 patients, 8 patients had 
tumor reduction from baseline, including patient reaching 27% reduction, only 3% 
below the threshold for the RECIST criteria for response. Furthermore, the 
treatment has been well tolerated and 3 out of the 12 patients (25%) are still on 
treatment with progression-free survival higher than 6 months.  
  
Therefore, we believe that the study should continue with the accrual of the 
additional 9 patients with the primary endpoint remaining the overall response rate. 
In this case, the Minimax design will be replaced by a simple enrollment of 21 
patients. 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the overall response rate (ORR) for the combination of ramucirumab and 
atezolizumab in patients with NSCLC who have previously received an ICB. 
 
2.2 
Secondary Objectives 
 
1. To determine the overall survival (OS) for the combination of ramucirumab and 
atezolizumab in patients with NSCLC who have previously received an ICB. 
2. To determine the progression-free survival (PFS) for the combination of ramucirumab 
and atezolizumab in patients with NSCLC who have previously received an ICB.  
3. To determine clinical benefit rate (CBR) for the combination of ramucirumab and 
atezolizumab in patients with NSCLC who have previously received an ICB.  CBR is 
defined as the percentage of patients who have achieved responses or stable disease.  
4. To evaluate toxicity and tolerability of this combination as measured by NCI-CTCAE 
version 5.0. 
 
2.3 
Exploratory Objectives 
 
1. To explore the relationship of the immunophenotype of peripheral blood immune cells 
and response to combined therapy. 
2. To explore the changes in tumor immune cell infiltrate after treatment and relationship 
with response.  
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed squamous or non-squamous non-small cell 
lung cancer.  Patients with known EGFR or ALK mutations are eligible only if they 
have received at least one line of targeted therapy for these mutations. 
 


Page 10 of 41 
 
2. Availability of archival biopsy tissue or willingness to undergo a “baseline” biopsy 
prior to initiation of the trial for biomarker analysis, including PD-L1 by IHC.   
 
Note: Results of PD-L1 testing are not required for enrollment.  
 
3. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by 
chest x-ray, or ≥ 10 mm with calipers by clinical exam. 
 
4. Prior use of an immune checkpoint blocker alone or in combination therapy. 
 
5. At least 18 years of age. 
 
6. ECOG performance status ≤ 1 (see Appendix A) 
 
7. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500 /cumm 
b. Platelets ≥ 100,000 /cumm 
c. Hemoglobin ≥ 9.0 g/dL 
d. Total bilirubin ≤ 1.5 x ULN 
e. AST(SGOT)/ALT(SGPT) ≤ 3.0 x ULN or 5.0 x ULN in the setting of liver 
metastasis 
f. Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min. if serum creatinine is >1.5 
times the ULN, a 24-hour urine collection to calculate creatinine clearance must be 
performed 
 
8. Adequate coagulation function as defined by: 
a. INR ≤ 1.5 
b. PTT/aPTT < 1.5 x ULN 
 
Note: 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). 
 
9. Urinary protein ≤ 1+ on dipstick or routine urinalysis; if urine dipstick or routine 
analysis is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1 g of protein 
in 24 hours to allow participation 
 
10. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she must inform her treating physician 
immediately. 


Page 11 of 41 
 
 
11. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Treatment with cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-
tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1.  
 
Note: Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea or premedication for 
contrast dye allergy) are eligible. The use of inhaled corticosteroids for chronic 
obstructive pulmonary disease (COPD) and mineralocorticoids (e.g., fludrocortisone) 
for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
 
2. A history of other malignancy ≤ 3 years previous with the exception of patients with a 
negligible risk of metastasis or death and with expected curative outcome (such as 
adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, 
localized prostate cancer treated surgically with curative intent, or ductal carcinoma in 
situ treated surgically with curative intent) or undergoing active surveillance per SOC 
management (e.g., Rai Stage 0 chronic lymphocytic leukemia, prostate cancer with 
Gleason score ≤ 6 and prostate-specific antigen (PSA ≤ 10 ng/mL, etc.). 
 
3. Currently receiving any other investigational agents. 
 
4. Symptomatic or untreated asymptomatic brain metastases. Patients with treated brain 
metastases are eligible if they are 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 randomization, 
or after surgical resection performed at least 28 days prior to randomization.  The 
patient may have no evidence of Grade ≥1 CNS hemorrhage based on pretreatment 
MRI or IV contrast CT scan (performed within 21 days before randomization).  
 
5. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to atezolizumab, ramucirumab, any other immune checkpoint blockade, 
chimeric or humanized antibodies, fusion proteins, or other agents used in the study. 
 
6. Receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), 
dipyridamole or clopidogrel, or similar agents.  Once-daily aspirin use (maximum dose 
325 mg/day) is permitted. 
 
7. Arterial or venous thromboembolic event, including but not limited to myocardial 
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,  
within 6 months prior to enrollment. 
 


Page 12 of 41 
 
8. Uncontrolled or poorly controlled hypertension (> 160 mmHg systolic or > 100 mmHg 
diastolic for > 4 weeks) despite standard medical management. 
 
9. Gastrointestinal perforation, and/or fistula, or risk factors for perforation within 6 
months prior to enrollment.  
 
10. Grade 3 or 4 gastrointestinal bleeding within 3 months prior to enrollment. 
 
11. History of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune 
thyroid disease, vasculitis, or glomerulonephritis. 
 
Note: Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible. Patients with controlled type 1 diabetes mellitus on 
a stable insulin regimen are eligible. 
 
12. History of idiopathic pulmonary fibrosis, pneumonitis (including drug-induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.  
 
13. Hemoptysis (defined as bright red blood or ≥ ½ teaspoon) within 2 months prior to 
Cycle 1 Day 1 or with radiographic evidence of intratumor cavitation or radiologically 
documented evidence of major blood vessel invasion or encasement by cancer. 
 
14. Serious or non-healing would, ulcer, or bone fracture within 28 days prior to Cycle 1 
Day 1. 
 
15. Undergone major surgery within 28 days prior to Cycle 1 Day 1, or minor 
surgery/subcutaneous venous access device placement within 7 days prior to Cycle 1 
Day 1, or has elective or planned major surgery to be performed during the course of 
the clinical trial. 
 
16. Known clinically significant liver disease, including cirrhosis at a level of Child-Pugh 
B or worse, cirrhosis (any degree) with a history of hepatic encephalopathy or clinically 
meaningful ascites resulting from cirrhosis (defined as ascites from cirrhosis requiring 
diuretics or paracentesis), fatty liver, and inherited liver disease.  
 
17. Active hepatitis B virus (HBV) or hepatitis C virus (HCV)  infection (defined as, HBV 
surface antigen (HBsAg) positive and HBV core antibody (HbcAb) positive with reflex 
positive HBV DNA. Note: Patients with past or resolved hepatitis B infection (defined 
as having a negative HBsAg test and a positive HBcAb test or treated HCV with 
negative HCV RNA are eligible. 
 
18. Active tuberculosis. 


Page 13 of 41 
 
 
19. Administration of a live, attenuated influenza vaccine within 4 weeks before Cycle 1 
Day 1 or at any time during the study.  
 
20. Severe infections within 2 weeks prior to Cycle 1 Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1 Day 1. 
Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible.  
 
21. History of deep venous thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous 
thrombosis are not considered “significant”) during the 3 months prior to Cycle 1 Day 
1. 
 
22. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
serum pregnancy test within 7 days of study entry. 
 
23. Known HIV-positivity. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 


Page 14 of 41 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Ramucirumab will be given intravenously over the course of an hour on an outpatient basis 
on Day 1 of each 21-day cycle at a dose of 10 mg/kg. 
 
Atezolizumab will be given intravenously on an outpatient basis on Day 1 of each 21-day 
cycle at a dose of 1200 mg.  The initial dose will be administered over 60 minutes (+/- 15 
minutes).  If the first infusion is tolerated without infusion-associated events, the second 
infusion may be delivered over 30 minutes (+/- 10 minutes). 
 
Ramucirumab and atezolizumab may be given in any order on treatment days. 
 
5.2 
Toxicity and Response Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of Cycle 2 and have not had any disease assessment. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1 Ramucirumab 
 
Patients may not be receiving chronic antiplatelet therapy, including aspirin, 
nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, 
and others), dipyridamole or clopidogrel, or similar agents.  Once-daily aspirin use 
(maximum dose 325 mg/day) is permitted. 
 
Patients who experience infusion-associated symptoms may be treated 
symptomatically with diphenhydramine, and/or cimetidine or another H2 receptor 
antagonist, as per standard practice (for sites outside the United States, equivalent 
medications may be substituted per local practice). 


Page 15 of 41 
 
 
In the event of additional reaction, systemic hydrocortisone or another 
corticosteroid may be administered at the discretion of the treating physician. 
 
Montelukast will be administered daily for 7 days, starting 6 days prior to treatment 
with the final dose on Day 7, per the treating physician’s discretion. 
 
5.3.2 Atezolizumab 
 
Concomitant therapy includes any prescription medications or over the counter 
preparations used by a patient between the 7 days preceding the screening 
evaluation and the treatment discontinuation visit. 
 
Patients who experience infusion-associated symptoms may be treated 
symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or 
cimetidine or another H2 receptor antagonist, as per standard practice (for sites 
outside the United States, equivalent medications may be substituted per local 
practice). Serious infusion associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated (e.g., 
supplemental oxygen and β2-adrenergic agonists). 
 
Systemic corticosteroids and TNFα inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician. If feasible, alternatives to corticosteroids should 
be considered. Premedication may be administered for Cycles ≥2 at the discretion 
of the treating physician. The use of inhaled corticosteroids and mineralocorticoids 
(e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed. Megestrol administered as appetite stimulant is acceptable 
while the patient is enrolled in the study.  
 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic 
or therapeutic anticoagulation therapy (such as low-molecular-weight heparin or 
warfarin at a stable dose level), or other allowed maintenance therapy should 
continue their use. Females of reproductive potential should use highly effective 
means of contraception. 
 
It is strongly recommended that:  
• Traditional herbal medicines not be administered because the ingredients of 
many herbal medicines are not fully studied and their use may result in 
unanticipated drug-drug interactions that may cause, or confound 
assessment of, toxicity. 
• The use of a RANKL inhibitor (denosumab) be discontinued during the 
study; this agent could potentially alter the activity and the safety of 
atezolizumab. 
 


Page 16 of 41 
 
Patients are not allowed to receive immunostimulatory agents, including, but not 
limited to, IFN-α, IFN-γ, or IL-2, during the entire study. These agents, in 
combination with atezolizumab, could potentially increase the risk for autoimmune 
conditions. 
 
Patients should also not be receiving immunosuppressive medications, including, 
but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide. 
These agents could potentially alter the activity and the safety of atezolizumab. 
Systemic corticosteroids and anti-TNFα agents may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician. If feasible, alternatives to these agents should 
be considered. 
 
In addition, all patients (including those who discontinue the study early) should 
not receive other immunostimulatory agents for 10 weeks after the last dose of 
atezolizumab. 
 
5.4 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative serum pregnancy test within 7 days prior to the first day of study treatment.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 6 months following the last day of study treatment.  
 
If a patient is suspected to be pregnant, both study drugs should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 6 months after the last day of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.5 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 


Page 17 of 41 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.6 
Duration of Follow-up 
 
Patients will be followed every 3 months for 2 years or until death, whichever occurs first. 
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications for Ramucirumab  
 
Treatment modifications for toxicities not listed below will be made at the discretion of the 
PI. Treatment may be held for a maximum of 6 weeks before a patient must be removed 
from study treatment.  Patients who discontinue ramucirumab must come off study but may 
continue to receive atezolizumab as standard of care. 
 
6.1.1 Infusion-Related Reactions  
 
Reduce the infusion rate of ramucirumab by 50% for grade 1 or 2 infusion-related 
reactions. Permanently discontinue ramucirumab for grade 3 or 4 infusion-related 
reactions.  
 
6.1.2 Hypertension  
 
Interrupt ramucirumab for grade 3 hypertension until controlled with medical 
management. Permanently discontinue ramucirumab for severe hypertension that 
cannot be controlled with antihypertensive therapy or any grade 4 hypertension.  
 
6.1.3 Proteinuria  
 
Interrupt ramucirumab for urine protein levels ≥ 2 g/24 hours. Reinitiate treatment 


Page 18 of 41 
 
at a reduced dose once the urine protein level returns to < 2 g/24 hours. If the protein 
level ≥ 2 g/24 hours reoccurs, interrupt ramucirumab and reduce the dose again 
once the urine protein level returns to < 2 g/24 hours. Permanently, discontinue 
ramucirumab for urine protein level > 3 g/24 hours, if there is a third occurrence of 
> 2 g/24 hours, if the protein level does not return to < 2 g/24 hours within 2 weeks, 
or in the setting of nephrotic syndrome. 
 
6.1.4 Venous and Arterial Thromboembolic Events, Gastrointestinal 
Perforation, Fistula, or Grade 3 or 4 Bleeding  
 
Ramucirumab should be permanently discontinued in the event of a gastrointestinal 
perforation or fistula formation.  
 
Patients with who develop grade 3 or 4 venous thromboembolism may receive 
anticoagulation and continue ramucirumab therapy provided that the tumor does 
not confer an excessive bleeding risk, in the opinion of the patient’s physician.  
 
Grade 3 or 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 SAE 
mechanism.  
 
6.1.5 Hepatic Encephalopathy or Other Serious Signs of Liver Impairment  
 
For grade 2 liver test elevations, hold ramucirumab.  Permanently discontinue 
ramucirumab for grade 3 or 4 liver test elevations or other signs of serious liver 
impairment. Signs of serious liver impairment include hepatorenal syndrome or 
other signs as determined by the treating physician.  
 
6.1.6 Reversible Posterior Leukoencephalopathy Syndrome  
 
If RPLS is diagnosed, ramucirumab must be permanently discontinued. All cases 
of RPLS must be reported via the SAE mechanism. 
 
6.1.7 Other Non-Hematologic Adverse Events 
 
If any other grade 3 non-hematologic adverse event occurs, hold the dose of 
ramucirumab and consult with the PI. 
 
If any other grade 4 non-hematologic adverse event occurs, discontinue treatment 
with ramucirumab. 
 
6.2 
Dose Modifications for Atezolizumab 
 
Atezolizumab dose reduction is not allowed. However, study treatment may be temporarily 


Page 19 of 41 
 
suspended in patients experiencing toxicity considered to be related to study treatment for 
up to 60 days after the last dose if they experience toxicity that require a dose to be 
withheld. If atezolizumab is withheld because of toxicity for > 60 days after the last dose, 
then the patient will be discontinued from atezolizumab treatment and will be followed for 
safety and efficacy.  
 
Recommendations for dosage modifications are provided in the table below: 
 
Adverse Reaction 
Severity (by 
CTCAE Grade) 
Dosage Modifications 
Pneumonitis 
2 
Withhold dose until grade 1 or resolved 
and corticosteroid dose ≤ 10 mg/day (or 
equivalent) 
3 or 4 
Permanently discontinue 
Hepatitis 
AST or ALT 3-5 
x ULN or total 
bilirubin 1.5-3 x 
ULN 
Withhold dose until grade 1 or resolved 
and corticosteroid dose ≤ 10 mg/day (or 
equivalent) 
AST or ALT > 5 
x ULN or total 
bilirubin > 3 x 
ULN 
Permanently discontinue 
Colitis or diarrhea 
2 or 3 
Withhold dose until grade 1 or resolved 
and corticosteroid dose ≤ 10 mg/day (or 
equivalent) 
4 
Permanently discontinue 
Endocrinopathies 
(including but not 
limited to hypophysitis, 
adrenal insufficiency, 
hyperthyroidism, and 
type 1 diabetes 
mellitus) 
2, 3, or 4 
Withhold dose until grade 1 or resolved 
and clinically stable on hormone 
replacement therapy 
Other immune-
mediated adverse 
reactions involving a 
major organ 
3 
Withhold dose until grade 1 or resolved 
and corticosteroid dose ≤ 10 mg/day (or 
equivalent) 
4 
Permanently discontinue 
Infections 
3 or 4 
Withhold dose until grade 1 or resolved 
Infusion-related 
reactions 
1 or 2 
Interrupt or slow the rate of infusion 
3 or 4 
Permanently discontinue 
Persistent grade 2 or 3 
adverse reaction 
(excluding 
endocrinopathies) 
2 or 3 that does 
not recover to 0 
or 1 within 60 
days after last 
dose 
Permanently discontinue 
Inability to taper 
Inability to 
Permanently discontinue 


Page 20 of 41 
 
corticosteroid 
reduce to ≤ 10 
mg/day (or 
equivalent) 
within 60 days 
after last dose 
Recurrent grade 3 or 4 
adverse reaction 
Recurrent grade 
3 or 4 
Permanently discontinue 
 
Dose interruptions for reasons other than toxicity (e.g., surgical procedures) may be 
allowed, with PI approval. The PI will determine the acceptable length of interruption.  
 
Patients who discontinue atezolizumab must come off study. 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix B for definitions and Appendix C for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through 30 days after the last administration 
of study drug.  All adverse events must be recorded on the toxicity tracking case report form (CRF) 
with the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
• Laboratory adverse events that are not clinically significant 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
7.1 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
Reporting will be conducted in accordance with Washington University IRB Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the change. 
   
7.2 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI (or designee) is required to notify the QASMC of any unanticipated problems 
involving risks to participants or others occurring at WU or any BJH or SLCH institution 
that have been reported to and acknowledged by HRPO.  (Unanticipated problems reported 
to HRPO and withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
qasmc@wustl.edu.  Submission to QASMC must include the myIRB form and any 
supporting documentation sent with the form. 


Page 21 of 41 
 
 
7.3 
Reporting to Eli Lilly 
 
Eli Lilly must be notified within 24 hours 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 
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. 
 
All instances of reversible posterior leukoencephalopathy must be reported to Eli Lilly via 
the SAE mechanism. 
Any venous or arterial event leading to discontinuation of ramucirumab therapy will be 
considered serious and should be reported to Eli Lilly via the SAE mechanism 
 
7.4 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Ramucirumab (Cyramza) 
 
8.1.1 Ramucirumab Description 
 
Ramucirumab is a recombinant human IgG1 monoclonal antibody that specifically 
binds to vascular endothelial growth factor receptor 2. Ramucirumab has an 
approximate molecular weight of 147 kDa. Ramucirumab is produced in 
genetically engineered mammalian NS0 cells. 
 
8.1.2 Clinical Pharmacology 
 
Ramucirumab is a vascular endothelial growth factor receptor 2 antagonist that 
specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-


Page 22 of 41 
 
A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated 
activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, 
and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in 
an in vivo animal model. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetic (PK) characteristics of ramucirumab are similar for patients 
with gastric cancer, NSCLC, and mCRC based on a population PK analysis. The 
mean (% coefficient of variation [CV%]) clearance for ramucirumab was 0.015 
L/hour (30%) and the mean terminal half-life was 14 days (20%). 
 
8.1.4 Supplier 
  
Ramucirumab is an investigational agent for this trial and will be supplied by 
Lilly Oncology, free of charge to the patient. 
 
8.1.5 Dosage Form and Preparation 
 
Ramucirumab is available in two dose strengths: 
• 100 mg/10 mL (10 mg per mL) solution, single dose vial 
• 500 mg/50 mL (10 mg per mL) solution, single dose vial 
 
8.1.6 Storage and Stability 
 
Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep the 
vial in the outer carton in order to protect from light. 
 
8.1.7 Administration 
 
Calculate the dose and the required volume of ramucirumab needed to prepare the 
infusion solution. Vials contain either 100 mg/10 mL or 500 mg/50 mL at a 
concentration of 10 mg/mL solution of ramucirumab.  
 
Withdraw the required volume of ramucirumab and further dilute with only 0.9% 
Sodium Chloride Injection in an intravenous infusion container to a final volume 
of 250 mL. Do not use dextrose containing solutions.  
 
Gently invert the container to ensure adequate mixing.  
 
DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other 
solutions or co-infuse with other electrolytes or medications.  
 
Store diluted infusion for no more than 24 hours at 2°C to 8°C (36°F to 46°F) or 4 
hours at room temperature (below 25°C [77°F]).  
 


Page 23 of 41 
 
Discard vial with any unused portion of ramucirumab.  
 
Visually inspect the diluted solution for particulate matter and discoloration prior 
to administration. If particulate matter or discolorations are identified, discard the 
solution.  
 
Administer diluted ramucirumab infusion via infusion pump over 60 minutes 
through a separate infusion line. Use of a protein sparing 0.22 micron filter is 
recommended. Flush the line with sterile sodium chloride (0.9%) solution for 
injection at the end of the infusion.  
 
8.2 
Atezolizumab (Tecentriq) 
 
8.2.1 Description 
 
Atezolizumab is a human monoclonal antibody based on a human IgG1 framework 
containing heavy chain VHIII and light chain VκI subgroup sequences. The 
recombinant antibody consists of two heavy chains (448 amino acid residues each) 
and two light chains (214 amino acid residues each) with inter- and intra-chain 
disulfide bonds that are typical of IgG1 antibodies. Atezolizumab incorporates an 
amino acid substitution (asparagine to alanine) at position 298 in the CH2 domain 
of each heavy chain resulting in a non-glycosylated antibody that has minimal 
binding to Fcγ receptors and, consequently, prevents Fc-effector function and 
depletion of cells expressing PD-L1 at expected concentrations in humans. 
Therefore, atezolizumab lacks the N-linked oligosaccharides typically observed on 
other CHO-derived monoclonal antibodies. 
 
8.2.2 Pharmacokinetics and Drug Metabolism 
 
On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab 
appeared to show linear pharmacokinetics at doses ≥ 1 mg/kg. For the 1-mg/kg and 
20-mg/kg dose groups, the mean apparent CL and the mean Vss had a range of 3.20 
to 4.44 mL/day/kg and 48.1 to 65.7 mL/kg, respectively, which is consistent with 
the expected profile of an IgG1 antibody in humans. 
 
8.2.3 Supplier(s) 
 
Atezolizumab will be commercially available. 
 
8.2.4 Dosage Form and Preparation 
 
The atezolizumab drug product is provided in the following configurations: 
(1) The atezolizumab drug product produced using the Phase I manufacturing 
process is provided in a single-use, 2-cc USP/Ph. Eur. Type 1 glass vial as 
a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. The vial is designed to deliver 1.2 mL (150 


Page 24 of 41 
 
mg) of atezolizumab solution but may contain more than the stated volume 
to enable delivery of the entire 1.2 mL volume. The atezolizumab drug 
product is formulated as 125 mg/mL atezolizumab in 20 mM histidine 
acetate, 240 mM sucrose, 0.02% polysorbate 20, pH 5.5 (Phase I 
formulation). 
 
(2) The atezolizumab drug product produced using the Phase III manufacturing 
process is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 glass vial as 
a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. The vial is designed to deliver 20 mL (1200 
mg) of atezolizumab solution but may contain more than the stated volume 
to enable delivery of the entire 20 mL volume. The atezolizumab drug 
product is formulated as 60 mg/mL atezolizumab in 20 mM histidine 
acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8 (Phase III 
formulation). 
 
8.2.5 Storage and Stability 
 
Atezolizumab must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt until use. 
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer. No preservative is used in atezolizumab drug product; therefore, the 
vial is intended for single use only. Discard any unused portion of drug left in a 
vial. Vial contents should not be frozen or shaken and should be protected from 
direct sunlight. 
 
8.2.6 Administration 
 
Atezolizumab will be given intravenously at a dose of 1200 mg.  
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Peripheral Blood 
 
Patients will have up to 40 mL of blood collected in 4 pink top EDTA tubes at baseline and 
Cycle 2 Day 1. Patients with hemoglobin below 10 mg/dL will only have 30 mL. 3 EDTA 
tubes collected.  
 
9.2 
Biopsy Samples 
 
When available, archival biopsy tissue will be used for a baseline biopsy. If baseline tissue 
is not available, the patient will undergo a baseline biopsy prior to initiation of the trial. 
 
When feasible, a repeated tumor biopsy will be obtained between Cycles 2 and 3 after the 
scheduled CT scan. 
 
9.3 
Processing and Storage 


Page 25 of 41 
 
 
Tissue samples will be sent to Siteman Cancer Center Tissue Procurement Core (TPC) 
and processed according to TPC standard operating procedures. Biospecimens will be 
cryopreserved and stored for future analysis. 
 
10.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted within 2 weeks prior to start of protocol 
therapy.  Scans and x-rays must be done no more than 4 weeks prior to the start of the protocol 
therapy.  Cycles are 21 days long.  There is a +/- 3 day window for all assessments and procedures. 
 
 
 
Screening 
Baseline 
C1
D1 
C2
D1 
After 
Cycle 2 
D1 of 
subsequent 
cycles 
End of 
every 2 
cycles 
EOT 
F/U3 
Informed consent 
X 
 
 
 
 
 
 
 
 
H&P, ECOG PS 
X 
 
 
X 
 
X 
 
X 
 
CBC 
X 
 
X 
X 
 
X 
 
 
 
CMP 
X 
 
X 
X 
 
X 
 
 
 
PTT/aPTT, INR 
X 
 
 
 
 
 
 
 
 
TSH6 
X 
 
X 
 
 
 
 
 
 
Hepatitis B and 
C test 
X 
 
 
 
 
 
 
 
 
Pregnancy test1 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
X 
 
X 
 
 
 
CT scan 
X 
 
 
 
 
 
X 
 
 
Ramucirumab 
 
 
X 
X 
 
X 
 
 
 
Atezolizumab 
 
 
X 
X 
 
X 
 
 
 
Research blood 
 
X 
 
X 
 
 
 
 
 
Archival tumor 
X5 
 
 
 
 
 
 
 
Fresh biopsy 
X5 
 
 
X4 
 
 
 
 
Survival 
 
 
 
 
 
 
 
X 
AE assessment 
 
X --------------------------------------------------------------------------- X2 
1. For women of childbearing potential only 
2. For 30 days after end of treatment 
3. Every 3 months for 2 years; may be done by phone. 
4. When feasible, the biopsy will follow CT scan performed between Cycles 2 and 3 
5. When available, archival biopsy tissue will be used for a baseline biopsy. If baseline tissue is not available, the patient 
will undergo a baseline biopsy prior to initiation of the trial. 
6. Reflex to free T3, free T4. 
 
 
 
 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 


Page 26 of 41 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Concomitant Medications Form Continuous.  See Section 7.0 for reporting requirements 
Research Tissue Form 
Baseline, after Cycle 2/before Cycle 3 
Research Blood Form 
Baseline, C2D1 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 3 months for 2 years 
Death Form 
Time of death 
RECIST Form 
Baseline, end of every even numbered cycle, and end of 
treatment 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
11.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 1.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 


Page 27 of 41 
 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 


Page 28 of 41 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 


Page 29 of 41 
 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).  
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 


Page 30 of 41 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed in 4-6 weeksby the Principal Investigator. 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD*** 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD**** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 


Page 31 of 41 
 
***        If the patient is clinically stable, treatment may continue with repeated scans in 4 weeks to 
rule out pseudoprogression 
**** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
12.4.6 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert(s) 
independent of the study at the study’s completion.  Simultaneous review of the 
patients’ files and radiological images is the best approach.  
 
 


Page 32 of 41 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date  
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Power analysis and/or interim analysis (if described in the protocol) 
• Summary of toxicities  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Endpoints 
 
The primary objective of this study is to determine the overall response rate (ORR) for the 
combination of ramucirumab and atezolizumab in patients with NSCLC who have 
previously received an ICB.   
 
The secondary objectives include 


Page 33 of 41 
 
• To determine the overall survival (OS) for the combination of ramucirumab and 
atezolizumab in patients with NSCLC who have previously received an ICB. 
• To determine the progression-free survival (PFS) for the combination of ramucirumab 
and atezolizumab in patients with NSCLC who have previously received an ICB.  
• To determine clinical benefit rate (CBR) for the combination of ramucirumab and 
atezolizumab in patients with NSCLC who have previously received an ICB.  CBR is 
defined as the percentage of patients who have achieved responses or stable disease.  
• To evaluate toxicity and tolerability of this combination as measured by NCI-CTCAE 
version 5.0. 
 
The exploratory objectives include 
• To explore the relationship of the immunophenotype of peripheral blood immune 
cells and response to combined therapy. 
• To explore the changes in tumor immune cell infiltrate after treatment and 
relationship with response.  
 
14.2 
Study Design 
 
This single institution study will be designed using Simon’s two-stage MiniMax design. 
We plan to enroll twenty-one (21) advanced-stage NSCLC patients. 
 
Assuming a null hypothesis of ORR less than 5% in this setting, we hypothesize that ORR 
of 20% or higher warrants further investigation. A total number of 21 patients allows an 
80% power at 1-sided alpha of 0.1 to detect the expected difference. If 4 or more responders 
are observed at the end of the trial, we would conclude that there is preliminary evidence 
for efficacy warranting further investigation.  
 
14.3 
Data Analysis 
 
Demographic and clinical characteristics of the sample, as well as toxicity by grade and 
loss to follow up will be summarized using descriptive statistics. Overall response rate 
(ORR) and clinical benefit rate (CBR) will be evaluated using the RECIST 1.1 criteria 
according to investigator’s assessment, and their 1-side 90% confidence intervals will also 
be calculated. Kaplan-Meier product limit estimator will be used to describe the 
distribution of overall survival (OS) and progression free survival (PFS). The association 
between response and the immunophenotype of peripheral blood immune cells will be 
summarized using descriptive statistics. Although data analysis will be primarily 
descriptive, permutation test will be used to rank the strength of association.   Specifically, 
we first compute the observed test statistics for the differences between responders and 
non-responders. Then the null distribution of the test statistics will be generated by 
simulating 10,000 datasets where the status of response was randomly shuffled. The 
permutation p-values equal the proportion of simulations from the null distribution that 
exceed the observed test statistics.  Similar analysis will be performed for the association 
between response and the changes in tumor immune cell infiltrate after treatment.  


Page 34 of 41 
 
 
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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development service. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 


Page 37 of 41 
 
APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


Page 38 of 41 
 
APPENDIX B: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 


Page 39 of 41 
 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
For the purposes of this protocol, the following events are also defined as a SAE: 
o Any venous or arterial event leading to discontinuation of ramucirumab therapy  
o Reversible posterior leukoencephalopathy syndrome of any grade  
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 


Protocol Version: 04/27/20 
 
Page 0 of 41 
APPENDIX C: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Eli Lilly 
Serious AND unexpected suspected 
adverse reaction 
 
 
Report within 24 hours 
Unexpected fatal or life-threatening 
suspected adverse reaction 
 
 
Report within 24 hours  
Reversible posterior 
leukoencephalophathy (any grade) 
 
 
Report within 24 hours  
Any venous or arterial event leading 
to discontinuation of ramucirumab 
therapy 
 
 
Report within 24 hours  
Unanticipated problem involving 
risk to participants or others 
Report within 10 working days.  If 
the event results in the death of a 
participant enrolled at 
WU/BJH/SLCH, report within 1 
working day. 
Report via email after IRB 
acknowledgment 
 
Major deviation 
Report within 10 working days.  If 
the event results in the death of a 
participant enrolled at 
WU/BJH/SLCH, report within 1 
working day. 
 
 
A series of minor deviations that are 
being reported as a continuing 
noncompliance 
Report within 10 working days.   
 
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
Complaints 
If the complaint reveals an 
unanticipated problem involving 
risks to participants or others OR 
noncompliance, report within 10 
working days.  If the event results in 
the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 
 
 


Protocol Version: 04/27/20 
 
Page 1 of 41 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Eli Lilly 
working day.  Otherwise, report at 
the time of continuing review. 
Breach of confidentiality 
Within 10 working days. 
 
 
Incarceration 
If withdrawing the participant poses 
a safety issue, report within 10 
working days.   
 
If withdrawing the participant does 
not represent a safety issue and the 
patient will be withdrawn, report at 
continuing review. 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be reported in the toxicity 
table in the DSM report which is typically due 
every 6 months. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review.