A Phase II Study of Ramucirumab for Advanced, Pre-Treated Biliary Cancers
Phase: PHASE2
Conditions: Cholangiocarcinoma, Liver and Intrahepatic Bile Duct Carcinoma, Stage III Gallbladder Cancer AJCC v7, Stage III Intrahepatic Cholangiocarcinoma AJCC v7, Stage IIIA Gallbladder Cancer AJCC v7, Stage IIIB Gallbladder Cancer AJCC v7, Stage IV Gallbladder Cancer AJCC v7, Stage IVA Gallbladder Cancer AJCC v7, Stage IVA Intrahepatic Cholangiocarcinoma AJCC v7, Stage IVB Gallbladder Cancer AJCC v7, Stage IVB Intrahepatic Cholangiocarcinoma AJCC v7, Unresectable Gallbladder Carcinoma
Sponsor: M.D. Anderson Cancer Center

2015-0393 
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THEUNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER 
DIVISION OF CANCER MEDICINE 
TITLE PAGE 
Protocol 2015-0393: A Phase II Study of Ramucirumab for Advanced, Pre-treated Biliary 
Cancers 
PI: 
Milind Javle, M.D. 
The University of Texas MD Anderson Cancer Center 
Department of Gastrointestinal Medical Oncology 
1515 Holcombe Blvd. 
Unit 0426 
(713) 792-2828
(713) 745-9926 (fax)
mjavle@mdanderson.org
MD Anderson Cancer Center Collaborators: 
Robert A. Wolff, M.D. 
Gauri Varadhachary, M.D. 
Kanwal Raghav, M.D. 
Ahmed Kaseb, M.D. 
Linus Ho, M.D. 
Xuemei Wang, M.S. 
Priya Bhosale, M.D. 
Asif Rashid, M.D. 
Lianchun Xiao, M.S. 
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TABLE OF CONTENTS 
 
 
1.0 
Study Rationale 
2.0 
Background 
3.0 
Drug Information 
4.0 
Objectives 
5.0 
Patient Eligibility 
6.0 
Treatment Plan 
7.0 
Evaluation during Study 
8.0 
Criteria for Removal from the Study 
9.0 
Response Evaluation 
10.0 
Statistical Methods 
11.0     Data and Protocol Management 
12.0  Correlative Studies 
13.0     Safety Reporting of Adverse Events  
14.0 
References 
 
APPENDICES 
 
 
 
Appendix 1 – ECOG Performance Status 
Appendix 2 – Ramucirumab- Additional Information 
 
 
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1. STUDY RATIONALE 
 
Biliary cancers are a heterogeneous group of malignancies with a limited number of 
chemotherapeutic options in advanced disease. The current standard of care for palliative 
treatment of biliary cancers is the combination of gemcitabine and cisplatin1. There is no clear 
second-line therapy in biliary cancers after progression on gemcitabine and cisplatin. A 
retrospective study of second-line therapies at MD Anderson demonstrated a median 
progression free survival in this population of 2.7 months with a multitude of therapies used2. 
Angiogenesis has been shown to be a potential target for biliary cancers in a variety of small 
phase II studies3-5. Ramucirumab is a novel monoclonal antibody that targets the vascular 
endothelial growth factor receptor 2 (VEGFR2). It is FDA-approved for the treatment of 
advanced gastric cancer, and inhibits tumor-induced angiogenesis through high affinity binding 
to VEGFR26.  
 
 
2. BACKGROUND 
 
2.1 Biliary Cancers 
 
Biliary cancers are comprised of intrahepatic cholangiocarcinoma, extrahepatic 
cholangiocarcinoma, and gallbladder carcinoma. They are an aggressive group of malignancies 
but heterogeneous in their presentations and clinical pictures. The majority of patients present at 
an advanced stage, and median survival of locally-advanced or metastatic biliary tract cancers is 
less than one year. These malignancies are characterized by lymph node involvement and 
distant metastases7.  
 
Gallbladder cancer (GBC) is the most common form of biliary tract cancers. Internationally, 
Israel has the highest incidence worldwide, with 7.5 cases per 100,000 men and 13.8 cases per 
100,000 women. Other countries with significant incidence rates include Mexico, Bolivia, 
Chile, and northern Japan8. In the US, about five thousand new cases are reported every year. 
The incidence has been on the decline owing to the increase in the number of cholecystectomies 
for other reasons like acute or chronic symptomatic cholecystitis.  Less than 10 percent of 
patients with GBC live more than five years after diagnosis. The mortality is very high and is 
attributed to the late diagnosis and an advanced stage of the disease9. 
 
At the same time, cholangiocarcinoma is a highly fatal cancer of the biliary tree.  In the United 
States, approximately 5,000 new cases of cholangiocarcinoma are diagnosed annually; these 
cases are equally distributed between intra-hepatic cholangiocarcinoma (ICC) and extrahepatic 
cholangiocarcinoma (ECC)10. Data from the National Cancer Institute’s Surveillance, 
Epidemiology and End Results (SEER) indicate that the incidence of ICC is increasing11. The 
incidence of ICC in the US almost tripled between 1975 and 199912. The reasons behind this 
increase are not clear. 
 
 
 
 
 
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Chemotherapy for biliary cancers 
 
Gemcitabine has been the mainstay of chemotherapy in biliary cancers. The ABC-01 study was 
a phase II trial that examined the combination of gemcitabine and cisplatin in advanced biliary 
cancers. 86 patients were randomized to gemcitabine alone versus the doublet regimen. The 
primary endpoint of 6-month progression-free survival was 45.5% vs. 57.1% in the two arms 
with median time to progression being 8 months with the gemcitabine and cisplatin 
combination13. The benefit of the addition of cisplatin to gemcitabine was verified with the 
ABC-02 study, a randomized phase III trial of 410 patients with overall survival as the primary 
endpoint. The authors found that the combination of gemcitabine and cisplatin significantly 
improved median overall survival (11.7 months vs. 8.1 months) and progression-free survival 
(8.0 months vs. 5.0 months) compared to gemcitabine alone1. 
 
Therapy in refractory biliary cancers 
There has not been any randomized controlled phase II or III trials of second or third-line 
therapies in biliary cancers thus far. A recent review of second-line therapy that included 14 
phase II trials indicated a mean overall survival (OS) of 7.2 months, progression-free survival 
(PFS) of 3.2 months and response rate (RR) of 7.7% with second-line therapy14. Similarly, a 
large retrospective review of second line therapy for 300 BC patients from Italy also showed a 
median OS of 7.2 months15. A retrospective review from MD Anderson Cancer Center 
indicated a median PFS of 2.7 months (95% CI 2.3-3.8 months) with a median OS of 13.8 
months (95% CI 12-19.3 months) in those receiving second-line chemotherapy for 
cholangiocarcinoma2. There is no “standard” second-line chemotherapy after gemcitabine and 
cisplatin; FOLFOX, irinotecan, capecitabine and erlotinib are used in practice16-20. 
 
Rationale for targeting angiogenesis in biliary cancers 
Expression of pro-angiogenic factors such as VEGFs and angiogenesis play an important role in 
biliary cancers. VEGF and VEGFR overexpression has been reported in 30-50% of biliary 
cancer cases and are associated with worse prognosis21-23. Estrogens interact with insulin-like 
growth factor (IGF1) and its receptor (IGF1-R) to simulate the growth of cholangiocarcinoma. 
Estrogens also stimulate the expression and secretion of VEGF-A, VEGF-C and VEGFRs in 
cholangiocarcinoma cell lines potentially altering cholangiocarcinoma proliferation and tumor 
neoangiogenesis24. Conversely, inhibition of cholangiocarcinoma proliferation also inhibits 
VEGF expression. Endothelin 1 (ET-1) inhibited the proliferation of cholangiocarcinoma 
xenografts in nude mice, which was associated with a down-regulation of VEGF-A and VEGF-
C expression25. 
 
A phase II trial of gemcitabine, oxaliplatin, and bevacizumab enrolled 35 patients with biliary 
cancers and resulted in a RR of 40% and PFS/OS of 7.0/12.7 months, which compared 
favorably with historic controls5. Lubner and colleagues reported a multicenter phase II trial of 
bevacizumab and erlotinib in patients with unresectable biliary cancer. The confirmed partial 
response rate in this study was 12%, median OS was 9.9 months, and TTP was 4.4 months, 
suggesting an effect of bevacizumab in this disease4. In the ABC-03 trial, Valle and colleagues 
examined the effects of adding cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, to 
traditional treatment with cisplatin/gemcitabine. This group performed a randomized phase II 
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study that included 124 chemotherapy-naive biliary cancer patients who received 
cisplatin/gemcitabine with or without cediranib.  Patients assigned to cediranib had a 
significantly improved RR compared with patients assigned to placebo. (44% vs. 19%, 
respectively (p = .0036). Patients receiving placebo were also more likely to progress (28% 
progressive disease vs 10% for cediranib). However, this did not result in improved OS26. 
Modest anti-tumor efficacy against biliary cancers was also demonstrated with multi-targeted 
anti-angiogenic tyrosine kinase inhibitors including sorafenib and sunitinib3,27-29. 
 
Ramucirumab is a fully human IgG1 monoclonal antibody that is a specific and direct inhibitor 
of VEGFR-2, where it binds to the extracellular VEGF-binding domain with high degree of 
specificity and affinity, at picomolar dose range. It thus prevents the binding of the VEGF 
ligand to the VEGF-R2 receptor. In the phase I trial for patients with advanced solid tumors, 
(n=37) ramucirumab demonstrated encouraging early evidence of efficacy at a range of dose 
levels including the one enrolled patient with biliary cancer who experienced stable disease 
lasting over 5 months30. Ramucirumab was recently shown to improve survival compared with 
placebo in advanced gastric cancer, with a median overall survival of 5.2 months in the 
ramucirumab arm, and 3.8 months in the placebo arm. The main toxicity seen was an increase 
in hypertension in the ramucirumab group31. Additionally, a double-blind, randomized, phase 
III study of previously treated gastric and gastroesophageal junction cancers included 665 
patients randomized to raumucirumab plus paclitaxel versus placebo plus paclitaxel32. In this 
study, the combination arm showed an improvement in overall survival (9.6 months vs. 7.4 
mths, p=0.017), providing further rationale for the use of ramucirumab in refractory gastric 
cancer. 
 
Initial data with ramucirumab in biliary cancer 
In the initial 43 patient cohort that was enrolled in this phase II trial, 42 patients with 
cholangiocarcinoma and gallbladder cancers received treatment.  Ramucirumab was well 
tolerated with 9 grade 3 toxicities including anorexia, dehydration, hypertension, hyponatremia, 
proteinuria and vomiting.  There were no grade 4 toxicities.  The median PFS for all patients 
who received treatment was 2.73 months (95% CI 1.91-8.03 months) and median OS was 6.31 
months (95% CI 4.7 months – not reached).  The overall response rate was 0% and disease 
control rate (SD + PR + CR) was 44%.  Importantly, 6 patients (13%) were on treatment for > 
24 weeks.  Of these, 3 were on treatment for at least 44 weeks.  In reviewing the genomic data 
on the 6 patients with prolonged periods of stable disease, we noted that 4 of the 6 harbored 
mutations in DNA repair pathways (BRCA, FANCA, ARID1A) and 1 patient had an FGFR 
alteration 
 
3.  DRUG INFORMATION 
 
3.1 RAMUCIRUMAB 
1. The Product 
Ramucirumab is an anti-VEGF Receptor 2 recombinant human monoclonal antibody of the 
IgG1 subclass. Ramucirumab drug product is a sterile, preservative-free solution for 
infusion oframucirumab formulated in an aqueous solution at a concentration of 10 mg/mL 
(500 mg/50-mL vial). The buffer contains 10 mM histidine, 75 mM sodium chloride, 133 
mM glycine, and 0.01% polysorbate 80. It is administered as an intravenous infusion at a 
dose of 8 mg/kg over 60 minutes every two weeks. 
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2. Indication 
In the United States, ramucirumab is indicated for the treatment of advanced gastric and 
gastroesophageal cancers either alone or in combination with paclitaxel after prior 
fluoropyrimidine- or platinum-containing chemotherapy.  
 
It is also indicated in combination with docetaxel for treatment of metastatic non-small cell 
lung cancer with disease progression after platinum-therapy.  
 
Accessed via: http://pi.lilly.com/us/cyramza-pi.pdf 
3. Introduction 
Ramucirumab is a recombinant human monoclonal antibody of the immunoglobulin G 
subclass 1 that specifically binds to the extracellular domain of the VEGFR2. This prevents 
the binding of activating ligands (VEGF-A, VEGF-C, VEGF-D) to the receptor. This 
inhibition results in inactivation of downstream signaling pathways that promote migration 
and proliferation of human endothelial cells. 
 
4. Preclinical Studies with Ramucirumab  
Preclinical pharmacodynamic data demonstrated that ramucirumab binds        specifically 
and with high affinity to human VEGFR2, and not to murine VEGFR2 or the related human 
VEGF receptors, VEGFR-1 and VEGFR-3. Furthermore, a surrogate antibody for 
ramucirumab was tested with demonstration of potent antiangiogenic effects in multiple 
mouse xenograft solid tumor models, including gastric, hepatic, breast, colorectal, non-
small cell lung, and pancreatic cancer models (Ramucirumab investigator’s brochure).    
 
5. Clinical Studies In Gastrointestinal malignancies with Ramucirumab 
The REGARD trial randomized patients with advanced gastric or GE junction cancers in a 
2:1 fashion to ramucirumab versus best supportive care. These patients had previously 
received platinum or fluoropyrimidine therapy. Patients who received ramucirumab has an 
improvement in 12-week PFS from 15.8% to 40.1% with overall survival being 
significantly improved as well (5.2 vs. 3.8 months)31. 
 
The RAINBOW trial randomized 665 advanced, refractory gastric or GE junction patients 
to receive paclitaxel plus ramucirumab versus paclitaxel plus placebo. The addition of 
ramucirumab to paclitaxel significantly improved median PFS from 2.9 months to 4.4 
months. Objective response rate was similarly improved from 16% to 28%. Further, the 
combination of paclitaxel with ramucirumab resulted in a significant improvement in 
overall survival from 7.4 months to 9.6 months32.  
 
6. Potential Risks of Ramucirumab Toxicities  
The most common toxicities reported with Ramucirumab as monotherapy include 
hypertension (16%), diarrhea (14%), headache (9%), and hyponatremia (6%). Class-related 
effects such as hemorrhage (3.4%), arterial thromboembolic events (1.7%), and 
gastrointestinal perforations (0.7%) were rarely noted. Infusion-related reactions were 
initially seen in 16% of patients prior to the institution of premedication recommendations. 
 
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7.   Further Information and Storage 
      See Appendix 2 for Package Insert and Investigator’s Brochure 
       
 
4.     OBJECTIVES 
 
PRIMARY 
Determine the progression-free survival (PFS) of ramucirumab in advanced biliary cancers 
(intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) 
who have received prior chemotherapy. 
 
SECONDARY 
• Determine the response rate (RR) and disease control rate (partial response + 
complete response + stable disease) of ramucirumab in advanced biliary cancers 
• Determine overall survival (OS) of ramucirumab in advanced biliary cancers 
• Evaluate the toxicity of ramucirumab in advanced biliary cancers 
 
EXPLORATORY 
• Correlate the carbohydrate antigen (CA) 19-9 response (defined as >50% decrease 
from baseline) with tumor response, PFS and OS 
• Correlate baseline tumor gene expression profile with PFS  
• Correlate pre- and post-therapy CT imaging to quantify iodine content, atomic 
numbers, and Z-values and correlate with response 
5. 
PATIENT ELIGIBILITY 
Patients will be included in the study based on the following inclusion and exclusion criteria.    
INCLUSION CRITERIA 
1. Patient must have cholangiocarcinoma, gallbladder cancer or adenocarcinoma on liver 
biopsy with clinical features consistent with biliary primary/ cholangiocarcinoma.   
 
2. Metastatic or unresectable disease documented on diagnostic imaging studies. 
 
3. Must have received at least one regimen containing gemcitabine chemotherapy. 
 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 (Appendix 
1).   
 
5. The patient has adequate hepatic function as defined by a total bilirubin ≤1.5 mg/dL 
(25.65 μmol/L), and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 
3.0 times the upper limit of normal (ULN; or 5.0 times the ULN in the setting of liver 
metastases). 
 
6. The patient has adequate hematologic function, as evidenced by an absolute neutrophil 
count (ANC) ≥1000/µL, hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets 
≥100,000/µL. 
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7. The patient does not have: 
a. Cirrhosis at a level of Child-Pugh B (or worse) or 
b. Cirrhosis (any degree) and a history of hepatic encephalopathy or clinically 
meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is 
defined as ascites from cirrhosis requiring diuretics or paracentesis. 
8. The patient has adequate renal function as defined by a serum creatinine ≤1.5 times the 
ULN, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute 
(that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to 
calculate creatinine clearance must be performed).  
 
9. The patient’s urinary protein is ≤1+ (≤30-100 mg/dl) on dipstick or routine urinalysis 
(UA; if urine dipstick or routine analysis is ≥2+ (≥100-300 mg/dl), a 24-hour urine 
collection for protein must demonstrate <1000 mg of protein in 24 hours to allow 
participation in this protocol). 
 
10. The patient must have adequate coagulation function as defined by International 
Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) (PTT/aPTT) < 
1.5 x ULN.). Patients on full-dose anticoagulation must be on a stable dose (minimum 
duration 14 days) of oral anticoagulant or low molecular weight heparin. If receiving 
warfarin, the patient must have an INR ≤3.0 and 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). 
 
11. 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). 
 
12. Female patients of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to enrollment. 
 
13. Patients must sign an Informed Consent and Authorization indicating that they are 
aware of the investigational nature of this study and the known risks involved. 
 
14.  Patient is ≥ 18 years of age on the day of consenting to the study. 
 
15. In the ten patient expanded cohort, patients diagnosed with DNA repair or FGFR 
genetic aberrations will be enrolled.  
 
EXCLUSION CRITERIA 
 
1.  The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to 
enrollment. 
 
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2. Prior therapy with any agent targeting the VEGFR pathway to include bevacizumab, 
pazopanib, and other anti-angiogenesis inhibitors. 
 
3.   The patient has a history of deep vein thrombosis, pulmonary embolism, or any other 
significant thromboembolism, including portal venous thrombosis (venous port or catheter 
thrombosis, incidental pulmonary embolism diagnosed on imaging studies or superficial 
venous thrombosis are not considered “significant”) during the 3 months prior to 
randomization. 
 
4. The patient has experienced any arterial thromboembolic events, including but not 
limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or 
unstable angina, within 6 months prior to enrollment. 
 
5. The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or 
> 100 mmHg diastolic for >4 weeks) despite standard medical management. 
 
6. The patient has a serious or non-healing wound, ulcer, or bone fracture within 28 days 
prior to enrollment. 
 
7. The patient has undergone major surgery within 28 days prior to enrollment, or 
subcutaneous venous access device placement within 7 days prior to enrollment. 
 
8. The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-
inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or 
clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is 
permitted. 
 
9. The patient has elective or planned major surgery to be performed during the course of 
the clinical trial. 
 
10. The patient is pregnant or breast-feeding. 
 
6. 
 TREATMENT PLAN 
This is an open-label phase II study.  Patients with advanced biliary cancers will be enrolled.  
All patients must be registered on the M. D. Anderson Cancer Center Clinical Oncology 
Research (CORe) system prior to initiation of treatment. 
This study will enroll up to 60 patients to at MD Anderson Cancer Center.  Accrual is projected 
to be 2.5 subjects per month. If this study proceeds to a future trial for patients with DNA repair 
gene of FGFR mutations, data obtained from this expanded cohort of 10 patients will be 
included in final analysis. 
 
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This will be an open-label, single arm study with each cycle being 14 days. Ramucirumab will 
be administered at 8 mg/kg intravenously on day 1 of the cycle. Restaging will be done every 4 
cycles (+/- 1week).  Treatment will be continued until progression unless other reasons for 
study discontinuation occur as listed in section 8 “Criteria for Removal from the Study.” 
Additionally, patients who have therapy interrupted for consolidative therapies (including, but 
not limited to radiation therapy, radioembolization, and chemoembolization) or at the 
physician’s discretion, will remain on study for survival analyses. 
 
Table 2: Starting Dose Level 
Drug 
Dose 
Infusion Time 
Schedule (in 14-day 
cycle) 
IV 
Ramucirumab 
8 mg/kg 
60 min (+/- 5 min) 
Day 1 
 
Dosing and Administration 
The study drug will be provided by the sponsor and administered in the following order with 
the specified pre-medications: 
o Premedication should be with an IV H1 agonist, diphenhydramine 50 mg in NS 
50 mL IV within 30 minutes prior to treatment  
o Ramucirumab 8 mg/kg in NS to final volume of 250 mL IV over 60 minute on 
day 1 repeated every 14 days 
Dose Modifications and Toxicity Management 
Dose modifications and treatment delays based on observed drug-related toxicity will be 
performed as described below. Any toxicity associated or possibly associated with 
ramucirumab treatment should be managed according to standard medical practice. 
 
Specific adverse events of concern, which may or may not be associated with ramucirumab 
therapy, include infusion reactions, hypertension, arterial or venous thrombotic events, 
bleeding (hemorrhagic) events, and proteinuria. These are specified in greater detail below. 
A cycle of therapy may be delayed up to 3 weeks to allow for weather events, patient’s personal 
emergencies, observation of holidays, or other unforeseen delays that the Investigator deems to 
be in the best interest of the patient. For any dose interruptions, re-initiation of therapy may be 
delayed for a maximum of 30 days to allow recovery from any toxicity. In exceptional cases 
where subjects are responding, re-initiation of therapy after missing > 30 consecutive days of 
treatment may be done on a case-by-case basis after confirmation with the Primary Investigator. 
 
Toxicity will be graded according to the NCI CTCAE, Version 4.0 (which is available at: 
http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm). For any event 
which is apparent at baseline, the dose modification will apply according to the corresponding 
shift in toxicity grade if the investigator feels this is appropriate, (e.g. if a patient has grade 1 
asthenia at baseline which increases to grade 2 during treatment, this will be considered as a 
shift of 1 grade and treated as a grade 1 toxicity for dose modification purposes).   
 
Dose modifications of ramucirumab will be done based on the specific toxicity. Once a dose of 
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any study drug has been reduced, it should not be increased at a later time.  Reasons for dose 
modifications or delays, the supportive measures taken, and the outcome will be documented in 
progress notes. Growth factors may be used to treat hematologic toxicity and will not constitute 
a dose reduction. A maximum of a 3-week treatment delay is permitted to allow recovery of 
toxicities. 
Table 3: Dose Levels 
Dose Level 
Ramucirumab (mg/kg) 
0 – baseline 
8 
-1 
6 
-2 
5 
 
Hematologic Toxicity 
Though myelosuprression is expected to be rare, in the event dose modifications are required at 
the beginning of a cycle due to hematologic toxicities, dose of ramucirumab may be adjusted as 
detailed below.  
Table 4: Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) 
ANC 
 
Platelets 
Timing 
≥ 1,500 cells/mm3 
AND 
≥ 75,000/uL 
Treat on time 
< 1,500 cells/mm3 
OR 
< 75,000/uL 
Delay by 1 week 
intervals until 
recovery 
 
Special Instructions Regarding Treatment of Chemotherapy-related Toxicity 
Dose modification or delay may occur in the setting of lower Grade toxicity if the treating 
physician believes that it is in the interest of a subject’s safety.  Alopecia and nausea and/or 
vomiting that can be controlled by antiemetics do not require dose modification or interruption.  
No dose reduction or interruption will be required for anemia as it can be satisfactorily 
managed by transfusions. Dose reductions for non-hematologic toxicity should be as below.  
 
Table 5: Dose Modifications for Ramucirumab on Day 1 of Each Cycle (Non-
Hematologic Toxicity)* 
Toxicity/Dose Held 
Ramucirumab dose this cycle 
Grade 0-2 toxicity 
Same as Day 1 previous cycle  
Grade 3 toxicity 
Decrease ramucirumab 
to next lower dose level 
Grade 4 toxicity 
Off protocol treatment 
Dose held in 2 previous 
consecutive cycles 
Decrease ramucirumab to next lower dose level and 
continue throughout the rest of treatment 
   * Drug-specific toxicities are explained in greater detail below with appropriate modifications 
 
6.1 G-CSF Administration 
The exact dosage amount and schedule for G-CSF support will be left to the treating 
physician’s discretion.  A recommended approach would be to administer G-CSF 5 
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mcg/kg/day (rounded to the nearest vial size per investigator’s standard of care) 24 hours 
after chemotherapy until recovery to the predetermined neutrophil count. 
 
6.2 Infusion-related reactions 
Infusion reactions are defined according to the NCI-CTCAE Version 4.02 definition of 
infusion-related reactions, (General disorders and administration site conditions, p. 23). 
Symptoms occurring during or following infusion of investigational therapy may also 
be defined according to adverse event categories such as allergic reaction, anaphylaxis, 
or cytokine release syndrome (Immune system disorders, p. 26). In the setting of 
symptoms occurring during or following infusion of investigational therapy, the adverse 
event term “Infusion-related Reaction” and any additional terms (including those not 
listed here) that best describe the event should be used. Those described above should be 
graded as follows: 
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Table 6:  NCI-CTCAE v 4.02 Infusion-related Reactions 
 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
 
Infusion- 
related 
reaction 
 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤ 24 hrs 
 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for clinical sequelae 
 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 
Death 
 
Definition: A disorder characterized by an adverse reaction to the infusion of pharmacological or biological substances. 
 
Allergic 
reaction 
 
Transient flushing 
or rash, drug fever 
<38 degrees C 
(<100.4 degrees F); 
intervention not 
indicated 
 
Intervention or infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics); 
prophylactic medications 
indicated for ≤ 24 hrs 
 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 
Death 
 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 
Death 
 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
like substances from mast cells, causing a hypersensitivity immune response. Clinically, it  presents  with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness and may lead to death. 
 
Cytokine 
release 
syndrome 
 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, I.V. 
fluids); prophylactic 
medications indicated for 
≤ 24 hrs 
 
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
 
Life-threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
 
Death 
 
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is 
caused by the release of cytokines from the cell. 
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If a patient experiences a Grade 1 or 2 infusion reaction, the infusion rate should  be 
decreased for the duration of the infusion and all subsequent infusions, as directed in the 
protocol. In addition, patients with Grade 1 and 2 infusion reactions should be treated 
according to standard medical practices. After a Grade 1 or 2 infusion reaction, patients 
should be premedicated with antihistamines, steroids, acetaminophen, etc, as appropriate for 
subsequent infusions. 
A Grade 3 or 4 infusion reaction will require immediate treatment, including the use of 
epinephrine, bronchodilators, and/or glucocorticoids for symptomatic bronchospasm, I.V. 
fluids and/or pressors for hypotension, and immediate and permanent discontinuation of 
ramucirumab with appropriate supportive care.  
Consistent with usual medical practice, selected parenteral medications may be utilized for 
Grade 2 infusion-related reactions as detailed below.  
The following are general treatment guidelines for ramucirumab infusion-related reactions: 
Grade1 
• Slow the infusion rate by 50% 
• Monitor the patient for worsening of condition 
• For subsequent infusions, c o n t i n u e  t o  premedicate with diphenhydramine 
hydrochloride 50 mg 
I.V. (or equivalent); additional premedication may   be administered at   the 
investigator’s discretion 
 
Grade2 
• Stop the infusion 
• Administer 
diphenhydramine 
hydrochloride 
50 
mg 
I.V. 
(or 
equivalent), 
acetaminophen 650 mg orally for fever, and oxygen 
• Resume the infusion at 50% of the prior rate once the infusion reaction has resolved 
or decreased to Grade 1; the infusion duration should not exceed 2 hours 
• Monitor for worsening of condition 
• For subsequent infusions, c o n t i n u e  t o  premedicate with diphenhydramine 
hydrochloride 50 mg 
I.V. (or equivalent); additional premedication may   be administered at   the 
investigator’s discretion
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For a second Grade 1 or 2 infusion reaction, administer dexamethasone 8-10 mg I.V. (or 
equivalent); then, for subsequent infusions, premedicate with diphenhydramine hydrochloride 
50 mg I.V. (or equivalent), acetaminophen 650 mg orally, and dexamethasone 8-10 mg I.V. 
(or equivalent). 
Grade 3 
• Stop the infusion and disconnect the infusion tubing from the patient 
• Administer 
diphenhydramine 
hydrochloride 
50 
mg 
I.V. 
(or equivalent), 
dexamethasone 10 mg I.V. (or equivalent), bronchodilators for bronchospasm, and 
other medications/treatment as medically indicated 
• Patients who have a Grade 3 infusion reaction will not receive further 
ramucirumab treatment, but will continue to be followed on the protocol 
 
Grade 4 
• Stop the infusion and disconnect the infusion tubing from the patient 
• Administer diphenhydramine hydrochloride 50 mg I.V. (or equivalent), 
dexamethasone 10 mg I.V. (or equivalent), and other medications/treatment as 
medically indicated 
• Give epinephrine or bronchodilators as indicated 
• Hospital admission for observation may be indicated 
• Patients  who  have  a  Grade  4  infusion  reaction  will  not  receive  further  
ramucirumab treatment, but will continue to be followed on the protocol 
 
6.3 Hypertension 
If a patient develops hypertension during the study, he/she should be treated with 
antihypertensive medications according to standard medical practice. 
 
Grade<3 
• If the hypertension is not associated with symptoms, continue ramucirumab and 
initiate anti-hypertensive therapy. 
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• If the hypertension is associated with symptoms, hold ramucirumab until 
symptoms resolve and initiate anti-hypertensive therapy. 
• If ramucirumab therapy is held more than once for hypertension (ie, symptomatic 
hypertension, markedly elevated blood pressure unresponsive to anti- hypertensive 
therapy), the dose of ramucirumab should be reduced upon re- treatment (refer to 
protocol for dose and frequency).  A second dose-reduction (refer to protocol for 
dose and frequency) should be undertaken if an additional postponement of therapy is 
required. 
 
Grade 3 (systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg; medical intervention 
indicated; more than one drug or more intensive therapy than previously used indicated) 
• For Grade 3 hypertension not associated with symptoms, continue 
ramucirumab with more intensive anti-hypertensive therapy.  If systolic BP remains ≥ 
160 or diastolic BP ≥ 100 mmHg > 2 weeks after initiation of additional anti-
hypertensive therapy, hold ramucirumab while continuing appropriate anti-
hypertensive therapy. 
• If the hypertension is associated with symptoms, hold ramucirumab until symptoms 
resolve and initiate anti-hypertensive therapy. 
• If ramucirumab therapy is held more than once for hypertension (ie, symptomatic 
hypertension, markedly elevated blood pressure unresponsive to anti-hypertensive 
therapy), the dose of ramucirumab should be reduced upon re- treatment . A second 
dose-reduction should be undertaken if an additional postponement of therapy is 
required. 
 
Grade 4 or refractory 
Patients with Grade 4 hypertension (life-threatening consequences, eg, malignant 
hypertension, transient or permanent neurologic deficit, hypertensive crisis; or urgent 
intervention indicated) or patients whose hypertension is poorly controlled (> 160 mmHg 
systolic or > 100 mmHg diastolic for > 4 weeks) despite appropriate oral medication (> 2 oral 
agents at maximum tolerated dose) will be discontinued from study therapy. 
 
6.4 Thrombotic Events 
Investigators should perform all testing required to fully characterize arterial or venous 
thrombotic/vascular events. The incidence, type, and diagnostic tests used for the diagnostic 
confirmation of thrombotic/vascular events will be collected and reported. Because of the 
high rate of venous thrombotic events in patients with upper gastrointestinal malignancies, 
and because therapy with antiangiogenic agents has been shown to be feasible in the setting 
of anticoagulation in patients with upper gastrointestinal malignancies, patients who 
develop Grade 3-4 venous thrombotic events (deep vein thrombosis [DVT] or pulmonary 
embolism [PE]) may continue study therapy if the event is not considered to be life-
threatening in the opinion of the investigator, the patient is asymptomatic, and/or the 
event can be adequately treated with low molecular weight heparin-based therapy. 
Grade 3-4 arterial thromboembolic events, or any PE/DVT occurring or intensifying during 
anticoagulant therapy, will warrant discontinuation of study therapy. 
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6.5 Hemorrhagic Events 
Ramucirumab therapy should be discontinued in the event of any Grade 3-4 bleeding 
(hemorrhagic) event. 
 
6.6 Proteinuria 
If, while on therapy, a patient has proteinuria ≥ 2+ per a dipstick ( e q u i v a l e n t  t o  
≥ 1 0 0 - 3 0 0  m g / d l ) or routine urinalysis, ramucirumab therapy will continue as 
scheduled, and a 24-hour urine collection will be conducted prior to the subsequent 
scheduled treatment cycle.   If the protein level is < 2g/24 hours, the patient will 
continue on study therapy at the same dose without interruption. If the protein level is 2 to 
3 g/24 hours, study therapy for the subsequent cycle will be held for up to 2 weeks and a 
24-hour urine collection will be repeated. Treatment will resume at a reduced dose level (6 
mg/kg every other week) once the protein level returns to < 2g/24 hours. A second dose 
reduction (to 5 mg/kg every other week) is permitted if the protein level > 2g/24 hours 
recurs. The patient will be discontinued from the study if the protein level is > 3g/24 
hours, if there is a third occurrence of proteinuria > 2 g/24 hours, or if the protein level does 
not return to < 2g/24 hours within 2 weeks. 
 
6.7 Gastrointestinal Perforation 
An infrequent incidence of gastrointestinal perforations has been associated with some 
antiangiogenic therapeutic agents, most specifically in the context of colorectal cancer 
(treated with combination regimens including anti-VEGF antibodies and cytotoxic 
chemotherapy)  and  in  advanced  ovarian  cancer.    These  events  may be  associated  
with
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extensive abdominal/peritoneal disease burden. Gastrointestinal perforation has 
been reported from clinical studies investigating ramucirumab. The incidences of 
these events to date and presence of significant comorbidities and risk factors 
preclude any definitive association with ramucirumab, although ongoing surveillance 
remains essential. Three gastrointestinal perforations have been reported in Phase 2 
studies investigating ramucirumab (overall incidence, 0.8% of patients). Two of 
these events occurred on the ovarian cancer study (CP12-0711) and one on the 
prostate cancer study (CP18-0601). All three cases were reported as SAEs; the events 
on the ovarian cancer study included a Grade 4 colonic perforation (considered 
probably related by the investigator) and a Grade 5 bowel perforation (considered 
unrelated); the perforation occurring on the prostate cancer study was a Grade 3 
rectal perforation (possibly related). Each of these events was characterized by 
extensive abdominal and/or pelvic tumor burden, including an obstructing lesion 
immediately distal to an area of dilated intestine and perforation (Grade 5 event on 
the ovarian cancer study), a diffusely infiltrated peritoneum (Grade 4 event on the 
ovarian cancer study), and prior pelvic radiation (Grade 3 event on the prostate cancer 
study). Ramucirumab should be permanently discontinued in the event of a 
gastrointestinal perforation. 
 
Concomitant Medications 
Supportive care, including but not limited to anti-emetic medications, may be 
administered at the discretion of the Investigator.  Erythropoietin and G-CSF may be 
administered at the discretion of the investigator, consistent with institutional 
guidelines.  
 
7.  EVALUATION DURING STUDY 
• 
Patients must begin Cycle 1 within 14 days of signing the informed consent 
document and after the screening assessments. Treatment will be 
administered by qualified and trained site personnel in a hospital, clinic, or 
other out-patient setting appropriate for chemotherapeutic infusions. All 
assessments should be performed within 72 hours of each specified time 
parameter, with the exception of Cycle 1 in which assessments must be 
conducted within 24 hours (except those noted), or if medical or scheduling 
conditions require a delay. Request of 20 unstained tumor slides of 5 to 10 
microns thick will be sent at enrollment. 
 
Day 1 of each cycle (except where noted) 
• 
Inclusion/exclusion review (Cycle 1 only)  
• 
Directed physical exam 
• 
Vital Signs  
• 
Measurement of weight (kg) and BSA calculation prior to dosing.  
• 
ECOG Performance Status (see Appendix 1)  
• 
Hematology: CBC with differential and platelet count  
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• 
Serum chemistries: glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase albumin, LDH, total protein, and electrolytes (sodium, potassium, 
phosphorus, chloride, C02, magnesium, calcium).   In patients with known 
Gilbert’s syndrome, it is recommended to perform a direct bilirubin and indirect 
bilirubin. 
• 
CA 19-9 
• 
Urinalysis  
• 
AEs using the NCI CTCAE (http://ctep.info.nih.gov) 
• 
Concomitant medication notation    
Prior to Cycles 4, 8, 12, etc.  
• 
In order to more precisely determine time to progression, the investigator is 
encouraged to obtain radiological assessments earlier if there is a strong clinical 
suspicion of disease progression, in order to either confirm or refute the clinical 
impression.  
• 
Reassessment of the extent of tumor should be made by the same imaging methods 
used to establish baseline tumor measurements.  
Table 7: Study Assessments (treatment cycle is 14 days) 
Evaluation or Procedure 
Screening1 
Study Treatment  
End of 
Treatment 
Evaluation11 
30-day Post-
Treatment 
Evaluation12/Long 
Term Follow-up 
 
 
On or before Day 
1 of each cycle  
 
 
Informed consent 
X 
 
 
 
Medical History 
X 
 
 
 
Physical Examination 
X 
X3,4 
X 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
X3,4 
X 
 
Vital Signs (Blood Pressure) 
X 
X3,4 
X 
 
ECOG Performance Status 
X 
X 3,4 
X 
 
Hematology
10 
X 
X
3,4 
X 
 
Biochemistry10 
X 
X
3,4 
X 
 
Urinalysis10 
X 
X3,4 
X 
 
Serum or urine pregnancy test (for females 
of child-bearing potential)  
X 
 
 
 
Tumor Tissue Collection 
X
2 
 
 
 
Toxicity assessment 
X 
X3.4 
X 
X
8 
Diagnostic Imaging for Tumor Assessment, 
preferably dual-energy CT7 
X 
Every 4 cycles
5 
X
6  
X6 
Survival  
 
 
 
X
9 
 
1. Informed consent must be obtained before any evaluations are initiated.  Diagnostic 
imaging studies must be completed within 28 days prior to first day of study 
treatment. All other baseline evaluations, except for height (which can be obtained at 
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any time prior to enrollment), must be completed within 7 days prior to first dose of 
study drug. 
2. When patients are enrolled, we will collect their pre-existing tissue biopsies, if 
available, for testing. The Oligo GEArray® Human Angiogenesis Microarray profiles 
the expression of 113 genes involved in modulating the biological processes of 
angiogenesis and will be investigated for correlation with outcome, include PFS. 
Archival tumor biopsy specimens will be used. This investigation will be performed 
at MD Anderson Core Facility. 
3. For Cycle 1, baseline evaluations will suffice as they are performed within 7 days 
prior to first dose of study drug (except for imaging studies which are performed 
within 28 days prior). 
4.  Within 72 hours prior to start of the cycle (except for Cycle 1 as noted above). 
5.  Imaging should be obtained every 4 cycles (+/- 1week).  Evaluations earlier than 
every 4 cycles are allowed if, in the investigator’s opinion, this evaluation is in the 
patient’s best interest.    
6. The end of treatment imaging does not have to be repeated if recent imaging has been 
completed within 4 weeks.  For patients discontinued from the study for reasons other 
than progression, it is recommend to perform every 12 weeks (+/- 5 week) after the 
End of Treatment Evaluation visit until documentation of progression or for 12 
months after their first dose of study drug, whichever comes first, if no other anti-
cancer treatment is given.   
7. CT of the chest, abdomen, and pelvis. MRI may be used in cases where it is felt to be 
unsafe to perform CT secondary to patient's history of dye allergy, or if the tumor is 
not adequately seen on CT for the purposes of this study. 
8. Treatment-related adverse events occurring during study treatment or within 30 days 
(window of 28-35 days allowed) after the last administration of study drug(s) will be 
followed until resolution or stabilization.  If the patient is unable or unwilling to 
return to M. D. Anderson for this assessment, the patient will be contacted by phone 
for this assessment.   
9. Every 3 months (+/- 5 weeks) from Post-Treatment Evaluation. 
10. Hematology: complete blood count with differential. Chemistry:  glucose, creatinine, 
BUN, total bilirubin, AST, ALT, alkaline phosphatase, albumin, LDH, total protein, 
and electrolytes (sodium, potassium, phosphorus, chloride, C02, magnesium, 
calcium).  Tumor markers (CA19-9) as indicated. Tumor markers are performed 
every 2 cycles.  In patients with known Gilbert’s syndrome, it is recommended to 
perform a direct bilirubin and indirect bilirubin. 
11. Within 10 days of decision to discontinue study treatment.  
12. At 28-45 days from last dose of study medication. 
 
 
 
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7.1 End of treatment evaluations  
Within 10 days of decision to discontinue treatment 
• 
The investigator will evaluate the results of the following clinical and laboratory 
assessments to be conducted at the time the patient discontinues study treatment: 
• 
Physical examination with neuropathy assessment 
• 
ECOG Performance Status 
• 
Weight 
• 
Vital signs (blood pressure) 
• 
Hematology:  complete blood count with differential 
• 
Biochemistry:  glucose, creatinine, BUN, total bilirubin, AST, ALT, alkaline 
phosphatase albumin, LDH, total protein, and electrolytes (sodium, potassium, 
phosphorus, chloride, C02, magnesium, calcium).  Tumor markers (CA19-9) as 
indicated.  In patients with known Gilbert’s syndrome, it is recommended to 
perform a direct bilirubin and indirect bilirubin. 
• 
Urinalysis 
• 
Concomitant medication notation 
• 
Toxicity (adverse events) assessment (including neurologic toxicities) using NCT 
CTCAE Version 4.0 
• 
Tumor evaluations including CT scan or MRI of the chest, abdomen, and pelvis 
(if recent imaging within 4 weeks, tumor evaluation does not need to be repeated) 
7.2 Follow-up (off-treatment)   
Follow-up/observation for all treatment related adverse events will be through Day 30 
(Day 28 to Day 45 allowed) following the last dose of study drug or until resolution or 
stabilization of the toxicity or start of another treatment regimen. If it is not feasible for 
the patient to return to M. D. Anderson for the Day 30 toxicity assessment, the patient 
will be contacted by phone for this assessment.  
 
Patients with documented (radiological) disease progression at any point during the study 
will discontinue treatment with study drugs under this protocol. Objective evidence of 
progressive disease will be recorded at the time of progression.  Patients without evidence 
of progression while on study, regardless of the number of treatment cycles received, will 
be followed for progression until it is documented.  If a patient is off treatment with no 
documented disease progression and no subsequent anti-cancer treatment is received, 
he/she should be followed every 12 weeks (+/- 5 weeks) after the End of Treatment 
Evaluation visit with tumor evaluations until disease progression is documented or for 12 
months after their first dose of study drug, whichever comes first. 
 
7.3     Long-term followup 
All patients will be followed for survival status approximately every 3 months 30-day 
post-treatment evaluation.  Survival status may be obtained by checking the electronic 
medical record or by telephone call.   
 
 
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8. 
 CRITERIA FOR REMOVAL FROM THE STUDY  
 
Subjects who meet the following criteria should be discontinued from study treatment:  
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) as determined by the treating physician 
• Patient decides to withdraw from the study  
• General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator.   
 
9. 
RESPONSE EVALUATION 
 
9.1 Measurement of effect  
Response and progression will be evaluated in this study using the new international 
RECIST criteria (version 1.1, 2009) proposed by the RECIST committee33.  All patients 
who have measurable disease according to the RECIST criteria and who have their 
disease re-evaluated will be evaluable for response.  For the purposes of this study, 
patients should be reevaluated for response approximately every 4 cycles.  Note:  Lesions 
are either measurable or non-measurable using the criteria provided below. The term 
“evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
 
9.2 Definitions 
All sites of disease should be followed as either target or non-target lesions, as 
categorized at baseline.  All measurable lesions up to a maximum of 2 lesions per organ 
or 5 lesions in total, representative of all involved organs should be identified as target 
lesions, while all other lesions (either additional measurable lesions or non-measurable 
lesions) should be classified as non-target lesions. In cases where a target lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 
mm should be assigned. To ensure comparability, the baseline radiology/scans and 
subsequent radiology/scans to assess response should be performed using identical 
techniques (eg, scans performed immediately following bolus contrast administration 
should be made with a standard volume of contrast, the identical contrast agent, and 
preferably the same scanner). The same method, radiological or physical, should be 
employed and assessed by the same individual on each occasion, when possible.  
 
9.3 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >10 mm with CT scan (with minimum 
slice thickness no greater than 5mm, or 10mm caliper measurement by clinical exam, or 
20mm by chest X-ray).  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
Pathological lymph nodes may also be considered as target or non-target lesions.  To be 
considered pathologically enlarged and measurable (target lesion), 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). Lymph nodes with a short axis ≥ 10 mm but < 15 mm 
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should be considered non-target lesions. Lymph nodes that have a short axis < 10 mm are 
considered non-pathologic and should not be recorded. The short axis measurement of 
any lymph node that is considered a target lesion should continue to be recorded 
regardless if the node progresses to below 10 mm. This may prevent the sum of lesions 
from being zero even if complete response criteria are met, since a normal lymph node is 
defined as having a short axis of < 10 mm.  In rare circumstances, when a target lymph 
node is believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned.  
 
9.4 Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥ 10 to <15mm short axis) as well as truly non-
measurable lesions.  Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, abdominal masses (not followed by CT or MRI).  For bone and cystic 
lesions, please refer to the RECIST criteria (version 1.1, 2009). 
 
9.5 Target lesions 
All measurable lesions up to a maximum of five lesions total (and a maximum of two 
lesions per organ) 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) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  A sum of the 
diameters for all target lesions (longest for non-nodal lesions, short axis for nodal lesions) 
will be calculated and reported as the baseline sum diameters (LD).  The baseline sum 
diameters will be used as reference by which to characterize the objective tumor 
response. 
 
9.6 Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Non-target lesions include measurable lesions that exceed 
the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions. It is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g. “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).   Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up.  
 
9.7 Guidelines for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
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Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  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 Magnetic Resonance Imaging.  Conventional CT and MRI should 
be performed to obtain images of 5 mm or less slice thickness. 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. 
Cytology, Histology.  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
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. 
 
9.8 Response criteria 
Evaluation of target lesions 
• Complete Response (CR): Disappearance of all target and non-target lesions 
including normalization of elevated tumor marker level. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
All non-target lymph nodes must be non-pathological in size (< 10 mm short axis). 
Complete response must be confirmed at a second tumor assessment not less than 4 
weeks apart from the assessment at which CR was observed. 
 Partial Response (PR):  At least a 30% decrease in the sum of LD of target lesions 
taking as reference the baseline sum LD. Partial response must be confirmed at a 
second tumor assessment not less than 4 weeks apart from the assessment at which 
PR was observed. 
 Progressive Disease (PD): At least a 20% increase (and an absolute increase of at 
least 5 mm) in the sum of LD of measured lesions taking as references the smallest 
sum LD recorded since the treatment started. Appearance of new lesions will also 
constitute PD. In exceptional circumstances, unequivocal progression of non-target 
lesions may be accepted as evidence of disease progression. 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 Non-CR/Non-PD:  Persistence of 1 or more non-target lesions and/or maintenance of 
tumor marker level above the normal limits. 
 
 
 
 
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Evaluation of non-target lesions 
• Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level 
• Incomplete Response/ Stable Disease (SD): 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 
• Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail, and the 
progression status should be confirmed at a later time by the study chair. 
• Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
9.9 Time point evaluation 
At each protocol specified time point, a response assessment occurs. Table 9 provides a 
summary of this for patients who have measurable disease at baseline. Table 10 provides 
a summary of this for patients with non-measurable (therefore non-target) disease. 
 
Table 8: Response for measurable disease 
Target 
Lesions 
Non-target Lesions  
New Lesions  
Overall 
Response  
Best Response for this 
Category also Requires  
CR 
CR 
No 
CR 
≥ 4 weeks Confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
≥ 4 weeks Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once ≥ 6 
weeks from baseline 
Not All 
Evaluated 
Non-PD 
No 
NE 
NE 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. NE = inevaluable 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.  
 
 
 
 
 
 
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Table 9: Response for non-measurable disease 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
NE = inevaluable a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised.  
9.10 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
Table 10: Response Assignment 
Overall Response First Time 
Point 
Overall Response Subsequent 
Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR 
CR 
SD 
SD provided minimum criteria 
for SD duration met, otherwise, 
PD 
CR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise, 
PD 
CR 
NE 
SD provided minimum criteria 
for SD duration met, otherwise, 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria 
for SD duration met, otherwise, 
PD 
PR 
NE 
SD provided minimum criteria 
for SD duration met, otherwise, 
NE 
NE 
NE 
NE 
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NE = inevaluable.  If a CR is truly met at first time point, then any disease seen at a subsequent time 
point, even disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR).  Best response would depend on whether minimum duration for 
SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions 
were likely still present and in fact, the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR.  
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration.”  Every effort should be made to document the 
objective progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
9.11 
Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessment at a minimum follow-up interval of 6 weeks after the criteria for 
response are first met.  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks. 
 
 
9.12 
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 recurrent disease is objectively documented. 
 
9.13 
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.  
 
10. 
STATISTICAL METHODS 
10.1 
Study design and sample size  
This is a single arm, open label, phase II trial to assess the efficacy and toxicity of 
ramucirumab in patients with pre-treated, advanced bile duct cancer. The primary 
objective is to evaluate the efficacy of the therapy. The primary endpoint is the 
progression-free survival (PFS).  A maximum of 60 patients will be enrolled in the study 
at an estimated accrual rate of 2-3 patients per month. The study will monitor for futility 
and safety so that it will stop early if based on the interim data, it is unlikely the PFS will 
be better than that estimated from historical data or the study drug is too toxic. 
 
 
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10.2  Primary efficacy endpoint 
The primary endpoint is PFS, which is calculated as the time period from the date of 
treatment start to the date of disease progression or to the date of death, whichever occurs 
first, or to the last follow-up date if patients are alive without disease progression. It is 
expected that the median PFS time will be 3 months or more under this study treatment. 
If the trial continues to accrual of 60 patients and maintains sufficient follow-up to 
observe 35 events (PD/death) with a median PFS of 3 months, then the 95% credible 
interval for the median PFS would extend from 2.1 to 4.2 months. 
 
10.3  Futility monitoring 
For futility monitoring, we will monitor PFS using the methods of Thall et al and we will 
stop enrolling patients to the study if the median PFS is not likely to be longer than that 
from the historical data, which is around 3 months.  Specifically, the trial will be stopped 
if Pr (lamda(E)  >  lamda(S) | data from the trial) < 0.05, where lamda(S) is the median 
PFS for historical patients under conventional care with an inverse gamma distribution 
IG(58.25,171.75), which corresponds to a mean of 3 months and a standard deviation of 
0.4 month (variance = 0.16), the corresponding 95% CI of (2.32, 3.88) months. The prior 
for lamda(E) is assumed to be IG(2.5625, 4.6875),  corresponding to a mean of 3 months 
and a larger standard deviation of 4 (variance=16, the corresponding 95% CI is 0.72-
10.67).   Futility monitoring will start once 5 patients have been enrolled. Assuming an 
accrual rate of 2 per month and an additional follow-up of 6 months, the operating 
characteristics for the futility stopping rule under various scenarios are summarized in 
Table 11 below, with results based on 5000 simulations.  
 
Table 11: Operating characteristics for futility monitoring   
Median PFS (M) 
Prob(Stop Early) 
Mean No. of Patients 
(25%, 75%) 
6 
0.0058  
49.5 (50, 50)   
4.5 
 0.0216 
49.1 (50, 50)   
3 
 0.1674 
44.2 (50, 50)   
2 
0.855   
23.7 (10,37)   
1.5 
0.9992 
12.3 (7, 16)   
 
10.4 
Toxicity monitoring 
Unacceptable toxicities will also be monitored closely for the study drug using the 
method of Thall et al (1995). Denote the probability of unacceptable toxicity by TE,  
Unacceptable toxicity will be defined as follows, using the National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. For the 
purpose of toxicity monitoring, only unacceptable toxicities that occur in the first 28 days 
(i.e., 2 cycles) will be counted when assessing the stopping boundary. That is, a patient 
will be classified as not having toxicity if the patient has been treated for 28 days and no 
unacceptable toxicity has been observed. 
• Grade 4 neutropenia lasting ≥ 5 days or Grade 3 or 4 neutropenia with 
fever and/or infection 
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• Grade 4 thrombocytopenia (or Grade 3 with bleeding) 
• Grade 4 anemia 
• Grade 3 or 4 non-hematological toxicity [excluding electrolyte 
abnormalities, alopecia or grade 3 nausea that is correctable with usual 
supportive medications] 
• Dosing delay greater than 14 days due to treatment-emergent AEs or 
related severe laboratory abnormalities 
• Grade 3 hypersensitivity reaction with premedication (Grade 3 
hypersensitivity reaction without premedication is not considered a 
DLT) 
• Grade 4 hypersensitivity reaction with or without premedication 
• Drug-related fever ≤ Grade 3 will not be considered a DLT.   
We assume TE ~ beta (0.3, 0.7).  We will stop the enrollment if at any point Pr(PE > 
0.30 | data)  >0.9. That is, we will stop the trial if, at any time during the study, we 
determine that there is more than 90% chance that the unacceptable toxicity rate is 
more than 30%. This toxicity monitoring rule will be applied after the first 5 patients 
have been enrolled and evaluated, and then in cohort size of 5. The corresponding 
stopping boundaries are to stop the trial if (number of patients with unacceptable 
toxicities / number of patients) ≥4/5, 6/10, 8/15, 9/20, 11/25, 13/30, 15/35, 16/40, 
18/45.  The operating characteristics (OCs) are listed in Table 12. 
 
                 Table 12: OCs for unacceptable toxicity monitoring 
True Prob(unacceptable 
tox)  
Pr(stop) 
mean # Pts (25%, 50%, 75%) 
0.1  
0.0006 
49.97 (50, 50, 50) 
0.2  
0.0225 
49.21 (50, 50, 50) 
0.3  
0.2215 
43.59 (50, 50, 50) 
0.4  
0.6869 
30.12 (15, 25, 50) 
0.5  
0.9597 
17.77 (10, 15, 20) 
 
Multc Lean V2.1 and OneArmTTE Version 4.1.1 were used for the trial design. 
 
10.5 
Futility monitoring in CTC website  
The Department of Biostatistics will provide and maintain a website (“Clinical Trial 
Conduct”:  https://biostatistics.mdanderson.org/ClinicalTrialConduct/) for futility 
monitoring for this study. The Clinical Trial Conduct website resides on a secure server, 
and access is gained through usernames and passwords provided to personnel responsible 
for enrolling patients and updating patient data.  The website is accessed through a 
browser using secure socket layer (SSL) technology. Personnel responsible for enrolling 
patients on trials, which includes the principal investigator(s), research nurse(s), and data 
coordinator(s), will be trained by members of the Department of Biostatistics in the use 
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of the trial website; the importance of timely updating of follow-up times and recording 
of events will be emphasized in training. 
 
10.6 
Analysis method 
Data analysis will be performed using SAS or S-plus, as appropriate. The median PFS 
time will be estimated by Bayesian posterior estimates, along with the 95% credible 
interval.  Toxicity will be reported by type, frequency and severity. Highest toxicity 
grades per patient per course will be tabulated for adverse events and laboratory 
measurements. 
 
Demographic and baseline laboratory results will be summarized using descriptive 
statistics, including means with standard deviations, or medians with ranges, histograms 
and box-plot. Fisher’s exact test and Wilcoxon rank test will be used in the data analyses 
of categorical and continuous variables, respectively. Progression-free survival and 
overall survival functions will be estimated using the Kaplan-Meier method. The two-
sided log-rank test will be used to assess the differences of time to events between 
groups, and Cox proportional hazards model will also be fitted to evaluate the association 
between time-to-event outcomes and tumor gene expressions. The correlation between 
pre- and post- therapy CT imaging results will be assessed through Spearman correlation 
and Wilcoxon signed rank test will be used to assess whether the change in CT imaging 
between pre- and post-therapy is statistically significant. In addition, logistic regression 
analyses will be performed to assess the association between CT imaging results or 
CA19-9 response (defined as >50% decrease from baseline) and tumor response.  
 
11. 
DATA AND PROTOCOL MANAGEMENT 
Designated research personnel must enter the information required by the protocol onto 
electronic Case Report Forms (CRFs). The University of Texas MD Anderson Cancer 
Center’s Clinical Oncology Research (CORE) system, and the University of Texas MD 
Anderson Cancer Center’s Protocol Data Management System (PDMS) CRF system 
will be used for this study.  PDMS is a clinical research information management system. 
The PDMS CRF is an electronic document designed to record all the protocol-required 
information to be reported on each trial subject. 
PDMS provides data entry templates as defined in the protocol. Laboratory results are 
automatically transferred from MD Anderson Cancer Center Laboratory Medicine’s 
server to PDMS each morning. Users must have clearance through the MD Anderson 
Cancer Center Information Services Security Department in order to access PDMS. 
PDMS login is password protected.   The Investigator is responsible for verifying and 
providing source documentation for all adverse events and assigning attribution for each 
event for all subjects enrolled on the trial.  
 
12. 
CORRELATIVE STUDIES 
All patients who sign consent for this study will provide consent for the collection of 
previously collected paraffin embedded tissue.  Up to 20 unstained slides of 5 to 10 
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microns thick will be requested from the outside institution or prepared from the patient’s 
tumor block, if applicable.  Any residual tumor tissue above what is specified here will be 
returned to the sending institution.  Collected paraffin embedded tissue will be handled 
by GI Medical Oncology research personnel.  Only the PI and her authorized research 
staff will have access to the identifiable information from this study.  All the samples 
extracted from the paraffin tissue used in this study will be coded and identifiers (name, 
medical record number) will not be present on any material that is undergoing analysis.  
Patient information and relevant data will be stored on password –protected institution 
computers behind the institution firewall.  At the closure of this study all unused material 
will be either returned to the sending institution or destroyed. 
 
When patients are enrolled, we will collect their pre-existing tissue biopsies, if available, 
for testing. The Oligo GEArray® Human Angiogenesis Microarray profiles the 
expression of 113 genes involved in modulating the biological processes of angiogenesis 
and will be investigated for correlation with outcome, include PFS. Archival tumor 
biopsy specimens will be used. This investigation will be performed at MD Anderson 
Core Facility. Recent data suggest that gene expression profiling may be predictive for 
response to anti-angiogenic agents34. In addition, baseline VEGF-A in plasma was 
suggested as a possible predictive biomarker in a trial of bevacizumab in gastric cancer.  
Similarly, focal amplification of VEGFA in hepatocellular carcinoma predicted 
sensitivity to sorafenib both in animal models and in humans35-37. 
 
Contrast enhanced dual-energy CT’s that are triphasic or liver protocol will be utilized as 
standard of care imaging. This will consist of an arterial phase and a portal venous phase 
which will be performed on the 64-slice dual-energy CT scanner. All patients will be 
scanned in the cranio-caudal direction from the dome of the liver to the iliac crest during 
inspiratory breath-hold. Iodinated contrast medium will be intravenously administered via 
an automated dual-syringe power injector according to a body weight. The timing for the 
arterial phase scan will be determined by care bolus technique. AP scanning will start 
after the attenuation coefficient of abdominal aortic blood reached 100 HU. All images 
will be post processed to obtain the iodine and water images.  Additional analysis will be 
done on the AW work station. This will allow for iodine content quantification pre- and 
post-therapy as well as calculation of atomic numbers and Z-values of the tumor in these 
patients38,39.  These quantifications will then be correlated with RECIST response 
measurements. 
 
13. 
SAFETY REPORTING OF ADVERSE EVENTS 
13.1 
Adverse Event Reporting and Definitions  
An adverse event is the appearance or worsening of any undesirable sign, symptom, 
or medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting 
study drug. Abnormal laboratory values or test results constitute adverse events 
only if they induce clinical signs or symptoms, are considered clinically significant, 
or require therapy. 
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Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, 
laboratory test or other means, will be collected and recorded and followed as 
appropriate.  Adverse events will be collected from the signing of the informed 
consent until 30 days after the last dose of study drug, or any time after that if the PI 
determines the event is related to the study drug. 
 
The occurrence of adverse events should be sought by non-directive questioning of 
the patient at each visit during the study. Adverse events also may be detected when 
volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse 
event should be evaluated to determine: 
• The severity grade (mild, moderate, severe or grade 1-5) 
• Its relationship to the study drug(s) (suspected/not suspected) 
• Its duration (start and end dates or if continuing at final exam) 
• Action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; 
concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
• Whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or discontinuation, 
starting or stopping concomitant treatments, changes in the frequency or nature of 
assessments, hospitalization, or any other medically required intervention. Once an 
adverse event is detected, it should be followed until its resolution, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Information about common side effects already known about drug can be found in 
the Investigators’ Brochure or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as 
needed. 
13.2 Adverse event attribution 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
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Adverse events for this protocol will be recorded using the Recommended 
Adverse Event Recording Guidelines for phase II protocols.   
 
Recommended Adverse Event Recording Guidelines  
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
Phase II 
Phase II 
Phase II 
Unlikely 
 
 
Phase II 
Phase II 
Phase II 
Possible 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Probable 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
Definitive 
Phase II 
Phase II 
Phase II 
Phase II 
Phase II 
 
The Investigator is responsible for verifying and providing source 
documentation for all adverse events and assigning attribution for each event 
for all subjects enrolled on the trial. 
 
13.3 Serious adverse event (SAE) reporting  
A serious adverse event is one that at any dose (including overdose): 
• Results in death 
• Is life-threatening
1 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization 
• Results in persistent or significant disability or incapacity
2 
• Is a congenital anomaly or birth defect 
• Is an important medical event
3 
1“Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred.  
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious.  Examples of such 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.  
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A new diagnosis of cancer during the course of a treatment should be considered as 
medically important.   
 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event 
reporting.  A copy of the CTCAE Version 4.0 can be downloaded from the CTEP 
homepage (http://ctep.info.nih.gov).  All appropriate treatment areas should have access 
to a copy of the CTCAE Version 4.0.  All adverse clinical experiences, whether observed 
by the investigator or reported by the patient, must be recorded, with details about the 
duration and intensity of each episode, the action taken with respect to the test drug, and 
the patient’s outcome.  The investigator must evaluate each adverse experience for its 
relationship to the test drug and for its seriousness. 
Pregnancies 
Pregnancies occurring while the subject (or female partner of a male subject) is on study 
or within 30 days after the subject’s last dose of ramucirumab are considered expedited 
reportable events.  If the subject is on ramucirumab, it is to be discontinued immediately.   
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(i.e., spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the Investigator should 
follow the procedures for Expedited Reporting of SAEs to Lilly. 
Any suspected fetal exposure to ramucirumab must be reported to Lilly within 24 hours 
of being made aware of the event.  The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to ramucirumab should also be reported. 
Lilly Drug Safety Contact Information: 
Eli Lilly 
Global Product Safety Fax Number: 
(866) 644-1697 or (317) 453-3402 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
All adverse experience reports must include the patient number, age, sex, weight, severity 
of reaction (mild, moderate, severe), relationship to drug (probably related, unknown 
relationship, definitely not related), date and time of administration of test medications 
and all concomitant medications, and medical treatment provided.   The investigator is 
responsible for evaluating all adverse events to determine whether criteria for “serious” 
and as defined above are present.  The investigator is responsible for reporting adverse 
events to Lilly as described below. 
 
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Expedited reporting by investigator to Lilly 
Serious adverse events (SAE) are defined above.  The investigator must inform Lilly in 
writing using a Lilly SAE form of any SAE within 24 hours of being aware of the event.  
The written report must be completed and supplied to Lilly by facsimile within 24 hours.  
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product.  Information not available 
at the time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Lilly tracking number (I4T-US-I004) 
and the institutional protocol number should be included on SAE reports (or on the fax 
cover letter) sent to Lilly.  A copy of the fax transmission confirmation of the SAE report 
to Lilly should be attached to the SAE and retained with the patient records. Participating 
study sites must report SAEs to Lilly as described and within 24 hours of awareness.  
Participating sites should also report SAEs to MD Anderson Cancer Center, the primary 
study site. 
 
Report of Adverse Events to the Institutional Review Board 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) 
of a serious adverse event according to institutional policy.   
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly 
associated to the drug, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) by telephone or by fax.  Fatal or life threatening 
SAEs that meet the criteria for reporting to the FDA must be reported to the FDA within 
7 calendar days after awareness of the event.  All other SAEs that meet the criteria for 
reporting to the FDA must be reported to the FDA within 15 calendar days after 
awareness of the event.  A clear description of the suspected reaction should be provided 
along with an assessment as to whether the event is drug or disease related.    
Adverse event updates/IND safety reports 
Lilly shall notify the Investigator via an IND Safety Report of the following information: 
• Any AE associated with the use of drug in this study or in other studies that is 
both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
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The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects. The Investigator must keep copies of all 
AE information, including correspondence with Lilly and the IRB/EC, on file. 
 
 
 
14.  
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Yi JH, Thongprasert S, Lee J, et al: A phase II study of sunitinib 
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functional information by quantifying iodine uptake of melanoma metastases. 
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Appendix 1 – Eastern Cooperative Oncology Group Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2 Ramucirumab – Additional Information 
SEE ATTACHED PACKAGE INSERT AND INVESTIGATOR’S BROCHURE 
 
 
 
 
 
 
 
 
  
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