Clinical trial NCT02726399
Conditions: Gastric Cancer Gastroesophageal Junction Cancer
Keywords: Ramucirumab Trastuzumab Capecitabine Cisplatin HER2-Positive 15-301
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2016-03-18; Completion date: 2019-02-26
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to compare any good and bad effects of using ramucirumab along with the usual trastuzumab and chemotherapy to using the usual chemotherapy and trastuzumab alone.

Detailed description:

Arms: arm 1: This will be a single arm study of ramucirumab 8mg/kg administered intravenously on days 1 and 8 + trastuzumab (8 mg/kg loading dose; 6 mg/kg maintenance) administered intravenously every 21 days. On subsequent cycles for all patients capecitabine 850mg/m2 will be added, taken orally twice a day for fourteen days (days 1 through 14) followed by a 7 day rest period, in addition to cisplatin 80mg/m2 administered as an IV infusion every 21 days. Each cycle consists of 21 days.
Interventions: intervention 1: Ramucirumab intervention 2: Trastuzumab intervention 3: Capecitabine intervention 4: Cisplatin
Intervention descriptions: intervention 1: Ramucirumab 8mg/kg administered intravenously on days 1 and 8 ever 21 days intervention 2: Trastuzumab (8 mg/kg loading dose; 6 mg/kg maintenance) administered intravenously every 21 days intervention 3: Capecitabine 850mg/m2 will be added, taken orally twice a day for fourteen days (days 1 through 14) followed by a 7 day rest period intervention 4: Cisplatin 80mg/m2 administered as an IV infusion every 21 days

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 1 of 47
 
 
  
 
 
 
 
Phase II study of ramucirumab with trastuzumab, fluoropyrimid ine, and platinum in 
patients with metastatic HER2-positive gastroesophageal junction and gastric 
cancer 
 
 
PROTOCOL FACE PAGE FOR 
MS K THE RA P E UT IC /D IA GN OS T IC P RO T OC OL 
 
 
Principal 
Investigator/Department: 
Yelena Y. Janjigian, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
David Ilson, MD, PhD 
Medicine 
Investigator(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Andrew Epstein, MD 
James Harding, MD 
Yelena Y. Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Eileen O‘Reilly, MD 
Diane Reidy-Lagunes, MD 
Leonard Saltz, MD 
Neil Segal, MD, PhD 
Kenneth H. Yu, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Armin Shahrokni, MD 
Nitya Raj, MD 
Karuna Ganesh, MD 
Ellen Hollywood, NP 
Maria Pacis, NP 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
Robin Brenner, RN 
Pam Raasch, RN 
Anthony Yu, MD 
Marc Simmons, MD 
Marinela Capanu, PhD 
Wolfgang Weber, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Epidemiology/Biostatistics 
Nuclear Medicine 
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Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 2 of 47
 
 
 
 
 
Leticia Smith, APN 
Janet Cogswell, CRN 
Avni Desai, MD 
John Fiore, MD 
Stuart Lichtman, MD 
Jahan Aghalar, MD 
Juliana Eng, MD 
Jia Li, MD, PhD 
Wanqing Iris Zhi, MD, PhD 
Adriana Olivo,NP 
Lori Gofter, CRN Arlyn 
Apollo, MD Pamela 
Drullinsky, MD Zoe 
Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Kenneth Ng, MD 
Erin Scansarole, CRN 
Krysti Corrado, CRN 
Elizabeth Won, MD 
Parisa Momtaz, MD 
Chung-Han Lee, MD, PhD 
Philip Caron, MD, PhD 
Alice Zervoudakis, MD 
Gloria Wasilewski, CRN 
Jason Konner, MD 
Serena Wong, MD 
Jacqueline Bromberg, MD 
PhD 
Collette Owens, MD 
Azadeh Namakydoust, MD 
Loren Michel, MD 
Marina Shcherba, DO 
Nursing 
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Medicine 
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Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 3 of 47
 
 
 
 
 
Consenting 
Professional(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Andrew Epstein, MD 
James Harding, MD 
David Ilson, MD, PhD 
Yelena Y. Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Eileen O‘Reilly, MD 
Diane Reidy-Lagunes, MD 
Leonard Saltz, MD 
Neil Segal, MD, PhD 
Kenneth H. Yu, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Armin Shahrokni, MD 
Nitya Raj, MD 
Ellen Hollywood, NP 
Maria Pacis, NP 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
 
Avni Desai, MD John 
Fiore, MD Stuart 
Lichtman, MD Jahan 
Aghalar, MD Jia Li, 
MD, PhD 
Wanqing Iris Zhi, MD, PhD 
Juliana Eng, MD 
 
Arlyn Apollo, MD 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Kenneth Ng, MD 
 
Elizabeth Won, MD 
Chung-Han Lee, MD, PhD 
Philip Caron, MD, PhD 
Alice Zervoudakis, MD 
Parisa Momtaz, MD 
 
Jason Konner, MD 
Medicine 
Medicine 
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Medicine 
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Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 4 of 47
 
 
 
 
 
Serena Wong, MD 
Jacqueline Bromberg, MD 
PhD 
Collette Owens, MD 
Azadeh Namakydoust, MD 
Loren Michel, MD 
Marina Shcherba, DO 
Medicine 
Medicine 
 
Medicine 
Medicine 
Medicine 
Medicine0 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ple ase Note: A Consenting Profe ssional must have comple ted the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
 
 
OneMSK Sites 
Westchester 
Rockville Centre 
Commack 
Basking Ridge 
Monmonth 
Manhattan 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 5 of 47 
 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA......................................................................6 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ...............................................................................6 
 
3.0 
BACKGROUND AND RATIONALE .....................................................................................6 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ..........................................................13 
 
4.1 
Design..............................................................................................................................13 
 
4.2 
Intervention ......................................................................................................................14 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS...........................................................................14 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY...........................................................................17 
 
6.1 
Subject Inclusion Criteria .................................................................................................17 
 
6.2 
Subject Exclusion Criteria................................................................................................18 
 
7.0 
RECRUITMENT PLAN .......................................................................................................19 
 
8.0 
PRETREATMENT EVALU ATION ......................................................................................20 
 
9.0 
TREATMENT/INTERVENTION  PLAN ...............................................................................21 
 
10.0 EVALU ATION DURING TREATMENT/INTERVENTION..................................................22 
 
11.0 TOXICITIES/SIDE EFFECTS .............................................................................................24 
 
11.2 Trastuzumab .........................................................................................................................31 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................38 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................39 
 
14.0 BIOSTATISTICS .................................................................................................................39 
 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES41 
 
15.1 Research Participant Registration ...................................................................................41 
 
16.0 DAT A M AN AGEMENT ISSUES.........................................................................................42 
 
16.1 Quality Assurance............................................................................................................42 
 
16.2 Data and Safety Monitoring .............................................................................................42 
 
17.0 PROTECTION OF HUMAN SUBJECTS............................................................................42 
 
17.1 Privacy .............................................................................................................................42 
 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................43 
 
17.2.1.......................................................................................................................................44 
 
18.0 INFORMED CONSENT PROCEDURES............................................................................44 
 
19.0 REFERENCES ....................................................................................................................45 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 6 of 47 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single arm Phase II study of ramucirumab in combination with capecitabine/5-FU and a 
platinum and trastuzumab in patients with HER2-positive Stage IV gastric or gastroesophageal 
junction (GEJ) adenocarcinoma. The goal of the study is to determine the efficacy of the drug 
combination as measured by 6 month progression free survival (PFS). Eligible patients must be 
older than 18 years of age and must have histologically proven HER2-positive gastric or GEJ cancer 
(immunohistochemistry 3+ or FISH≥2.0). 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary: 
 
To determine the efficacy of ramucirumab in combination with capecitabine/5-FU and 
oxaliplatin/cisplatin and trastuzumab in patients with HER2-positive Stage IV gastric or GEJ 
adenocarcinoma as measured by 6 month PFS. 
 
Secondary: 
 
To establish the safety of ramucirumab in combination with capecitabine/5-FU, oxaliplatin/cisplatin 
and trastuzumab in patients with HER2-positive Stage IV gastric or GEJ adenocarcinoma. 
 
To establish response rate of ramucirumab with trastuzumab in patients with HER2-positive Stage 
IV gastric or GEJ adenocarcinoma. 
 
To observe other measures of efficacy of ramucirumab in combination with capecitabine/5-FU, 
oxaliplatin/cisplatin and trastuzumab, including response rate, median PFS, overall and 1-year 
survival in patients with HER2-positive Stage IV gastric or GEJ adenocarcinoma. 
 
 
 
Exploratory Objectives 
 
To explore molecular tumor characteristics associated with resistance and/or sensitivity to 
ramucirumab, trastuzumab and capecitabine/cisplatin using next-generation sequencing of available 
archival tumor specimens. 
 
To explore changes in 89 Zr-trastuzumab PET after trastuzumab and ramucirumab treatment. 
 
To  utilize  cell-free  tumor  DNA  (cfDNA)  from  blood  specimens  collected  during  the  course  of 
treatment  to  explore  mechanism   of  primary  and  acquired  resistance  to  ramucirumab   and 
trastuzumab therapy. 
 
 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Background 
Cancers originating in the GEJ and stomach constitute a global health problem. Gastric cancer is the 
fourth most common cancer and second leading cause of cancer mortality worldwide.
1  In 2015, an 
estimated 22,220 people will be diagnosed and 10,990 people will eventually die of their disease in 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
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Page 7 of 47 
 
 
 
 
 
the United States.2  Depending on tumor characteristics and stage, treatment modalities include 
combinations of surgery, chemotherapy, and radiation therapy.
1  Even with maximal therapy, 
prognosis for gastric cancer remains poor, with 5-year survival rate of 5%2,3 and median survival of 
10 to 14 months in Stage IV disease.
4-6  The poor prognosis is largely attributed to the fact that the 
majority of gastric cancer patients have metastatic disease at the time of presentation.1  Palliative 
chemotherapy is used to control tumor growth, improve quality of life and has been shown to prolong 
survival in patients with Stage IV disease.4-6   Among patients who initially respond to chemotherapy 
majority ultimately suffer disease progression. In addition, a significant proportion of gastric and GEJ 
patients have primary chemotherapy refractory disease. For these patients there is a need for 
development of new therapeutic options.6 
 
A meta-analysis of phase II and III randomized gastric cancer trials has shown that combination 
chemotherapy results in substantially improved overall survival compared with single-agent 
chemotherapy or best supportive care.7   Typically, a fluoropyrimidine and a platinum compound form 
the backbone of chemotherapy for patients with advanced gastric cancer. 
 
3.2 Capecitabine in combination with cisplatin in gastric cancer 
 
The REAL-2 trial was a randomized multicenter phase III study, which compared the efficacy and 
safety of capecitabine-based combinations and fluorouracil-based combinations in patients with 
advanced gastric cancer. 
6 In this study, 1002 patients were randomly assigned to receive triplet 
therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet 
therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The 
primary end point was non-inferiority in overall survival for the triplet therapies containing 
capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with 
cisplatin. Results from this study suggested that capecitabine and oxaliplatin are as effective as 
fluorouracil and cisplatin, respectively, in patients with previously untreated gastric cancer. For the 
capecitabine–fluorouracil comparison the hazard ratio (HR) for death in the capecitabine group was 
0.86 (95% confidence interval [C I], 0.80 to 0.99); for the oxaliplatin–cisplatin comparison the HR for 
the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). Median survival times in the ECF, ECX, EOF, 
and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival 
rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. Toxic effects of capecitabine 
and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower 
incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with 
slightly higher incidences of grade 3 or 4 diarrhea and neuropathy.6 
 
ML  17032,  another  phase  III randomized  trial,  evaluated  the combination  of capecitabine  and 
cisplatin (XP) vs. the combination of fluorouracil and cisplatin (FP) as first-line treatment in patients 
with  previously  untreated  advanced  gastric  cancer.13    The  results  of  this  study  suggest  that 
capecitabine  is as effective as fluorouracil in the treatment of patients  with advanced 
gastroesophageal cancers. A meta-analysis of the REAL-2 and ML17032 trials suggested that OS 
was superior in the 654 patients treated with capecitabine-based combinations  compared with the 
664 patients treated with fluorouracil-based combinations.8 
 
3.3 Targeting HER2: Trastuzumab 
 
Human epidermal growth factor receptor 2 (HER2; also known as ERBB2), a member of a family of 
receptors associated with tumor cell proliferation, apoptosis, adhesion, migration, and differentiation 
is an established biomarker and key driver of tumorigenesis  in gastric cancer.9  Approximately 20- 
30% of gastric and GEJ adenocarcinomas harbor HER2 overexpression.9,10 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 8 of 47 
 
 
 
 
 
Trastuzumab is a humanized monoclonal antibody (IgG1 isotype) directed against the extracellular 
region  of  HER2  that  induces  antibody-dependent   cellular  cytotoxicity,  inhibits  HER2-mediated 
signaling, and prevents cleavage of the extracellular domain of HER2.11  The ToGA study is the first 
randomized,   prospective,  multicenter,   phase  III  trial  to  evaluate  the  efficacy  and  safety  of 
trastuzumab in HER2-positive gastric and GEJ adenocarcinoma in combination with cisplatin and a 
fluoropyrimidine.9      In  this   study,   594  patients   were   randomly   assigned   to  study  treatment 
(trastuzumab  plus chemotherapy,  n=298; chemotherapy  alone, n= 296). The results  of this study 
established   the   benefit   of   trastuzumab   in  combination   with  cisplatin   and   fluoropyrimidine 
chemotherapy. Median overall survival was 13.8 months (95% CI 12–16) in those assigned to 
trastuzumab  plus  chemotherapy  compared  with  11.1  m onths  (10–13)  in  those  assigned  to 
chemotherapy alone (HR 0.74; 95% CI 0∙60–0∙91; p=0∙0046). Median progression-free survival was 
6.7 months (95% CI 6–8) in the trastuzumab plus chemotherapy group compared to 5.5 months (5– 
6)  in  the  chemotherapy  alone  grou p  (HR  0.71,  95%  C I 0.59–0.85;  p=0.0002).  Overall  tumor 
response rate, time to progression, and duration of response were significantly improved in the 
trastuzumab plus chemotherapy group compared to the chemotherapy alone group. Rates of overall 
grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 
[6%]) did not differ between groups.15  On the basis of these findings, trastuzumab is now considered 
a standard option for patients with HER2-positive advanced gastric and GEJ cancer when combined 
with a chemotherapy regimen consisting of a fluoropyrimidine (5-FU or capecitabine) and platinum 
(cisplatin or oxaliplatin). 
 
3.4 Targeting VEGFR2: Ramucirumab 
 
Vascular endothelial growth factor receptor (VEGFR)-2 plays a central role in tumor growth and 
metastasis by promoting pathologic angiogenesis.
12  Although many potential antiangiogenic targets 
exist, VEGF and its receptors play a central role in both physiologic and pathologic angiogenesis. 
VEGF  is  a  potent  pro-angiogenic  factor  that  not  only  stimulates  endothelial  cell  proliferation, 
migration  and survival,  but  also  increases  vascular  permeability.12    Angiogenesis  is  required  for 
invasive tumor growth and metastasis and constitutes an important point in the control of cancer 
progression. Inhibition of angiogenesis has demonstrated clinically significant improvements in 
outcomes in a variety of malignancies, including gastric cancer.13,14 
 
Ramucirumab  is  a fully human  immunoglobulin  IgG1  monoclonal  antibody  that  binds  with high 
affinity  to the extracellular  VEGF-binding  domain  of VEGFR-2  that  prevents  ligand  binding  and 
receptor-mediated pathway activation in endothelial cells.15  Based on the data outlined below, the U. 
S. Food and Drug Administration approved ramucirumab as either a single agent or in combina tion 
with paclitaxel for the treatment of patients  with metastatic,  gastric  or GEJ adenocarcinoma  with 
disease  progression  after  fluoropyrimidine/platinum   chemotherapy.  The  REGARD  trial  was  an 
international, randomized, double-blind, placebo-controlled, phase 3 trial in which 355 patients with 
advanced  gastric  or  GEJ  adenocarcinoma  and  disease  progression  after  first-line  platinum- 
containing or  fluoropyrimidine-containing  chemotherapy  were randomly assigned to receive  best 
supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks.16 
Median overall survival was 5.2 months  (2.3–9.9)  in patients  in the ramucirumab  group and 3.8 
months  (1.7–7.1)  in those in the placebo group (HR 0.776, 95% CI 0.603–0.998;  p=0.047). The 
study demonstrated that ramucirumab is the first biological treatment given as a single drug that has 
survival benefits in patients with advanced gastric or gastroesophageal junction adenocarcinoma 
progressing after first-line chemotherapy, thus validating VEGFR-2 signaling as an important 
therapeutic target in advanced gastric cancer. 
 
Ramucirumab has also shown efficacy with an acceptable safety profile in combination with 
paclitaxel in patients with advanced gastric or GEJ cancer whose disease had progressed after prior 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 9 of 47 
 
 
 
 
 
platinum/fluoropyrimidine-based chemotherapy in the randomized Phase 3 study, RAINBOW 
(N=665).
17The primary endpoint of OS was met; median OS was 9.63 months on the ramucirumab 
plus paclitaxel arm compared with 7.36 months on the placebo plus paclitaxel arm (HR=0.807, 95% 
CI: 0.678, 0.962; p=.0169). Grade 3 AEs occurring in >5% of patients on the ramucirumab plus 
paclitaxel arm were: neutropenia (40.7% ramucirumab plus paclitaxel arm; 18.8% placebo plus 
paclitaxel arm), leukopenia (17.4% vs. 6.7%), hypertension (14.1% vs. 2.4%), anemia (9.2% vs. 
10.3%), fatigue (7.0% vs. 4.0%), abdominal pain (5.5% vs. 3.3%), and asthenia (5.5% vs. 3.3%). 
Febrile neutropenia was reported in 3.1% in the ramucirumab plus paclitaxel arm and 2.4% placebo 
plus paclitaxel arm. 
 
A recently completed randomized, placebo-controlled, double-blind, Phase 2 study of ramucirumab 
in combination with mFOLFOX-6 as first-line therapy for advanced adenocarcinoma of the 
esophagus, GEJ, or stomach (N=168) showed improved PFS rate at 3-months (89.0% versus 
75.3%) and an improved disease control rate (DCR) (84.5% vs. 66.7%; p=.008), although did not 
show improved PFS or OS. A higher rate of discontinuation from study treatment for reasons other 
than progressive disease (PD) in the ramucirumab arm c ompared with the placebo arm was 
observed (50% vs. 19%), which led to lower study drug exposure in the experimental arm. These 
observations may have had a negative impact on the results of the PFS assessment of the entire 
study population. Overall, the safety profile for ramucirumab in this study was consistent with the 
known safety profile of ramucirumab. The most common Grade 3 AE (by consolidated AE) reported 
was neutropenia (26.8% ramucirumab arm vs. 36.3% placebo arm). Fatigue (18.3% in the 
ramucirumab arm vs. 15.0% in the placebo arm) and neuropathy (8.5% vs. 11.3%) reported at a 
similar frequency in each arm.
18
 
 
3.5 Rationale for combined VEGF and HER2 targeted the rapy 
 
Trastuzumab is the standard of care for patients with metastatic HER2-positive gastric cancer. 
However, the response rate in first line setting is only 47% with trastuzumab in combination with 
chemotherapy while acquired and intrinsic resistance to trastuzumab limits its efficacy. The short 
duration of response in some patients led to our hypothesis that combined inhibition of multiple 
oncogenic  pathways  that drive gastric  cancer growth may achieve a greater therapeutic  benefit. 
Cellular heterogeneity, redundancy of molecular pathways and effects of the microenvironment 
contribute to the survival, motility and metastasis of cells in solid tumors. It is unlikely that tumors are 
entirely dependent  on only one abnormally activated signaling pathway; consequently,  treatment 
with an agent that interferes with a single target may be insufficient.19  
 
Preclinical  and  clinical  studies  have  linked  VEGF  expression  and  HER2  signaling  in  human 
cancers.20  Co-expression of VEGF and HER2 in clinical tumor samples is associated with worse 
outcome in patients with advanced breast cancer.21   Furthermore, in HER2-positive breast cancer 
xenografts experiments treatment with VEGF-Trap ( VEGF-A, VEGF-B and placental growth factor 
inhibitor) alone, trastuzumab alone, or combination of VEGF-Trap and trastuzumab which resulted in 
synergist  effect  of dual  HER2  and  VEGF- A blockade.20   Compared  to either  agent  alone  or  to 
controls, treatment with the combination produced a striking and superior inhibition of tumor 
microvessel density as indicated by CD31 staining, cell proliferation as indicated by Ki67 staining 
and tumor growth (p = 0.008). 
 
Combined blockade of HER2 and VEGF exerts greater growth inhibition of HER2-overexpressing 
gastric cancer xenografts than individual blockade.
22  Singh et al. evaluated the antitumor effects of 
trastuzumab; VEGF-Trap and a combination of trastuzumab and VEGF-Trap in a gastric cancer 
xenograft model. Although trastuzumab and VEGF-Trap each moderately inhibited tumor growth, 
the combination of these agents exerted greater antitumor effect compared with either agent alone. 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
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Immunohistochemistry analyses indicated that the reduction in tumor growth was associated with 
decreased proliferation and increased apoptosis of tumor cells and decreased tumor vascular 
density. As indicated in Figure 1, the combined treatment resulted in fewer proliferating tumor cells, 
more apoptotic cells and reduced tumor vascular density compared with treatment with trastuzumab 
or VEGF-Trap alone, indicating that trastuzumab and VEGF-Trap had additive inhibitory effects on 
the tumor growth and angiogenesis of the gastric cancer xenografts. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. The combined inhibition of HER2 and V EGF reduces tumor growth more efficiently than single -agent 
inhibition. (a) Mice bearing NCI- N87Luc+tumor s w ere divided into four groups and treated w ith an isotype -control 
antibody, V EGF-Trap (VT) , trastuzumab (Tr) or a combination of V EGF-Trap and trastuzumab (VT+Tr) for 28 days . 
(b) The effect of treatment on vascular density. The scale bar represents 100 μm (n=7; *P<0.05 versus isotype  
control; *P<0.05 versus vascular endothelial grow th factor (VEGF)-Trap (V T) ; *P<0.05 versus trastuzumab (Tr)). 
IgG, immunoglobulin G. 
 
 
3.6 Clinical data to support VEGF and HER2 targeted therapy in HER2-positive gastric cancer. 
A recent multicenter phase II trial , led by investigators at Dana Farber, explored the combination of 
capecitabine/oxaliplatin with both bevacizumab (anti-VEGF A ligand monoclonal antibody) and 
trastuzumab in patients with stage IV HER2-positive gastric and GEJ adenocarcinoma. This study 
enrolled 35 patients and demonstrated that combination of capecitabine/oxaliplatin with 
bevacizumab and trastuzumab is safe and results superior efficacy compared to historical control of 
capecitabine/fluoropyrimidine and trastuzumab in HER2-positive gastric cancer. Patients received a 
loading dose of trastuzumab 4mg/kg, day 1. One week later, patients received bevacizumab 
7.5mg/kg/d1, trastuzumab 6mg/kg/d1, oxaliplatin 130mg/m
2/d1 and then q21d. Capecitabine-14 of 
21 days was decreased from 1700mg/m
2/d to 1200mg/m
2/d after 4 of the first 5 patients developed 
Grade 3 diarrhea. Primary endpoint was RR by RECIST 1.1, scored by independent Harvard Tumor 
Imaging Metrics Core. Safety for 30 patients (enrolled after CAP dose change): 16 patients required 
dose modification: capecitabine dose modification in 2 patients; oxaliplatin dose modification in 14 
patients; bevacizumab dose modification in 2 patients; none of the patients required trastuzumab 
dose reduction. Combination of chemotherapy with HER2 and VEGF inhibitors was well-tolerated 
overall with low rate of grade 3 or 4 toxicities. Patients with grade 3-4 adverse events: peripheral 
neuropathy in 3 patients; bleeding in 3 patients; thromboembolic event in 2 patients; 
hypertriglyceridemia in 2 patients; low ANC in 2 patients; hypertension in 1 patients; low platelets in 
1 patient; diarrhea in 1 patient. One patient died of cardiac arrest after 3 years on treatment 
 
In this trial, combination of chemotherapy with trastuzumab resulted in unprecedented response rate 
of 81% (95% C I, 0.59 - 0.88) by blinded review, median PFS 13.9 months (95%CI, 8.5 - 22.33); with 


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IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 11 of 47 
 
 
 
 
 
75% of patients progression free at 6 months, median OS 26.92 months (95%CI, 11.31 - 36.36) 
(Figure 2)
23. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 Waterfall plot of best response (left) and P FS w ith trastuzumab, be vacizumab, and 
capecitabine /oxaliplatin therapy. 
 
 
While these data suggest an important role of angiogenesis in the progression of HER2-positive 
gastric cancer, a first line trial exploring chemotherapy in combination with bevacizumab failed to 
meet its primary endpoints, therefore bevacizumab is not available for treatment of gastric cancer. 
Ramucirumab is approved by the U. S. Food and Drug Administration for patients with gastric and 
GEJ adenocarcinoma and is thus available to study in combination with trastuzumab. Our trial will be 
the first trial to explore first line combination fluoropyrimidine/platinum with ramucirumab and 
trastuzumab in HER2-positive gastric and GEJ cancer. 
 
3.7 Rationale for Correlative Studies 
 
3.7.1 
89 Zr-trastuzumab PETs as pharmacodynamic biomarker 
 
Table 1 
Primary 
M1 
M2 
M3 
ERBB2 CNV 
16.5 
8.9 
9.2 
2.5 
89Zr-P ET SUV 
Baseline 
21 
9 
16 
0 
P ost afatinib 
24 
7 
16 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3 A 89Zr-trastuzumab PET of a patie nt w ith he avily pre tre ated EG 
cancer before and 5 days after s ingle age nt afatinib therapy. B. 
Corresponding pre and post afatinib liver biops y showing pers is tent 
high HER2 immunohistochem istry e xpress ion (IHC 3+) in Segment 2 
liver les ion with pers istently high SUV uptake post afatinib indicate d in 
Table 1. 
Our group in collaboration with Drs. Lewis 
and Weber implemented functional 
imaging with
89 Zr-trastuzumab PET to 
characterize the extent of response 
heterogeneity to HER2 directed therapy 
between primary tumor and metastases in 
HER2-positive gastric and GEJ cancer. 
89Zr-trastuzumab is well-tolerated with 
ideal imaging interval of 5 days post 
injection. Figure 3 shows 89Zr- 
Trastuzumab PET images of a patient 
with heavily pretreated HER2 + GEJ 
cancer which demonstrate the selective 
and high accumulation of 89 Zr- 


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trastuzumab in posterior-esophageal lymph nodes and liver metastasis with very low background of 
uptake in normal organs. Table 1 shows the estimated 
89Zr-trastuzumab PET SUVs and 
corresponding HER2 copy number variation (CNV) in primary tumor and metas tases obtained during 
rapid autopsy of a patient treated with afatinib (Figure 3), where high 
89 Zr SUV value correlates with 
HER2 copy number. Heterogeneity in response is noted with dramatic decrease in lymph node 
uptake after 5 days of afatinib (EGFR/HER2 TKI) and persistently high uptake noted in liver lesions 
and primary esophageal mass. Post-afatinib liver biopsy showed persistently high HER2 expression 
(IHC3+ Figure 3).The patient had radiographic tumor response on 8 week CT, reduction in liver and 
lymph node metastasis.  At the time of therapy failure, the disease progressed in liver and primary 
tumor (sites of persistently high 89Zr-trastuzumab PET), while posterior esophageal mass had 
durable complete regression. 
 
89Zr-trastuzumab PET has a potential advantage over single site biopsies as it can non-invasively 
assess variation in level of HER2 and target engagement in both the primary tumor and all sites of 
metastases simultaneously.
24-26  Our preliminary data in 20 patients imaged thus far at MSK 
demonstrates that 89Zr-trastuzumab PET is feasible and provides exceptional image quality in 
HER2-positive gastric cancer patients with ideal imaging interval of 5 days post radiotracer injection. 
Thus far, by imaging HER2-positive gastric cancer patients with 89Zr-trastuzumab PET (IRB 13-165 
co-PI Janjigian) we have been able to demonstrate 1) the differences in degree of HER2 inhibition 
between afatinib vs afatinib + trastuzumab therapy and 2) variability in ERBB2 (HER2) amplification 
between primary tumor and sites of metastasis. The lead-in cycle with ramucirumab + trastuzumab 
will provide key pilot data on activity on targeted therapy without chemotherapy in first line HER2- 
positive gastric and GEJ cancer. In select patients, baseline and early assessment 
89Zr-trastuzumab- 
PET will be performed under IRB 13-165 with CT/MR I scan performed after the initial 3 weeks (1 
cycle). 
 
3.7.2 Ne xt Ge neration Se quencing in Esophagogastric cancer 
 
Investigators at Broad/DFCI and MSKCC recently led a comprehensive molecular and genomic 
characterization of gastric cancer, evaluating the mutations, copy-number, gene expression and 
DNA methylation across 295 cases through The Cancer Genome Atlas.27  While therapeutic 
development for gastric cancer has largely viewed the disease as a single entity, our unbiased 
informatics approach integrating somatic genomic alterations, methylation and gene expression led 
us to redefine the disease into four distinct subclasses. 1) Tumors with Epstein-Barr virus (EBV) 
infection showed profound hypermethylation, and had a novel finding of 80% of tumors harboring a 
PIK3CA mutation. 2) Microsatellite unstable (MSI) harbored DNA hypermethylation (distinct from 
that of EBV tumors) and had elevated somatic mutation rates with highly recurrent mutations of 
PIK3CA (42%) and ERBB3 (26%) with 12% of tumor having alterations of both genes. 3) Tumors 
with chromosomal instability (CIN) showed marked aneuploidy. While lacking common mutations of 
PIK3CA/ERBB3 they harbored recurrent amplifications of receptor tyrosine kinases, most notably 
HER2 (24%). 4) Tumors lacking aneuploidy and elevated rates of mutation or hypermethylation were 
termed genomically stable (GS), largely those of the diffuse histologic subtype. We identified that 
30% of these tumors harbored novel alterations of the Rho signaling pathway, somatic mutations of 
RHOA or fusion genes involving RHO GTPase activating proteins. This classification structure 
creates a foundation to develop rational therapeutics for distinct groups of patients.  At MSK next 
generation sequencing and gene copy number analysis is routinely performed on all advanced 
gastric tumors using next generation using the MSK-IMPACT TM assay (Integrated Mutation Profiling 
of Actionable Cancer Targets), an on-site 410 cancer-associated gene bait capture, next generation 
sequencing assay. 
 
Using available archival tumor samples from patients treated on the trial, we will profile genomic 
alterations in key cancer-associated genes found to drive resistance in esophagogastric cancer 


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using the IMPACT assay. In brief, DNA from each patient is sheared, and then both tumor DNA and 
normal DNA is end-repaired and ligated to adapters, minimally amplified with bar-coded primers, 
and the exons corresponding to the genes of interest are captured using Agilent SureSelect 
beads.
28,29  We have validated the robustness of this assay using DNA derived from formalin-fixed, 
paraffin embedded (FFPE) tumor tissue.  While TCGA is an international collaboration using 
previously untreated frozen primary tumor specimens c omprehensive molecular profiling is 
increasingly embraced in routine clinical practice on ‗less than perfect‘ archival paraffin embedded 
samples.28,29  A recent comparison with the TCGA results performed by our group compared to MSK 
cohort of esophagogastric cancer patients revealed an over-representation of the C IN subtype (65% 
vs. 50% in TCGA) in gastric cancer patients in United States using chemotherapy treated, metastatic 
tumor specimens.30  According to The Cancer Genome Atlas analysis of the four distinct molecular 
gastric cancer subtypes27, HER2-positive tumors are characterized by chromosomal instability (C IN), 
marked aneuploidy, and dependency on receptor tyrosine kinase signaling. It is therefore possible 
that recurrent amplification in key tyrosine kinases (such as EGFR22, HER331, HER4 and MET) 
contribute to drug resistance. In-depth analysis of tumor samples from patients enrolled in HER2- 
positive trials using next generation sequencing platforms may help identify gene signatures (beyond 
HER2 IHC or FISH) predictive of resistance to HER2 directed agents. 
 
3.7.3 Ce ll-Free DNA (cfDNA) 
Preliminary data obtained in collaboration with MSKCC Laboratory Medicine Core (E. Peerschke and 
A. Samoila) demonstrates that cf DNA collection is feasible and results in adequate DNA yield from 
peripheral blood collection of patient with metastatic HER-2 positive GE junction adenocarcinoma. 
Results from collection of sample from 6 patients treated in Dr. Janj igian‘s clinic, as summarized in 
the table below. Cell-free D NA (cfDNA) will be obtained from plasma samples collected at baseline, 
at week 3, every 9 weeks and at the time of treatment discontinuation. cfDNA will be subject to 
molecular profiling to ident ify ERBB2 amplifications and other gene operations related to protocol 
therapy response and resistance. 
 
 
cfDNA results 
EG Cancer 
Patient 
Tube ID 
Conc (pg/µl) 
Elution volume (µl ) 
Total yield (ng) 
1 
MJ_901 
716 
60 
43.0 
2 
AF_203 
158.4 
60 
9.5 
3 
SF_152 
248 
60 
14.9 
4 
EH_317 
754 
60 
45.2 
5 
AD_129 
1434 
60 
86.0 
6 
EV_233 
450 
60 
27.0 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This will be a single arm study of ramucirumab 8mg/kg administered intravenously on days 1 and 8 
+ trastuzumab (8 mg/kg loading dose; 6 mg/kg maintenance)  administered intravenously every 21 
days. CT/MR I scan will be performed after the initial 3 weeks (1 cycle) to determine response to 


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ramucirumab with trastuzumab, and every 9 weeks thereafter. On subsequent cycles for all patients 
capecitabine 850mg/m
2  will be added, taken orally twice a day for fourteen days (days 1 through 14) 
followed by a 7 day rest period, in addition to cisplatin 80mg/m 2 administered as an IV infusion every 
21 days. Each cycle consists of 21 days. As an alternative fluoropyrimidine, 5-fluorouracil may be 
considered  for  patients  who  cannot  be  administered  capecitabine  for  any  specific  reason.  5 - 
fluorouracil (5-FU) 800mg/m2/day will be administered on Day 1-Day 5 of every 21 days. Oxaliplatin 
may also be considered for patients who cannot be administered cisplatin for any specific reason. 
Oxaliplatin 130 mg/m2/day will be administered on Day 1 beginning with cycle 2. If the patient is not 
a good candidate for induction chemotherapy,  capecitabine/5-FU  and cisplatin/oxaliplatin  can be 
added during cycle 1 of treatment. Treatment will be administered on an outpatient basis. In an effort 
to prevent adverse events, all patients will be premedicated per institutional guidelines prior to 
treatment. All other antiemetics and supportive agents may be administered at the discretion of the 
primary oncologist. Treatment will be performed on the scheduled day ± 7 days to allow for clinic 
closure, holidays, and patient‘s preference.  Adverse events and clinical monitoring will take place 
during weekly physician visits for 6 weeks (2 cycles) followed by visits every three weeks thereafter. 
In case of discontinuation of capecitabine/5-FU and/or cisplatin/oxaliplatin due to cumulative toxicity, 
administration of ramucirumab 8mg/kg IV infusion on days 1 and 8 + trastuzumab 6mg/kg every 21 
days will be continued. 
 
All patients must be able to provide informed consent prior to enrollment. 
 
See Section 10 for treatment table. 
 
4.2 
Intervention 
 
Up to 37 patients will be enrolled on this clinical trial. Patients will receive ramucirumab 8mg/kg 
intravenously on days 1 and 8 + trastuzumab 8mg/kg administered as an IV infusion on cycle 1 
day 1. Patients must have evaluable or measurable disease and will undergo a computerized 
tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis 
<28 days  prior to start of therapy, at three weeks, and every nine weeks  thereafter  (every 3 
cycles), with a scheduling window of up to one to fourteen (1-14) days. CT scans occurring every 
9 weeks will coincide with the 6 month CT scan, and if necessary, an additional scan will be don e 
at 6 months. After cycle 1, capecitabine 850mg/m2   taken orally twice a day for fourteen days 
followed by a one week rest period, and cisplatin 80mg/m2  IV every 21 days will be administered 
in addition to ramucirumab 8mg/kg intravenously day 1 and 8 with trastuzumab 6mg/kg 
intravenously every three weeks. As an alternative fluoropyrimidine, 5-fluorouracil may be 
considered for patients who cannot be administered capecitabine for any specific reason. 5- 
fluorouracil  (5-FU)  800mg/m
2/day  will  be  administered  on  Day  1-Day  5  of  every  21  days. 
Oxaliplatin may also be considered for patients  who cannot be administered cisplatin for any 
specific reason. Oxaliplatin 130 mg/m
2/day will be administered on Day 1 beginning with cycle 2. 
The same imaging modality performed at baseline (CT or MRI) will be repeated at subsequent 
imaging. Intrapatient dose reduction will be allowed depending on the type and severity of toxicity 
encountered provided that criteria for patient withdrawal from study treatment have not been met. 
Once treatment is dose reduced, the patient should not go back to t he starting dose. Therapy will 
be administered in the outpatient setting,  with each cycle consisting of 21 days of continuous 
therapy. The cycle start date will coincide with the physician visit date. 
 
5.0     THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Table 5.1                    Tre atment Regimens/Dosing Schedule 
Drug 
Dose 
Time for Administration (21 day c ycle) 


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Ramucirumab
a  
8mg/kg IV  
Administered over approximately 60 min, D1,D8 
 
 
Trastuzumab 
8mg/kg 
Administered IV every 21 days 
6mg/kg 
 
Capecitabine
b,c  
850mg/m
2  
Administered orally twice daily on D1- D14 
 
Cisplatin
d  
80mg/m
2  
Administered IV on Day 1, 
up to maximum of 6 cycles 
 
 
5-Fluorouracil
e  
800mg/m
2/day 
Administered IV on Day 1 to Day 5 of every 21 days 
 
 
Oxaliplatinf  
130mg/m2  
Administered IV on Day 1 after cycle 1, for up to 
up to maximum of 8 cycles 
 
 
a. Ramucirum ab/trastuzumab will be administered until disease progression or other withdrawal criteria 
are met. Capecitabine/5-FU and cisplatin/oxaliplatin will be initiated after cycle 1. After 1 year, at the 
investigator's discretion, capecitabine/5-FU treatment can be discontinued. Cisplatin will be administered 
up to a maximum 6 cycles (oxaliplatin will be administered up to 8 cycles), in the absence of disease 
progression or until other withdrawal criteria are met. 
b. Capecitabine should be taken within 30 minutes after a meal. Total daily dose of capecitabine administered 
will be 1700 mg/m2. Patients who are unable to take capecitabine on the morning of Day 1 can start their 
capecitabine on the evening of Day 1, in which case the final dose of capecitabine for that cycle will be 
administered on the morning of Day 15. 
c. Premedication per institutional guideli nes is required prior to infusion of ramucirumab. 
d. Maintenance of satisfactory GFR and adequate hydration pre- and post-cisplatin administration 
should be performed per local clinical practices. 
e. As an alternative fluoropyrimidine, 5-FU, may be considered for eligible patients who cannot be 
administered capecitabine for any specific reason (such as malabsorption, difficulty swallowing, or other 
conditions that could affect intake of oral capecitabine medication). This decision should be made prior to 
randomization by the investigator, switching from capecitabine to 5-FU, or vice versa, will not be allowed 
during the study. 5-FU will be administered at 800 mg/m 2/day continuous IV infusion on Day 1-Day 5 
every 21-day cycle, after completion of the cisplatin infusion. 
f. As an alternati ve oxali platin, may be consi dered for eligibl e patients who cannot be admi nistered 
cisplatin for any specific reason. This decision shoul d be made prior to randomizati on by the 
investigator, switching from cisplatin to oxalipl atin, or vice versa, will not be allowed duri ng the study. 
Oxaliplatin will be administered at 130 mg/m 2 continuous IV infusion on Day 1every 21 day cycle, after 
completion of the first cycle. Patients may recei ve reduced dose of oxaliplati n at 20% or 30% dose 
reduction at treating physician discretion 
  
5.1.1. Premedication Prior to Administration of Ramucirumab 
Premedication  per  institutional  guidelines  is  required  prior  to  infusion  of  ramucirumab. 
Additional premedication may be provided at investigator discretion. 
 
5.1.2. Hydration Schedule for Cisplatin 
Maintenance of satisfactory GFR and adequate hydration pre- and post-cisplatin administration 
should be performed per local clinical practices. Cisplatin administration and hydration will be done 
per institutional  guidelines.  It is recommended  that a urinary output of 100 mL/h is maintained 


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before, during and after cisplatin administration. If clinically not contraindicated, patients should be 
advised to drink 3 liters id water or other acceptable fluid over a period of 24 hours before and 
after administration of cisplatin. The suggested hydration schedule is provided in table 5.1.2.1. 
 
 
Table 5.1.2.1 Hydration Schedule for Cisplatin Administration 
 
Time                    Supportive care and Hydration                                                    Duration 
T0a + 1h               Antiemetics                                                                                      15-30min 
1h 30min             Prehydration (1L 0.9% saline)                                                         60 min 
2h 30min             200mL Mannitol 20%                                                                       30min 
3h                        Cisplatin 80mg/m2  in500 mL 0.9% saline                                        60-120min 
4-5h                     Post hydration (1L 0.9% saline) + 20mmol KCl + 1g MgSO4                 2h 
Abbreviations: I.V. = intravenously; po = orally 
a Relative to the start of administration of ramucirumab 
 
5.1.3. Antiemetic Schedule for Cisplatin 
Antiemetic schedule will be done per institutional guidelines. Recommended antiemetic schedule for 
at-home medication after administration of cisplatin: aprepitant 80 mg PO once daily for 2 days, 
dexamethasone 4 mg PO (or equivalent) once daily for 3 days, ondansetron 8 mg PO twice daily for 1 
day (or equivalent), metoclopramide 10 to 20 mg PO 3 times daily if required. If aprepitant is not given 
then the dose of dexamethasone should be doubled. 
 
5.2. Preparation and Administration of Ramucirumab 
Ramucirumab will be provided by Lilly. Patients will receive ramucirumab by I.V. infusion over 
approximately 60 minutes at 8 mg/kg on Day 1 and Day 8 every 21 days in the absence of disease 
progression or until other withdrawal criteria are met. The first dose of ramucirumab is dependent upon 
the  patient's  baseline  body  weight  in  kilograms.  Ramucirumab  infusion  will  be  prepared  and 
administered in accordance to institutional guidelines. 
 
5.3. Preparation and Administration of Trastuzumab 
Trastuzumab will be administered  on every 3 week dosing schedule, with initial loading dose of 8 
mg/kg as a 90 minute infusion, followed by trastuzumab 6 mg/kg every 3 weeks, administered as a 30 
minute infusion if the initial loading dose was well tolerated. Trastuzumab infusion will be prepared and 
administered in accordance to institutional guidelines. 
 
5.4. Preparation and Administration of Cisplatin 
Investigators  should consult  the manufacturer‘s  instructions  for cisplatin  for complete  prescribing 
information  and follow  institutional  procedures  for  the administration  of cisplatin. Cisplatin will be 
2 
administered as an I.V. infusion of 80 mg/m over approximately 60 to 120 minutes on Day 1 every 21- 
day cycles,  up to a maximum  of 6 cycles  in the absence  of disease  progression  or  until  other 
withdrawal criteria are met. Cisplatin will be administered after the completion of the ramucirumab 
infusion. 
 
5.5 Preparation and Administration of Oxaliplatin 
Investigators should consult the manufacturer‘s instructions for Oxaliplatin for complete prescribing 
information and follow institutional procedures for the administration of Oxaliplatin. 
 
Oxaliplatin may be administered instead, at a dose of 130 mg/m 2/day as an I.V.over approximately 2 
hours on Day 1 every 21-day cycles, up to a maximum of 8 cycles in the absence of disease 


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progression or until other withdrawl criteria are met. Oxaliplatin will be administered after the completion 
of the pembrlizumab infusion. 
 
Oxaliplatin will continue until progression of disease, intolerable toxicity, or other withdrawal criteria are 
observed. After 1 year, at the treating physician‘s discretion, oxaliplatin treatment can be discontinued. 
 
 
5.6. Administration of Capecitabine 
Investigators should consult the manufacturer‘s instructions for capecitabine for complete prescribing 
information and follow institutional procedures for the administration of capecitabine. Capecitabine will 
2 
be orally self-administered at 850 mg/m twice daily on Day 1 through Day 14, followed by a 7-day 
non-dosing  interval  in  each  21-day  cycle  in  the  absence  of  disease  progression  or  until  other 
withdrawal criteria are met. Patients who are unable to take capecitabine on the morning of Day 1 can 
start their capecitabine on the evening of Day 1 in which case the final dose of capecitabine for that 
cycle will be administered on the morning of Day 15. Capecitabine should be taken within 30 minutes 
after a meal. Capecitabine will continue until PD, intolerable toxicity, or other withdrawal criteria are 
observed. After 1 year, at the investigator's discretion, capecitabine treatment can be discontinued. 
 
5.7 Preparation and Administration of 5-Fluorouracil 
Investigators should consult the manufacturer‘s instructions for 5-FU for complete prescribing 
information and follow institutional procedures for the administration of 5-FU. 
 
Only for patients unable to take oral medications (because of certain circumstances such as 
malabsorption, difficulty swallowing, or other conditions that could affect intake of oral capecitabine 
medication), 5-FU may be administered instead, at a dose of 800 mg/m2/day as a continuous infusion 
over 5 days (Day 1 to Day 5 of each cycle), every 21 days. This decision should be made prior to 
registration by the treating physician; switching from capecitabine to 5-FU, or vice versa, will not be 
allowed during the study. 5-FU will be administered after completion of the cisplatin infusion. 
 
5-FU will continue until progression of disease, intolerable toxicity, or other withdrawal criteria are 
observed. After 1 year, at the treating physician‘s discretion, 5-FU treatment can be discontinued. 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
• Patients must have pathologically or cytologically MSKCC confirmed diagnosis of 
gastric or GEJ adenocarcinoma. 
• Patients must have Stage IV gastric or GEJ adenocarcinoma with HER2 
overexpression and/or amplification as determined by next generation sequencing 
assay, immunohistochemistry (IHC 3+) or fluorescent in situ hybridization (FISH+ is 
defined as HER2:CEP17 ratio ≥ 2.0). MSKCC confirmation of HER2 status is not 
mandatory prior to enrollment and treatment on study. For patients with outside HER2 
testing, if sufficient tissue is available HER2 testing will be repeated at MSKCC for 
purpose of analysis and will not impact the patient‘s eligibility. 
• Available archival tumor tissue should be submitted to MSKCC for IMPACT analysis, 
but will not be required prior to registration. Note: if tissue is depleted, patient will still 
be eligible after discussion with the PI. 


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• 
Patients must have disease that can be evaluated radiographically. This may be 
measurable disease or non-measurable disease per RECIST 1.1. 
• 
Patients may have received no prior chemotherapy for Stage IV disease. Patients 
may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if 
more than 6 months have elapsed between the end of adjuvant therapy and 
registration. 
• 
Age of 18 years or older. 
• 
ECOG performance status 0-1. 
• 
Peripheral neuropathy ≤ grade 1 
• 
Patients who have adequate hepatic function as defined by a total bilirubin ≤1.5 
mg/dL (25.65 µmol/L) (except patients with Gilbert‘s disease), and aspartate 
transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 times UL N or ≤ 5.0 times 
the ULN in the setting of liver metastases. 
• 
Patients who have adequate hematologic function, as evidenced by absolute 
neutrophil count (ANC) ≥1500/µL, hemoglobin ≥9 g/dL (5.58 mmol/L), and platelets 
≥100,000/µL. 
• 
Patients who have adequate renal function as defined by a serum creatinine ≤1.5 x 
ULN, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute 
(that is, if serum creatinine is >1.5 x ULN, a 24-hour urine collection to calculate 
creatinine clearance must be performed). 
• 
Patients whose urinary protein is ≤1+ on dipstick or routine urinalysis (UA) If routine 
analysis is >2+, a 24-hour urine collection for protein must demonstrate <1000 mg of 
protein in 24 hours to allow participation in this protocol). 
• 
The patient must have adequate coagulation function as defined by International 
Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds 
above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin 
must be switched to low molecular weight heparin and have achieved stable 
coagulation profile prior to first dose of protocol therapy. 
• 
Patients, must be postmenopausal, surgically sterile, or using effective contraception 
(hormonal or barrier methods). 
• 
Female patients of childbearing potential must have a negative serum pregnancy test 
within 7 days of study entry. 
 
6.2 
Subject Exclusion Criteria 
 
•   Patients  who  have  uncontrolled  or  poorly-controlled   hypertension  (>139  mmHg 
systolic or >89 mmHg diastolic for >4 weeks) despite standard medical management. 
•   Patients receiving any concurrent anticancer therapy or investigational agents with the 
intention of treating gastric/GEJ cancer. Previously received trastuzumab as part of a 
regimen in the metastatic setting with evidence of progression. 89 Zr-trastuzumab use 
as imaging agent for 
89 Zr-trastuzumab PET permitted. 
•   Patients having: 
o Cirrhosis at a level of Child-Pugh B (or worse) or 
o 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. 
•   Active or clinically significant cardiac disease including: 


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o Congestive heart failure – New York Heart Association (NYHA) > Class II. 
o Active coronary artery disease. 
o Left ventricular function <50%. 
o Cardiac arrhythmias requiring anti-arrhythmic  therapy other than beta blockers or 
digoxin. 
o Unstable angina  (anginal symptoms  at rest), new-onset  angina within  3 months 
before  randomization,  or  myocardial  infarction  within  6  months  before 
randomization. 
o Patients who have 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 first dose of protocol therapy. 
o Patients   who  are   receiving   chronic   antiplatelet   therapy,   including      aspirin, 
nonsteroidal anti-infalmmatory drugs (NSAIDs, cinluding ibuprofen, naproxe n, and 
others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin (maximum 
dose 325 mg/day) is permitted. 
•   Evidence or history of bleeding diathesis or coagulopathy. 
•   Patients who have experienced any Grade 3-4 GI bleeding within 3 months prior to 
first dose of protocol therapy. 
•   Unwillingness to give written informed consent, unwillingness to participate, or inability 
to comply with the protocol for the duration of the study. 
•   Patients with prior trastuzumab treatment. 
•  Patients with known active brain or central nervous system metastases, including 
leptomeningeal  disease.  Patients  with treated  and asymptomatic  brain metastas es 
may be eligible after discussion with PI. 
•   Patients who are pregnant or breast-feeding. 
•   Patients with a serious or nonhealing wound, ulcer, or bone fracture within 28 days 
prior to enrollment. 
•   The patient has undergone major surgery within 28 days prior to first dose of protocol 
therapy 
•   Patients who have elective or planned major surgery to be performed during the 
course of the clinical trial. Minor surgery/subcutaneous venous access device 
placement within 7 days prior to first dose of protocol therapy is permitted. 
•   Patients may not have had radiation within 28 days prior to first dose.  weeks of 
registration. 
•  Patients may not have any other medical condition or reason, in that investigator‘s 
opinion, makes the patient unstable to participate in a clinical trial. 
•  The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), 
or any other significant thromboembolism (venous port or catheter thrombosis or 
superficial venous thrombosis are not considered ―significant‖) during the 3 months 
prior to first dose of protocol therapy. 
•  Patients may not have a prior history of GI perforation/fistula (within 6 months of first 
dose of protocol therapy) or risk factors of perforation. 
 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients that are eligible will be identified for enrollment from MSKCC clinical practice and 
clinic  lists.  No  additional  measures,  e.g.  advertisement,  payment  to  patients,  will  be 


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employed to recruit patients. Patients will be accrued to this study without regard for gender 
or minority status. 
 
Inclusion of women and minorities 
 
The investigators take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. There will be no limitation with regards to race or 
gender. 
 
Our institutional demographics for accrual of patients on esophageal, gastric and GE junction 
cancer trials reflect the national incidence of this disease: 10-15% of our patients have been 
women; African-American males comprise 3-5% of patients treated on protocol. Given that 
our  protocol  accrual  closely  reflects  the  national  incidence  of  this  disease,  no  specific 
strategy will be undertaken to recruit women or persons of color on this trial. None of the 
eligibility requirements (section 6) will make it difficult for diverse populations to participate in 
this trial. 
 
This protocol does not include children because the number of children with esophageal, 
gastric and GE junction cancer is very small and because the majority are already accessed 
by a nation-wide pediatric cancer research network. This statement is based on exclusion 4b 
of the NIH Policy and Guidelines on t he Inclusion of Children as Participants in Research 
Involving Human Subjects. 
 
8.0 
PRETREATMENT EVALUATION 
 
Pretreatment evaluation will be performed within 2 weeks of study entry and will include: 
• History, concomitant medications, and toxicity assessment. 
• Physical exam, vital signs, and performance status. 
• Serum pregnancy test for women of childbearing potential (WOCBP) 
In addition, all WOCBP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (e.g. late or missed period) at any time during 
study participation. 
• Routine urinalysis 
• Laboratory    evaluation    including    complete    blood    count,    magnesium    and 
comprehensive  chemistry  panel  (includes  BUN,  creatinine,  ALT,  AST,  albumin, 
glucose, total protein, calcium, bilirubin, bicarbonate, sodium, chloride, potassium, 
alkaline phosphatase), and INR&APTT 
• Research blood tests for cfDNA analysis. 
 
The following must be obtained within one month prior to starting protoc ol therapy: 
• CT/MR I scan  of  chest,  abdomen,  and  pelvis  <4  weeks  prior  to  start  of  study 
treatment. 
• Electrocardiogram 
• Assessment   of   Left   Ventricular   Ejection   Fraction   (LVEF)   as   measured   by 
echocardiography (ECHO) with speckle tracking. If an ECHO cannot be performed, a 
multi-gated acquisition scan (MUGA) scan can be performed. If possible, the same 
method of measurement is recommended throughout the study. 


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IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 21 of 47 
 
 
 
 
 
To be completed any time prior to starting therapy: 
• Histological confirmation of gastric or GEJ adenocarcinoma at MSKCC prior to study 
enrollment. 
• 
Patients with outside biopsies who do not have enough tissue for correlative studies 
will still be considered eligible. MSKCC confirmation of HER2 status is not mandatory 
prior to enrollment and treatment but should be confirmed. 
• 
Available archival tumor tissue should be submitted to MSKCC for future correlative 
analysis, but will not be required prior registration. Note: if tissue is depleted, patient 
will still be eligible after discussion with the PI. 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Treatment will be administered on an outpatient basis. Ramucirumab 8mg/kg will be 
administered intravenously on day 1 and day 8 + trastuzumab 8mg/kg administered as an IV 
infusion on cycle 1 day 1. CT/MR I scan will be performed after the initial three weeks (cycle 
1) to determine response, and every 9 weeks thereafter. CT scans occurring every 9 weeks 
will coincide with the 6 month CT scan, and if necessary, an additional scan will be done at 6 
months for assessment of PFS at 6 months. On subsequent cycles, capecitabine 850mg/m 2 
will be added for all patients, taken orally twice a day for fourteen days followed by a one 
week rest period, in addition to cisplatin 80mg/m2  administered as an IV infusion every (3 
weeks) 21 days, ramucirumab 8mg/kg IV on day 1 and day 8 + trastuzumab 6mg/kg every 3 
weeks. As an alternative fluoropyrimidine, 5-fluorouracil may be considered for patients who 
cannot   be   administered   capecitabine   for   any   specific   reason.   5-fluorouracil   (5-FU) 
800mg/m2/day will be administered on Day 1-Day 5 of every 21 days. Oxaliplatin may also be 
considered  for  patients  who  cannot  be  administered  cisplatin  for  any  specific  reason. 
Oxaliplatin 130 mg/m2/day will be administered on Day 1 beginning with cycle 2. If the patient 
is    not    a    good    candidate    for    induction    chemotherapy,    capecitabine/5-FU    and 
cisplatin/oxaliplatin  can be added during cycle 1 of treatment.   Each cycle consists  of 21 
days. In an effort to prevent adverse events, all patients will be premedicated per institutional 
guidelines   prior  to  treatment.   All  other  anti-emetics   and  supportive  agents   may  be 
administered at the discretion of the primary oncologist. Treatment will be performed on the 
scheduled day ± 7 days. Adverse events and clinical monitoring will take place during weekly 
physician visits for 6 weeks followed by every two weeks visits thereafter. In case of 
discontinuation of capecitabine and/or cisplatin due to cumulative toxicity, administration of 
ramucirumab 8mg/kg IV infusion day 1 and day 8 + trastuzumab 6mg/kg every three weeks 
will be continued. 
 
Grade 1 and 2 toxicities  will be managed with medical therapy specific  to the particular 
adverse reaction.  Intrapatient  dose reduction will be allowed  depending  on the type  and 
severity  of  toxicity  encountered  provided  that  criteria  for  patient  withdrawal  from  study 
treatment have not been met. Evaluation in person will be made when there is concern for a 
drug-related toxicity irrespective of grade. 
 
 
9.1 Collection of blood of cell-free DNA (cfDNA) 
 
Cell-free DNA (cfDNA) be obtained from plasma samples collected at baseline, week 3, every 9 
weeks, and at the time of treatment discontinuation 


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IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 22 of 47 
 
 
 
 
 
Approximately 20 ml of whole blood per visit (baseline, every 9 weeks, and treatment 
discontinuation) will be collected at ambient temperature into 2x 10mL cell free DNA BCT tubes for 
plasma isolation. 
 
 
 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Procedure 
Screena, p 
Cycle 1 (21 days)p 
Cycle 2g, p 
Cycle 3-p 
subsequent cycles 
EOT
c, p
 
F/U
d, p
 
D 
1 
D8 
D15 
D 
1 
D8 
D15 
D1 
D8 
D15 
Medical 
Hx/Dem ographics 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy 
Test 
X 
Tumor biopsy 
samples and blood 
collection for 
biomarkerse 
X 
Physical examb 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
Perform ance status 
X 
X
f
 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicities/AE 
assessment
h 
X 
Reported from screening throughout all subsequent 
cycles. 
X 
X 
Hem atologyb 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Chemistryb 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
INR&AP TT 
X 
Urinalysis b 
X 
Xf 
X 
X 
X 
X 
X 
Research Test: 
cfDNA
q 
X 
X 
X E very 9 weeks 
(3 cycles) 
X 
MRI/ CT assessmenti 
X 
X 
E very 9 weeks (3 
cycles) after initial 
CT 
X 
X 
Conc omitant 
medicationsj 
X 
All medications taken during the study will be docum ented 
X 
12-l ead ECG 
X 
Xf 
ECHO/ MUGA0 
X 
X 
E very 12 weeks (4 
cycles) o 
89Zr- trastuzumab 
PET
n 
X 
X 
Ram ucirum abk 
X 
X 
X 
X 
X
g
 
X 
Trastuzumabl 
X 
X 
X
g
 
Capecitabine/5-FU+ 
cisplatin/oxaliplatin
m 
X 
X
g
 
Capecitabine 
compliance 
X 
X 
X 
 
ECG = electrocardiogram; ECHO = echocardiogram; EOT = end of treatment; FU = foll ow -up; LVEF = left 
ventricular ejection fraction; h = hour(s); hx = history; MUGA = m ultiple gated acquisition scan 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 23 of 47 
 
 
 
 
 
Radi ological imagi ng studies  <28 days  prior to start of study  treatment,  other screeni ng eval uation  within 2 
weeks pri or to start of study treatment. 
 
a 
Radi ological imagi ng studies  and electrocardi ogram  <28 days  prior to start of study  treatment,  other 
screening evaluation within 2 weeks pri or to start of study treatment. 
b 
Physical  exam  (vital  signs  [BP,  heart  rate,  tem perature],  weight,  and  a revi ew  of body  sys tem s ), 
chemistry, and urinalysis on intended days 1 and 15 of each cycle prior to chemotherapy or ≤ 72 h pri or 
to  dosing.  If  chem otherapy   is  delayed  then  the  physical  exam  must  be  repeated   weekly  until 
retreatment or ≤ 72 h pri or t o dosing. Hem atology and physical exam will be done weekly for the firs t 6 
weeks and on the intended days 1 and days 15 of each cycle pri or to the chemotherapy or ≤ 72 h pri or 
to dosing thereaft er. 
c 
Within 14 days of tum or progression or study treatment discontinuation.  If permanent discontinuati on o f 
the study drug falls on a scheduled vis it, examinations as defi ned for EOT shoul d be perform ed ins te ad 
of the exami nations of the scheduled visit. If patient is unabl e to come i n to see M D, a nurse phone call 
to eval uate toxicities can be substituted. 
d 
Assessment by treating medical oncol ogist as clinically indicated. For those patients no longer foll owed 
by MSKCC  MD,  a nurse will  make  a follow up phone call every  3 m onths  to assess  pati ent‘s  vital 
status. 
e 
A sample of archi val tum or biopsy, or other availabl e tumor biopsy and one time research blood sam ple 
should be submitted for biomarker analysis during screeni ng. Patients should be consented for protocol 
#12-245. Tum or biopsy samples may also be submitted for bi omarker analysis at any other time duri ng 
the course of the clinical study. 
f 
Physical exam, laboratory assessments  and urinalysis are not requi red if screening assessments were 
done withi n 72 hours of fi rst dose. ECG is not requi red if screeni ng ECG was done within 7 days of fi rs t 
dose. 
g 
In cycle  2  procedures  will  be  perform ed  identical  to cycle  1.  Radiologic  tumor  assessment  will  be 
performed after the i nitial three weeks to determi ne response and e very 9 weeks thereafter. 
h 
AE monitori ng s houl d conti nue for at least 4 weeks following the l ast dose of study treatmen t. AEs  that 
occur within 30 days following the last study treatment will be foll owed until resoluti on. 
i 
The baseli ne and subsequent scans to assess response must be performed using identical techni que. 
Radi ological imagi ng studies to evaluate tum or status will be perform ed after the initial three weeks  (1 
cycle) to determine response and  every  9 weeks  thereaft er whil e on study  regardl ess of tre atm ent 
delays. CT scans occurring every 9 weeks will coincide with t he 6 m onth CT scan, and i f necess ary, an 
additional scan will be done at 6 months. F or subj ects who have entered the survi val follow -up peri od 
and have not yet experienc ed PD, every effort should be made to foll ow -up for tum or evaluati on ( by C T 
or M RI) until progression  of their m alignancy  every  9 weeks,  or until a new anticancer treatme nt  is  
started.  Window  of +/- 7 days  during  the  fi rst  cycle,  and  +/-14  days  for  all  subsequent  cycles  for 
radi ologic al imaging studies . Patient may have CT or M RI scan on an earli er or l ater dat e than all ow ed 
by the window of +/-14 days, if clinically indicated at the investigator‘s discretion. 
j 
All medication gi ven within 2 weeks prior to the start of study treatm ent. 
k 
Ram ucirum ab 8m g/kg admi nistered intravenously on day 1 and day 8. 
l 
Trastuzumab 8m g/kg administered as an IV i nfusion on cycle 1 day 1, foll owed by infusion of 6m g/kg 
every 3 weeks 
m   CT/MRI will be perform ed after the initial three weeks to determine response and every 9 weeks 
thereafter. On subsequent cycles capecitabine 850m g/m2 will be added, taken orally twice a day for 
fourteen days followed by a one week rest peri od, in addition to cisplatin 80mg/ m
2 admi nistered as an 
IV infusion every three weeks. Capecitabine may be skipped if clinically indicated. Only for patients 
unable to take oral medicati ons (because of certai n circumstances, such as malabsorption, difficulty 
swallowing, or other conditions that could affect intake of oral capecitabi ne medication), 5 -FU (800 
mg/m2/day continuous infusion on Day 1 to Day 5 of Cycle 2 an d on) may be considered. The decision 
to treat with capecitabine or 5 -FU needs to be made prior to randomization by the investigator. 
Switching between 5 -F U and capecitabi ne is not allowed. 
n 
Some patients will have 
89 Zr-trastuzum ab PE T at baseline and week 3 (any time between days 15 and 
21) only if deemed appropri ate by investigator. Patients will have to sign a written informed consent for 
13-165. Patient participation to this procedure is vol untary. 
o 
Baseline ECHO/MUGA must be obtained within one month prior to starting protocol therapy. ECHO with 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 24 of 47 
 
 
 
 
 
speckle tracking will be the preferred modality for LVEF assessment. When possible, the same method 
used to measure LVEF at baseline (either ECHO or MUGA) should be used throughout the study. Repeat 
LVEF assessments will be perform ed after 6 and 12 weeks of initiating protocol therapy, and thereafter 
every 12 weeks (4 cycles). Window of +/-14 days for ECHO/MUGA. 
p 
To avoi d violations  and deviations  from the protocol,  blood tests, CT/MRI scans,  and physician visits 
(including   physical   exam,   vitals,   blood   pressure,   weight,   performance   status,   and   concomitant 
medications) may vary by up to one to fourteen (1 -14) days to allow flexibility of scheduling. 
q 
Cell-free DNA (cfDNA ) will be obtai ned from plasma sampl es collected at baseline,  at week 3, every 9 
weeks  and  at  the  time  of treatm ent  discontinuation,  as  the  same  time  as the  MRI/CT eval uations . 
Research tests may vary by up to one to fourt een (1-14 days). 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
The investigator should withdraw a patient from ramucirumab for any of the following reasons: 
 
• Arte rial thromboembolic e vent (ATE): Any Grade 3-4 ATE occurring or worsening during 
anticoagulation therapy, require permanent discontinuation of ramucirumab therapy. Any 
ATE leading to discontinuation of ramucirumab therapy will be considered serious and 
should be reported via the serious adverse event (SAE) mechanism. 
• Ve nous thromboembolic e vent (VTE): A Grade 3 or 4 VTE occurring or worsening during 
anticoagulation therapy, that is considered by the investigator to be life-threatening, or 
symptomatic and not adequately treated by anticoagulation therapy. Any VTE leading to the 
discontinuation of ramucirumab therapy will be considered serious and should be reported 
via the serious adverse event (SAE) mechanism. 
• Severe bleeding: Grade 3-4 bleeding due to any reason 
• Hype rtension that cannot be medically controlled with antihypertensive therapy in patients 
with hypertensive crisis or hypertensive encephalopathy; patients with grade 4 hypertension 
must not receive further treatment with ramucirumab 
• Infusion-related re action: Grade 3-4 IRR must not receive further treatment with 
ramucirumab. 
• Gastrointestinal perforation or fistulae: Any clinically apparent GI perforation or fistulae; 
• Impaired wound healing: Discontinue ramucirumab if wound is not fully healed within 42 
days of withholding ramucirumab; 
• Ne w occurrence of hepatic e ncephalopathy and/or hepatorenal syndrome re sulting 
from liv er cirrhosis; 
• Reversible Posterior Le ukoencephalopathy Syndrome (RPLS); all cases of RPLS must 
be reported via the SAE mechanism 
• Urine protein: The patient will have ramucirumab permanently discontinued if the protein 
level is >3 g/24 hours, if there is a third occurrence of >2 g/24 hours, or if the protein level 
does not return to <2g/24 hours within 2 weeks. 
• Any Grade 4 (life-threatening) nonhematologic toxicity considered by the investigator to 
be possibly, probably or definitely related to ramucirumab; 
• Dose modifications: >2 dose reductions. 
• He patic encephalopathy: Any patient who expe riences signs of hepatic e ncephalopathy 
or other serious signs of liver impairment such as hepatorenal syndrome must be 
permanently discontinued from ramucirumab therapy. 
 
Patients who are permanently discontinued from ramucirumab will continue to be in the study, and 
should continue to receive the other study agent(s) in the absence of disease progression, in 
accordance with this protocol. 


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IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 25 of 47 
 
 
 
 
 
 
11.1.1. General Dose-Modification Guidelines for Ramucirumab 
• 
Treatment for the first cycle should only commence if all the inclusion criteria are met. For 
subsequent cycles, dose delay/modification  is permitted as described in section specific for 
ramucirumab, trastuzumab, capecitabine, and cisplatin. 
• 
Ramucirumab dose modifications are not required for hematologic laboratory abnormalities unless 
associated with clinical symptoms. As an initial step, the dose of chemotherapy should be reduced 
first before any dose reductions for ramucirumab are considered. 
• 
All study treatment will be discontinued in case of disease progression. 
• 
Dose modifications are permanent; no dose escalations allowed after dose reduction. 
• 
Control hypertension prior to initiating treatment with ramucirumab. 
• 
Temporarily suspend ramucirumab for severe hypertension until medically contro lll ed. 
• 
Ensure any wound is fully healed prior to commencing or continuing ramucirumab. 
• 
Ramucirumab/trastuzumab  therapy  should  continue  as  scheduled  if  there  is  a  delay  or 
discontinuation of capecitabine and/or cisplatin. When the subsequent cycle of chemotherapy 
is  initiated,  administration  of ramucirumab,  trastuzumab  and chemotherapy  will be 
resynchronized according to the study design described in this protocol (that is, the cycle will 
begin at Day 1 for ramucirumab, trastuzumab and chemotherapy). 
• 
Doses  of ramucirumab  omitted  are not  replaced  or  restored;  instead,  the patient  should 
resume the planned treatment cycles. 
• 
In the case of ramucirumab-related  toxicity, ramucirumab will be delayed for one week and 
administered on Day 8 of the treatment cycle provided that ramucirumab-related toxicities have 
resolved to Grade <2 or baseline. 
• 
If  a  toxicity  related  to  ramucirumab  does  not  resolve  in  the same  treatment  cycle,  the 
administration of ramucirumab can be delayed up to 42 days. If the toxicity does not resolve 
within 42 days, ramucirumab will be discontinued unless it is determined by the treating 
investigator that the patient might benefit from continuation of ramucirumab. 
• 
If there is a delay or modification in administration of ramucirumab due to toxicity, treatment 
with  other  study  agent(s)  should  continue  as  scheduled.   If  clinically  appropriate,   the 
investigator can delay all treatment components up to a maximum of 7 days to allow 
synchronized administration of all agents. 
• 
Patients with unresected primary tumors (or local recurrence) who develop Grade 3 and 4 
venous  thromboembolism   may  also  receive  anticoagulation  and  continue  ramucirumab 
therapy provided that the tumor does not confer an excessive bleeding risk, in the opinion of 
the treating physician. 
 
11.1.2. Dose-Modification Guidelines for Ramucirumab for Specific Adverse Events 
The sections below provide dose-modification guidelines for ramucirumab for specific AEs related 
to administration of ramucirumab. Refer to Section 11.0 for criteria for discontinuation of 
ramucirumab. 
 
Toxicity 
Grade 
Dose adjustment for 
Ramucirumab 
Reversible, non-life-threatening 
toxicity (for example, 
fatigue/anorexia/fever/laboratory 
abnormalities
a) 
For hypertension, see below. 
First 
instance 
3/4 
8 mg/kg (full dose) on recovery 
to Grade <1 within the same 
cycle without interruption 
Second 
instance 
3/4 
6 mg/kg (first dose reduction) for 
next dose on recovery to Grade 
<1 


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Approval date: 24-Nov-2017 
Page 26 of 47 
 
 
 
 
 
Subseque 
nt 
instances 
3/4 
Discontinue (if a third dose 
reduction is needed) 
Infusion-related reactions 
1-2 
If clinically indicated, stop the 
infusion temporarily and then 
reduce the infusion rate of 
ramucirumab by 50% 
>3 
Discontinue 
Hypertension controlled with medications 
1 
8 mg/kg (full dose) without 
interruption 
Resolution 
to Grade 
<2 within 3 
weeks 
2/3 
Delay ramucirumab 
administration. Administer 8 
mg/kg (full dose) once 
hypertension is contro lll ed with 
medications and is Grade <2 
within 3 weeks. 
Resolution 
to Grade 
<2 within 3 
to 6 weeks 
2/3 
Delay ramucirumab 
administration. Administer 
ramucirumab at 6 mg/kg if 
hypertension is Grade <2 by the 
fourth week. Discontinue 
ramucirumab if blood pressure 
does not improve to Grade <2 by 
the sixth week (42 days) despite 
medical management of 
hypertension. 
Uncontrolled hypertension, hypertensive crisis, 
hypertensive encephalopathy 
4 
Discontinue 
Congestive heart failure 
3/4 
Discontinue 
Proteinuria (urinalysis <2+)a 
Administer baseline or full 
previous dose of ramucirumab 
without interruption 
Proteinuria (urinalysis 2+) 
a
 
Administer baseline or full 
previous dose of ramucirumab 
without interruption. Perform a 
24-hour urine collection within 3 
days prior to the next 
ramucirumab dose 
administration. If the 24-hour 
collection shows proteinuria 
<2g/24 hours administer 
unchanged dose of 


Memorial Sloan Kettering Cancer Center
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Approval date: 24-Nov-2017 
Page 27 of 47 
 
 
 
 
 
ramucirumab. If >2g/24 hours 
then follow dose adjustment 
based on 24-hour collection 
(below) 
Proteinuria (urinalysis >2+) a 
Delay ramucirumab 
administration. Perform a 24- 
hour urine collection within 3 
days prior to the next 
ramucirumab dose 
administration. If the 24-hour 
collection shows proteinuria 
<2g/24 hours administer 
unchanged dose of 
ramucirumab. If >2g/24 hours 
then follow dose adjustment 
based on 24-hour collection 
(below) 
Proteinuria based on 24-hour urine 
collection >2g/24 hoursb 
First 
instance 
6 mg/kg once urinary protein 
returns to <2g/24 hours 
Second 
instance 
5 mg/kg once urinary protein 
returns to <2g/24 hours 
Third 
instance 
Discontinue (if a third dose 
reduction is needed) 
Proteinuria based on 24-hour urine collection 
>3g/24 hoursb  or in the setting of nephrotic 
syndrome 
Discontinue 
Arterial thromboembolic events, venous 
thromboembolic events, or bleeding 
3/4 
Discontinue 
Gastrointestinal perforation or fistulae 
Any 
Discontinue 
RPLS 
Discontinue 
Liver injury/liver failure 
Any 
Discontinue 
Abbreviations: RPLS = Reversible Posterior Leukoencephalopathy Syndrome 
a Dose modifications are not required for hematologic laboratory abnormalities unless associated with 
clinical symptoms. As an initial step, the dose of chemotherapy should be reduced first before any dose 
reductions for ramucirumab are considered. 
b Urinalysis test for proteinuria should be performed on day 1 and day 15 for the first 2 cycles, then on 
the first day of each cycle thereafter. If both urinalysis and 24-hour tests are performed, the results of 24- 
hour collection should be used for clinical decision-making. 
 
11.1.2.1. Treatment Guidelines for Specific Adverse Events Related to Ramucirumab 
Adverse events of concern, which may or may not be associated with ramucirumab therapy, may 
include IRRs, hypertension, arterial or venous thromboembolic events, bleeding (hemorrhagic) 


Memorial Sloan Kettering Cancer Center
IRB Number: 15-301 A(9) 
Approval date: 24-Nov-2017 
Page 28 of 47 
 
 
 
 
 
events, GI perforation, proteinuria, congestive heart failure (CHF), surgery and impaired wound 
healing, liver injury/liver failure, reversible posterior leukoencephalopathy syndrome (RPLS). 
 
11.1.3. Infusion-Related Reactions 
Any treatment-related infusion-related reactions are defined according to the NCI-CTCAE Version 4.0 
definition  (General  disorders  and  administration  site conditions).  Symptoms  occurring  during  or 
following infusion of investigational therapy may also be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome (Immune system disorders). In the setting 
of symptoms occurring during or following infusion of investigational therapy, investigators are 
encouraged to use the AE term "infusion-related reaction" and any additional terms (including those not 
listed here) that best describe the event. Consistent with usual medical practice, the patient should be 
clinically monitored and selected parenteral medications may be utilized for Grade 2 
allergic/hypersensitivity reaction as detailed below. Clinical and laboratory monitoring will be performed 
per institutional guidelines. 
 
Grade 1 IRR 
• Slow the infusion rate by 50%. 
• Monitor the patient for worsening of condition. 
• For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent); additional premedication may be administered at the investigator's discretion. 
 
Grade 2 IRR 
• 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 IRR has resolved or decreased to Grade 
1; the infusion duration should not exceed 2 hours. 
• Monitor for worsening of condition. 
• For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent); additional premedication may be administered at the investigator's discretion. 
 
For a second Grade 1 or 2 IRR, administer dexamethasone 8-20 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 8-20 mg I.V. (or equivalent). 
 
Grade 3 or Grade 4 IRR 
• Stop the infusion and disconnect the infusion tubing from the patient. 
• Administer diphenhydramine hydrochloride I.V. (or equivalent, per institutional guidelines), 
dexamethasone I.V. (or equivalent, per institutional guidelines), bronchodilators for 
bronchospasm, 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 3 or 4 IRR will not receive further ramucirumab treatment, but will 
continue to be followed on the protocol. 
 
 
11.1.4. Hypertension 
The following are general treatment guidelines for hypertension (an expected AE in patients 
receiving  ramucirumab)   that  develops   during  the  study.  Routine  clinical  and  laboratory 
monitoring is highly recommended in patients who develop de novo hypertension or experience a 


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deterioration in previous hypertension. Control hypertension prior to initiating treatment with 
ramucirumab. Monitor blood pressure prior to every administration of ramucirumab or more 
frequently as indicated during treatment. 
 
Grade 1 hypertension 
• Continue  ramucirumab  therapy  at baseline  or  previous  dose.  Initiate  or  continue 
antihypertensive therapy if clinically indicated. 
 
Grade 2 or Grade 3 hypertension 
• If the hypertension is not associated with symptoms, continue ramucirumab therapy and initiate 
or continue antihypertensive therapy. 
• If the hypertension  is associated with symptoms,  hold ramucirumab  therapy and initiate or 
continue antihypertensive therapy until symptoms resolve to Grade <2 (systolic BP < 140 mm 
Hg or diastolic BP <90 mm Hg) 
• If ramucirumab administration is interrupted due to hypertension or related symptoms, review 
blood pressure once a week for 3 weeks, and if less than Grade 2 administer previous dose of 
ramucirumab 
• Patient should be referred for cardiology evaluation for further hypertension management if 
grade >2 hypertension. 
 
If blood pressure improves to Grade <2 by the fourth week, reduce ramucirumab dose to 6 mg/kg on 
Day 1 and Day 8. 
• If blood pressure improves to Grade <2 by the sixth week, reduce ramucirumab dose 
to 5 mg/kg on Day 1 and Day 8. 
• If blood pressure does not improve to Grade <2 by the sixth week 
(42 days) discontinue ramucirumab. 
Grade 4 or refractory hypertension 
• Patients with Grade 4 hypertension (life-threatening consequences, for example, malignant 
hypertension, transient or permanent neurologic deficit, hypertensive crisis; or urgent 
intervention indicated) or patients whose hypertension is poorly controlled (>160 mm Hg 
systolic or >100 mm Hg diastolic for >6 weeks [>42 days]) despite appropriate oral medication 
(for example, 2 or more oral agents at maximum tolerated dose) will be discontinued from 
ramucirumab. 
 
11.1.5 Thromboembolic Events 
Investigators should perform all testing required to fully characterize arterial or venous 
thromboembolic/vascular events. The incidence and type of thrombotic/vascular events will be 
collected and reported. 
 
Ramucirumab therapy should be discontinued in the event of any Grade 3 or 4 arterial 
thromboembolic event or any Grade 3 or 4 venous thromboembolic event that is considered by the 
investigator to be life-threatening, or symptomatic and not adequately treated by anticoagulation 
therapy. At the investigator's discretion, ramucirumab therapy may be continued in the setting of an 
incidentally diagnosed, asymptomatic deep vein thrombosis or pulmonary embolism or following a 
symptomatic deep vein thrombosis or pulmonary embolism when symptoms have resolved with the 
institution of anticoagulation therapy. Ramucirumab should also be discontinued in the setting of a 
deep vein thrombosis or pulmonary embolism that occurs or intensifies while the patient is receiving 
therapeutic anticoagulation therapy. 
 
11.1.6 Bleeding (Hemorrhagic) Events 


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Serious hemorrhagic AEs have been reported from clinical studies investigating ramucirumab. 
Hemorrhagic complications are associated with some malignancies (e.g. variceal bleeding from portal 
hypertension in hepatocellular carcinoma, lower GI hemorrhage from bowel metastases in ovaria n 
carcinoma)  although  the  rate  of  these  complications   varies  considerably.  As  detailed  in  the 
ramucirumab IB, the incidences of hemorrhagic events to date, significant background incidence of 
bleeding in some malignancies, and use of concomitant antiplatelet therapy in some of the reported 
cases precludes any definitive association between bleeding and ramucirumab though ongoing 
surveillance and identification (and exclusion) of patients with high bleeding risk remain essential and 
are detailed in the inclusion/exclusion criteria. Discontinue ramucirumab in the event of a Grade 3 or 4 
bleeding (hemorrhagic) event. 
 
11.1.7 Proteinuria 
If, while on ramucirumab therapy, a patient has proteinuria 2+ per routine urinalysis test, a 24-hour 
urine collection will be conducted. If the protein level is <2 g/24 hours, the patient will continue on 
ramucirumab  therapy at the same dose without interruption.  If urinalysis shows  2+, administer  full 
previous dose of ramucirumab without interruption. Perform a 24-hour urine collection within 3 days 
prior to next ramucirumab  dose administration.  If the 24-hour collection shows  proteinuria <2g/24 
hours administer unchanged dose of ramucirumab. If the protein level is 2 g/24 hours, perform a 24-hour 
urine collection prior to the next planned dose of ramucirumab. Ramucirumab treatment will resume at 
a reduced dose level (6 mg/kg) once the protein level returns to <2 g/24 hours. The patient willl be 
discontinued from ramucirumab  treatment if the protein level is >3 g/24 hours, if there is a second 
occurrence of proteinuria 2 g/24 hours, or if the protein level does not return to <2 g/24 hours within 42 days of 
interruption ramucirumab. 
 
11.1.8 Gastrointestinal Perforation 
Patients  with  unresected  (or  recurrent)  primary  tumors,  mesenteric  or  peritoneal  disease  who 
participate in this clinical study may be at increased risk for GI perforation due to the nature of the 
disease (metastatic gastric cancer). 
 
An infrequent incidence of GI perforations has been associated with some antiangiogenic therapeutic 
agents, more 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 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. More  information 
about GI perforation may be found in the IB. Patients with a history of GI perforation within 6 months 
prior to randomization are excluded from participation. Ramucirumab should be permanently 
discontinued in the event of a GI perforation. 
 
11.1.9 Surgery and Impaired Wound Healing 
Surgery and impaired wound healing have been observed with some antiangiogenic agents. 
Ramucirumab will not be administered to patients who have undergone major surgery within 28 days 
prior to randomization or have undergone central venous access device placement within 7 days prior 
to first dose of study treatment, except if the procedure is minimally invasive (for example, introduction 
of PICC line) and the investigator does not anticipate any significant bleeding. 
 
11.1.10 Liver Injury/Liver Failure 
Liver  failure  or  other  significant  liver  injury  events, such  as  hepatic  encephalopathy,  have  been 
observed in patients receiving ramucirumab. Patients with the following conditions should not be 
enrolled in clinical trials with ramucirumab: 1) cirrhosis at a level of Child-Pugh Class B (or worse) or 


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2) cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites 
resulting from cirrhosis. "Clinically meaningful ascites" is defined as ascites resulting from cirrhosis and 
requiring ongoing treatment with diuretics and/or paracentesis. Ramucirumab should be discontinued 
in the event of any new occurrence of hepatic encephalopathy and/or hepatorenal syndrome resulting 
from liver cirrhosis. 
 
11.1.11 Reversible Posterior Le ukoencephalopathy Syndrome (RPLS) 
Reversible posterior leukoencephalopathy  syndrome is a clinical and radiologic syndrome typically 
consisting  of reversible cortical  neurological  dysfunction  and brain-imaging  findings  of subcortical 
edema involving the posterior circulation, particularly the occipital lobes . . The symptoms of RPLS 
most often include generalized seizures, headache, delirium, and cortical blindness, although these 
may  vary  significantly  and  occasionally  include  focal  neurological  deficits.  Magnetic  resonance 
imaging (MRI) represents the most reliable method for diagnosis. Clinical symptoms and MRI 
abnormalities  usually recover within days to weeks with proper management,  although permanent 
neurologic dysfunction has been reported. Across the ramucirumab clinical program, 2 blinded cases 
of RPLS have been reported. Both cases occurred in the ongoing double-blind, randomized, placebo- 
controlled Phase 3 Study evaluating FOLFIRI in combination with ramucirumab  versus  FOLFIRI in 
combination with placebo for patients with metastatic colorectal cancer. 
 
Reversible posterior leukoencephalopathy syndrome should be identified and treated promptly in order 
to minimize potential for permanent neurological damage. Treatment encompasses careful control of 
BP, withdrawal of potentially causative medication,  and administration of anti-convulsant  agents  to 
those  experiencing  seizures.  If  the  diagnosis  of  RPLS  is  confirmed  or  if  clinically  indicated, 
ramucirumab should be permanently discontinued. 
 
11.2 Trastuzumab 
Principal adverse effects include cardiac dysfunction, infusion related reactions, potentiation of 
chemotherapy related hematologic side effects. A complete listing of toxicities can be found in the 
trastuzumab package insert. 
 
11.2.1Trastuzumab Dose De lays or Modifications 
There will be no dose modifications of trastuzumab. Trastuzumab dose delays are permitted for 
Grade 3/4 clinical toxicity or at investigator discretion. Dose delays are not required for laboratory 
abnormalities unless associated with clinical symptoms. Omitted doses of trastuzumab are not 
 
Replaced or restored; instead, the patient should resume the planned treatment cycles. Patients who 
develop signs and symptoms of CHF should have trastuzumab held and should receive treatment for 
CHF. Patients with an asymptomatic absolute decrease in LVEF of >16 percentage points or an 
absolute decrease in LVEF of 10 to 15 percentage points to below the lower limit of normal should 
have trastuzumab held as outlined below. 
 
11.2.2 Congestive He art Failure and other Cardiac Dysfunction 
 
All patients must have a baseline evaluation of cardiac function including a measurement of LVEF by 
ECHO (with speckle tracking) prior to entry into the study. If an ECHO cannot be performed or is 
technically limited, a MUGA scan can alternatively be performed.  Patients with an LVEF </=40% may 
still be eligible after consultation with cardiology and study investigator. Patients with decreased LVEF 
should be optimized on medical therapy with ACE inhibitors, -blockers, diuretics, and cardiac 
glycosides,  as  needed  per  management  of cardiac  changes  below.    These  patients  should  be 
monitored for heart failure after cisplatin infusion as well. All patients will undergo regular cardiac 
monitoring throughout the study, including at baseline, 6 and 12 weeks after initiation of trastuzumab 


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therapy, and every 12 weeks (4 cycles) thereafter. During the course of trastuzumab therapy, patients 
should be monitored for signs and symptoms of CHF (i.e., dyspnea, tachycardia, new unexplained 
cough, neck vein distention, cardiomegaly, hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, 
peripheral edema, and rapid unexplained weight gain). Patients who develop signs or symptoms of 
CHF will be further evaluated with a repeat LVEF assessment  using the same method selected at 
baseline (either ECHO or MUGA) if possible. 
 
 
Management of Symptomatic Cardiac Changes 
Patients who develop signs and symptoms of CHF should have trastuzumab held and should receive 
treatment for CHF as recommended by the American Heart Association (AHA)/American College of 
Cardiology  (ACC)(e.g.,  ACE  inhibitors,  angiotensin-II  receptor  blockers,  -blockers,  diuretics,  and 
cardiac glycosides, as needed) with referral to cardiology for consultation. 
  
If  the  symptoms  of  CHF  resolve  with  treatment,  and/or  cardiac  function  improves  to  baseline, 
reinitiation of trastuzumab can be considered at the discretion of the investigator, after discussion with 
the  patient  concerning  the  risks  and  benefits  of continued  therapy  and  in  consultation  with  a 
cardiologist. If the patient is benefiting clinically from trastuzumab, the benefit of continued treatment 
may outweigh the risk of cardiac dysfunction or heart failure. If trastuzumab is restarted, continued 
surveillance  with  noninvasive  measures  of  LVEF  (MUGA  or  ECHO)  will  resume  as  regularly 
scheduled. Additional LVEF assessments  prior to the next regularly scheduled LVEF measurement 
may be performed at the investigator‘s discretion. 
 
Management of Asymptomatic Decreases in LVEF 
Trastuzumab can be continued in patients experiencing an asymptomatic absolute decrease in LVEF 
of <16 percentage points from baseline, when the ejection fraction remains within the imaging center's 
range of normal limits. Repeat measures of LVEF should be obtained using the methodology selected 
at  baseline  if  possible.  Close  follow-up  of  such  patients   is  recommended.  Patients  with  an 
asymptomatic absolute decrease in LVEF of >16 percentage points or an absolute decrease in LVEF 
of 10 to 15 percentage points  to below the lower limit of normal  should have trastuzumab  held. 
Referral to cardiology should be considered for evaluation and management of left ventricular systolic 
dysfunction  with  adherence  to  ACC/AHA  guidelines.  In  light  of  the  variability  inherent  in  the 
assessment of ejection fraction, consideration should be given to repeating the study within 4-7 days 
to confirm an observed decline. Repeat measures of LVEF should be obtained using the same 
methodology selected at baseline if possible, but at the discretion of the investigator or consulting 
cardiologist. If trastuzumab has been held for an asymptomatic decline in LVEF, a repeat measure of 
LVEF will be obtained within 1 month to evaluate for recovery of LVEF. If LVEF does not improve after 
repeat assessment  within 1 month, the patient should be monitored with monthly or as clinically 
indicated ECHOs/MUGAs until LVEF is improved. 
 
 
If cardiac function improves and LVEF no longer meets ―hold‖ criteria as defined above, trastuzumab 
may be restarted. If trastuzumab is restarted, continued surveillance with noninvasive measures of 
LVEF  (MUGA  or  ECHO),  using  the  optimal  methodology  as  determined  by the  investigator  or 
consulting cardiologist, will resume per the standard schedule.  Additional LVEF 
 
Assessments prior to the next regularly scheduled LVEF measurement may be performed at the 
investigator‘s discretion. If the patient is benefiting clinically from trastuzumab, the benefit of continued 
treatment may outweigh the risk of cardiac dysfunction even in the setting of an asymptomatic LVEF 
decline, and reinitiating of trastuzumab can be considered at the discretion of the investigator  after 
consultation with a cardiologist and discussion with the patient concerning the risks and benefits of 


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continued therapy. 
 
Caution should be exercised when treating patients with clinically significant cardiovascular disease 
such  as pre-existing  coronary  artery  disease  or  CHF.  Patients  with symptomatic  CHF,  unstable 
angina pectoris, or symptomatic  or poorly controlled cardiac  arrhythmia should not be enrolled in 
clinical trials with ramucirumab. Ramucirumab should be discontinued in the event of any Grade 3 or 4 
events consistent with CHF. 
 
11.2.3 Infusion-Related Re actions 
Any treatment-related infusion-related reactions are defined according to the NCI-CTCAE Version 4.0 
definition  (General  disorders  and  administration  site conditions).  Symptoms  occurring  during  or 
following infusion of investigational therapy may also be defined according to AE categories such as 
allergic reaction, anaphylaxis, or cytokine release syndrome (Immune system disorders). In the setting 
of symptoms occurring during or following infusion of investigational therapy, investigators are 
encouraged to use the AE term "infusion-related reaction" and any additional terms (including those not 
listed here) that best describe the event. Consistent with usual medical practice, the patient should be 
clinically monitored and selected parenteral medications may be utilized for Grade 2 
allergic/hypersensitivity reaction as detailed below. Clinical and laboratory monitoring will be performed 
per institutional guidelines. 
 
Grade 1 IRR 
• Slow the infusion rate by 50%. 
• Monitor the patient for worsening of condition. 
• For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent); additional premedication may be administered at the investigator's discretion. 
 
Grade 2 IRR 
• 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 IRR has resolved or decreased to Grade 
1; the infusion duration should not exceed 2 hours. 
• Monitor for worsening of condition. 
• For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg I.V. (or 
equivalent); additional premedication may be administered at the investigator's discretion. 
 
For a second Grade 1 or 2 IRR, administer dexamethasone 8-20 mg I.V. (or equivalent); then, for 
subsequent  infusions, premedicate with diphenhydram ine hydrochloride 50 mg I.V. (or equivalent), 
acetaminophen 650 mg orally, and dexamethasone 8-20 mg I.V. (or equivalent). 
 
 
11.3. Ge neral Dose-Modification Guidelines for Chemotherapy 
• Treatment for the first cycle should only commence if all the inclusion criteria are met and 
patient has been enrolled. For subsequent cycles, dose delay/modification is permitted as 
described in sections specific for ramucirumab, trastuzumab, capecitabine, 5-FU and cisplatin. 
All study treatment will be discontinued in case of disease progression. 
• Cisplatin and 5-FU dose modifications are permanent; no dose escalations allowed after dose 
reduction. Any patient who has had 2 dose reductions (50% of original dose) and who 
experiences a toxicity that would cause a third dose reduction must be discontinued from the 
study drug that is causing the toxicity. 


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• The dose of capecitabine should be determined at the start of each treatment cycle. Based on 
investigator's discretion, full dose of capecitabine can be re-administered after 1 dose reduction 
(25% dose reduction). Re-escalation is not allowed after the second dose reduction. The 
maximum number of dose reductions for capecitabine is 3 (75% of the original dose). 
• Doses of any study drug omitted for toxicity are not replaced or restored; instead, the patient 
should resume the planned treatment cycles. Supportive care (for example, colony-stimulating 
factors, blood and blood products, etc. can be administered  in accordance with the latest 
ASCO or other equivalent guidelines. 
• Dose modification, for non-serious and non-life-threatening toxicities like alopecia, altered taste 
or nail changes may not be required and the final decision is left to the discretion of the treating 
investigator. 
• In situations where concomitant toxicities of varying severity exist, dose modification will be 
tailored for the toxicity with highest CTCAE grading. 
• If there is a delay or modification in administration of study drug(s) due to toxicity, treatment 
with the other study agent(s) should also be held. If clinically appropriate, the investigator can 
delay  all  treatment  components   up  to  a  maximum  of  7  days  to  allow  synchronized 
administration of all agents. 
 
If a toxicity related to any component of chemotherapy does not resolve in the same treatment cycle, 
the administration of that component can be delayed up to 42 days. If the toxicity does not resolve 
within 42 days, that component will be discontinued unless it is determined by the treating investigator 
that the patient might benefit from continuation of the component. 
 
11.4 Capecitabine, 5-FU, Cisplatin, and Oxaliplatin Dose Delays and Modifications 
Trastuzumab dose interruptions are not required for laboratory abnormalities unless associated with clinical 
symptoms in which case trastuzumab may be held per investigator discretion. For hematologic laboratory 
abnormalities as an initial step, the dose of capecitabine/5-FU or cisplatin/oxaliplatin should be reduced first 
before any dose reductions for ramucirumab are considered. Capecitabine/5-FU or cisplatin/oxaliplatin will 
be held for grade 3 or 4 non-hematologic toxicity (with the exception of grade 3 electrolyte 
abnormalities) or for not meeting treatment parameters as described in the tables below on the day of 
treatment. If the toxicity has resolved and the patient meets treatment parameters but experienced 
interval toxicity, then for the purposes of determining dose reductions, the grade of toxicity should be 
that seen despite maximal medical management (i.e. intensive loperamide or tincture of opium for 
diarrhea). If multiple toxicities are seen the dose administered for a particular drug should be based 
on the most severe toxicity noted. In general, when multiple toxicities are experienced that can result 
in the dose reduction of multiple drugs, reducing multiple drugs at one time is the preferred approach. 
Treatment may resume when the toxicity has resolved to < grade 2, except as indicated below. 
 
 
 
Generally, during the first six cycles of therapy when treatment is held for chemotherapy related 
toxicity, all drugs (cisplatin or oxalplatin and capecitabine or 5-FU, Pembrolizumab/Trastuzumab) will 
be held for coordinated scheduling.  Re-evaluation visit should occur in no more than 7 days. For an 
elevated creatinine or for ototoxicity, cisplatin or oxaliplatin alone may be held at investigator discretion 
and the patient may continue with capecitabine or 5-FU without treatment delay. If capecitabine or 5- 
FU is held for more than 4 weeks for toxicity, patients will be taken off study, unless there is a clinical 
benefit. If there is a clinical benefit, patients may be retreated at a lower dose after resolution of toxicity 
to  NCI- CTCAE v4.0 grade 2, except as indicated below. Cisplatin or oxaliplatin and capecitabine or 
5-FU may each be dose attenuated, either in combination, or individually. For all toxicities, appropriate 
clinical judgment should be applied to manage the symptoms . 


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Starting dose 0 
Oxaliplatin 130 mg/m
2
 
Dose Level -1 
Oxaliplatin 90 mg/m2* 
Dose Level -2 
Discontinued 
 
 
 
Tables 11.4.1, 11.4.2, 11.4.3, 11.4.4, 11.4.5 11.4.6 ,11.4.7, 11.4.8, and 11.4.9 address specific 
chemotherapy dose delays and modifications instructions. Colony stimulating factors:  Patients should 
not routinely receive prophylactic colony stimulating factors (e.g., G-CSF, GM-CSF) during cycle 1. 
Subsequent use will be at the discretion of the treating physician. 
 
 
 
 
Table 11.4.1 Capecitabine dose levels 
 
Starting dose 0 
Capecitabine 850 mg/m
2 orally twice daily 
Dose Level -1 
Capecitabine 640 mg/m2 orally twice daily 
Dose Level -2 
Capecitabine 425 mg/m2 orally twice daily 
 
Table 11.4.2 Cisplatin dose levels 
 
Starting dose 0 
Cisplatin 80 mg/m
2
 
Dose Level -1 
Cisplatin 60 mg/m2 
Dose Level -2 
Cisplatin 40 mg/m2 
 
Table 11.4.3 Dose-modification guidelines for cisplatin  or oxaliplatin and capecitabine for 
thrombocytopenia, neutropenia, febrile ne utropenia, and infectiona. 
 
ANC Count (x 10
9/L) 
Plate let Count (x 109/L) 
Dose adjustment for cisplatin and 
cape citabine 
 
>1.5 and 
>100 
Maintain dose level without interruption 
1.0 
and/or 
<75 
Wait for counts to recoverb; if within 42 days of 
interruption, ANC >1.0 x 109/L and platelets 
>75 x 10
9/L, reduce by 1 dose level if 
permissible
c. 
<1.0   and 
Fever >38.5oC (101oF) or 
infection of any duration 
Abbreviations: ANC = Absolute Neutrophil Count. 
Reduce by 1 level on recovery of ANC >1.0 x 
109/L 
a. No chemotherapy should be administered if ANC <1.0 x 10
9/L and platelet count <75 x 10
9/L 
b. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops 
<1.0 x 10
9/L or that the platelet count drops <75 x 10
9/L, treatment with capecitabine should be 
interrupted 
c. Dose reductions of capecitabine for ANC <1.5 x 109/L but >1.0 x 109/L may be determined at the 
discretion of the investigator or institutional guidelines. In such situations, if administration of 
chemotherapy is prohibited, then capecitabine must be held until the ANC recovers to >1.5 x 109/L 
 
 
Table 11.4.4 Oxaliplatin dose levels 
 
 
 
 
 
*Or 104 mg/m
2 at discretion of treating physician 
 
Table 11.4.5 Dose -modification guidelines for nonhematologic adverse events thought to be 
re lated to capecitabine
a
 


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Toxicity CTCAE Grade s 
During a Course of Therapy 
Dose adjustment for next 
dose (% of starting dose) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
- First appearance 
Interrupt until resolved to Grade 
0-1 or pretreatment baseline 
75% 
- Second appearance 
50% 
- Third appearance 
Discontinue treatment 
permanently 
Not applicable 
Grade 3 
- First appearance 
Interrupt until resolved to Grade 
0-1 or pretreatment baseline 
75% 
- Second appearance 
50% 
- Third appearance 
Discontinue treatment 
permanently 
Not applicable 
Grade 4 
- First appearance 
Discontinue treatment 
permanently 
OR 
If the investigator deems it to 
be in the patient‘s best interest 
to continue, interrupt until 
resolved to Grade 0-1 or 
pretreatment baseline 
Not applicable 
OR 
50% 
- Second appearance 
Discontinue treatment 
permanently 
Not applicable 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; SmPC = Summary of 
Product Characteristics; USPI = United States Package Insert 
a. Adapted from Xeloda USPI and SmPC 
 
Table 11.4.6 Dose-modification guidelines for cisplatin or oxaliplatin for reduced glomerulal 
filtration rate 
 
Creatinine clearance requirement 
Dose adjustment for cisplatin 
>60 mL/min prior to Day 1 of Cycle 1-6 
Maintain dose level 
51-59 mL/min prior to Day 1 of Cycle 2-6 
Reduce 1 dose level, if permissible 
41-50 mL/min prior to Day 1 of Cycle 2-6 
Reduce 2 dose levels, if permissible 
<40 mL/min prior to Day 1 of Cycle 2-6 
Stop cisplatin or oxaliplatin permanently 
 
 
Table 11.4.7 Dose-modification guidelines for cisplatin  or oxaliplatin re lated for nonrenal and 
nonhematologic adverse events 
 
Toxicity 
Grade 
Dose adjustment for cisplatin 
Nausea/vomiting/diarrhea 
(either on its own or in 
>3 
Reduce 1 dose level, if 
permissible, on recovery to 


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combination) 
Grade 1 or below 
Ototoxicity 
>2 
Discontinue 
Neurotoxicity 
0-1 
No dose adjustment required 
Neurotoxicity 
2 
Reduce 2 dose levels, if 
permissible, on recovery to 
Grade 1 or below 
Neurotoxicity 
>3 
Discontinue 
Any other toxicity thought to be 
due to cisplatin 
4 
Discontinue 
 
For toxicities not listed in table 11.4.4, appropriate clinical judgment should be applied to manage any 
symptoms arising out of these AEs. For any AE which is Grade >3 or if the AE is considered clinically 
significant by the treating investigator, temporarily stop administering cisplatin to allow for recovery of 
the toxicity to Grade 1 or baseline, for a maximum period of 42 days. Once the toxicity recovers, 
reduce the dose of cisplatin by 1 dose level, if permissible. If the toxicity does not recover within the 
42-day period, permanently discontinue cisplatin. Discontinue cisplatin if a third dose reduction is 
required. 
 
Table 11.4.8 Dose modification guidelines for 5-FU related to nonhematologic adverse events 
 
Toxicity 
Grade 
Dose adjustment for 5-FU 
Diarrhea/stomatitis 
3 
Reduce 1 dose level, if permissible, on recovery to 
Grade 1 or below 
Diarrhea/stomatitis 
4 
Reduce 2 dose levels, if permissible, on recovery to 
Grade 1 or below 
Cardiac toxicity (related to 5-FU) >2 
Discontinue 
Skin toxicities 
>3 
Reduce 2 dose levels, if permissible, on recovery to 
Grade 1 or below 
 
Table 11.4.9 5-FU dose levels 
 
 
 
Starting dose 0 
5-FU 800 mg/m2 /day, Day 1-Day 5 
Dose Level -1 
5-FU 600 mg/m2 /day, Day 1-Day 5 
Dose Level -2 
5-FU 400 mg/m2 /day, Day 1-Day 5 
 
 
11.5 Supportive Care 
 
Patients should receive full supportive care measures per local institutional practice including but not 
limited to antidiarrhea gents, antiemetic agents, analgesics appetite stimulants and granulocyte growth 
factors as judged necessary by their treating physician. Additional palliative radiation therapy during 
the study is allowed if clinical indicated after consultation with Principal Investigator. 


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11.5.1 Therapy for Diarrhea 
 
In the event of diarrhea, the following supportive measures are strongly recommended as outline 
below. 
 
Upon the patient experience the first episode of loose stool, the patient should be given initial dose of 
loperamide, 2 capsules (4mg) by mouth, then 1 capsule (2mg) by month every 2 hours or 2 capsules 
every 4 hours overnight at least 12 hours after the first liquid stool and up to 12 hours after the last 
liquid stool. If diarrhea is not controlled with loperamide, consider capecitabine dose reduction and/or 
additional Lomotil (diphenoxylate hydrochloride and atropine sulfate) tablets. Patients should have 
access to loperamide and Lomotil for home use prior to the start of each cycle. 
 
11.5.2 Therapy for Hand-Foot Syndrome 
 
Patients should receive full supportive care measures per local institutional practice, prophylactic use 
of emollients and moisturizes to prevent hand-foot syndrome (HFS) is recommended. Immediate 
institution of supportive measures for symptomatic relief for patients with grade 1 or above hand foot 
syndrome is recommended. Treatment with pyridoxine (B6) at dose of 100 to 150mg per day is 
permitted. 
 
Use of cre ams 
•   Non-urea based creams may be applied liberally. 
•   Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be used sparingly and 
only to affected (hyperkeratotic) areas. 
•   Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day. 
Approximately 5% to 8% provides gentle chemical exfoliation. 
•   Topical analgesics (e.g. lidocaine 2%) are to be considered for pain control. 
•   Topical corticosteroids like clobetasol 0.05% should be considered for subjects with Grade 2 
or 3 HFS.  Avoid systemic steroids. 
Te nder areas should be protected as follows: 
•   Use socks/gloves to cover moisturizing creams 
•   Wear well-padded footwear 
•   Use insole cushions or inserts (e.g. silicon, gel) 
•   Foot soaks with tepid water and Epson salts 
 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
All patients who receive at least one dose of ramucirumab and began trastuzumab therapy will be 
evaluable for toxicity and response. Patients who did not begin ramucirumab therapy will not be 
evaluated for toxicity or response and will be replaced by a new patient. 
 
The primary endpoint of the study is the efficacy of the combination of ramucirumab and 
trastuzumab in addition to cisplatin and capecitabine in terms of progression free survival (PFS) at 6 
months. 
 
Secondary endpoints include toxicity, overall survival, response to ramucirumab and trastuzumab 
after the first cycle, best overall RECIST 1.1 response (CR+PR) to capecitabine/5-FU, 


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cisplatin/oxaliplatin, ramucirumab and trastuzumab, overall clinical benefit defined as stable disease 
(SD), complete response rate (CR), or partial response (PR) safety and tolerability. The type, 
frequency, severity, timing, and relationship of each adverse event will be determined as per the NC I 
Common Toxicity Criteria, version 4.0. Toxicity during cycle 1 and s ubsequent cycles will be 
reported. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops progressive disease on combination of ramucirumab and 
trastuzumab with cisplatin and capecitabine  he/she will be taken off study unless the investigator 
judges it to be of clinical benefit for the patient to continue on trial therapy. If at any time the patient 
develops unacceptable  toxicity that fails to resolve after a maximum treatment delay of 9 wee ks, 
he/she will be removed from study. Before being removed from the study, patients will be scanned to 
assess the response. If the off study scan shows progression of disease then the patient will be 
considered as a non responder, while a CR or PR will be considered as response. 
 
A patient will be withdrawn from the study treatment in the following circumstances: 
 
• The patient is no longer able to participate in the study (e.g., AE, surgery, concomitant 
diagnoses, concomitant therapies or administrative reasons); in such a case the 
Investigator‘s reason for a patient‘s removal must be recorded in CRDB. 
• Patient withdrawal of consent or election to discontinue participation in the trial 
• Significant deviation from the protocol or eligibility criteria; such events will be considered 
protocol violations and the patients will be removed from study. 
• Non-compliance with study or follow-up procedures. 
• Drug related AE(s) have not resolved after 4 weeks of treatment interruption. An exception 
could be considered upon discussion with Principal Investigator for patients who derive 
obvious clinical benefit according to the investigator‘s judgment. The dose reduction scheme 
provided should be followed in this case. 
• Repeated episodes of drug related toxicity despite dose reduction as indicated in Section 11. 
• Documented progressive disease 
 
 
As soon as a patient is withdrawn from the study treatment, the End of Treatment (EOT) visit has to 
be performed within 1-14 days after off treatment date. Every effort should be made to follow-up 
patients in case an adverse event is still ongoing at the time of withdrawal. Patients who show a 
clinical benefit (i.e., with either an objective tumor response or the absence of disease progression), 
may continue to receive additional treatment courses. Patients with radiologically documented 
progressive disease should be removed from the study unless the investigator judges it to be of 
clinical benefit for the patient to continue on trial therapy. 
 
14.0 
BIOSTATISTICS 
 
The phase III ToGA study established the benefit of trastuzumab in combination with cisplatin and 
fluoropyrimidine (CF) chemotherapy in HER2-positive metastatic gastric/GEJ adenocarcinoma. The 
trastuzumab/CF cohort from the ToGA will be used as historic control for this study. In ToGa patients 
assigned to receive trastuzumab + CF had a significant improvement in progression free survival 
(5.5 mos vs 6.7 mos, HR 0.71 [0.59-0.85], p=0.0002), overall survival (13.8 mo vs 11.1 mo, HR 0.74 
[0.6-0.91], p = 0.0046). Approximately 55% of the capecitabine/cisplatin/trastuzumab-treated 


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patients were progression free at 6 months. The hypothesis is that addition of ramucirumab to 
fluoropyrimidine and platinum and trastuzumab will improve outcome in previously untreated 
patients with HER2 GE junction gastric cancer. 
 
The primary endpoint is PFS, as measured from the start of the ramucirumab and trastuzumab to 
the date of either documentation of disease progression on chemotherapy with trastuzumab and 
ramucirumab or death. CT/MRI scan performed after the initial 3 weeks (1 cycle). With subsequent 
cycle for all patients capecitabine and cisplatin will be administered together with ramucirumab and 
trastuzumab. We will define progression of disease to chemotherapy with trastuzumab and 
ramucirumab per RECIST 1.1 criteria. Patients with measurable disease and with evaluable 
radiographically but non-measurable disease will be eligible for study entry. As per 
 
RECIST 1.1 criteria, any evidence of progression in non-measurable lesions, measurable lesions, or 
the development of new lesions, would qualify as disease progression. Using an exact single stage 
binomial design, we will accrue 37 Stage IV gastric and GE junction adenocarcinoma patients to 
differentiate between 6-month PFS of 55% and 75% with type I of 5% and power of 80%. If 26 or 
more patients are progression free at 6 months, capecitabine/5-FU/cisplatin/oxaliplatintrastuzumab 
+ramucirumab will be considered worthy of further investigation. Patients who come off study before 
6 months without documented progression will be considered as events for the primary endpoint of 6 
months PFS. Patients who come off study before 3 week CT scan will be considered inevaluable for 
primary endpoint and will be replaced. We anticipate enrollment to be 1-2 patients/ month with 
completion of accrual in approximately 36 months. Patients that come off study due to toxicity before 
6 months without documented progression will continue to be scanned to obtain 6 months 
assessment of progression. Patients that were lost to follow up or withdrew consent before 6 months 
without documented progression will be counted as events for the primary endpoint; however this is 
expected to be a rare occurrence. 
 
Patients  who  completed  at  least  one  cycle  of  trastuzumab  +  ramucirumab  will be considered 
evaluable. 
 
Secondary endpoints include response to ramucirumab and trastuzumab after the first cycle, best 
RECIST 1.1 response rate (CR+PR) and overall clinical benefit (SD+CR+PR) which will be 
estimated using binomial proportions along with exact 95% confidence intervals; survival endpoint 
will be measured from the start of treatment to death or last follow-up; overall survival, median PFS, 
overall and 1-year survival in patients with HER2-positive Stage IV gastric or GEJ adenocarcinoma 
will be estimated using the Kaplan-Meier method. Toxicity will be summarized using descriptive 
statistics. 
 
An exploratory analysis of correlative biomarkers will be performed. Presence of genomic alterations 
(categorized as binary) in archival tumor samples will be correlated with overall clinical benefit to 
protocol therapy using Fisher‘s exact test. In select patients, changes in 89 Zr-trastuzumab PET 
between baseline and Week 3 will be correlated with tumor response by CT using Wilcoxon rank 
sum test. We will also examine an optimal cut point for the change in SUV between baseline and 
Week 3 that best separates between responders and non-responders using the method of 
maximally selected chi square statistics of Miller and Siegmund.16 
 
Generalized estimating equations (GEE) will be used to look at associations between response and 
cfDNA while Cox regression with time dependent covariate will be used to associate survival with 
cfDNA. 


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Previous clinical trial has reported the frequency of adverse events attributable to treatment with 
capecitabine, oxaliplatin, bevacizumab and trastuzumab.
23  A similar frequency of adverse events will 
be considered attributable to ramucirumab and trastuzumab used in this trial and therefore 
acceptable. In order to reduce patient risk, the study design includes early termination of the trial in 
the event of excessive grade 4+ neutropenia, grade 3+ diarrhea despite adequate antidiarrheal 
management (loperamide and diphenoxylate/atropine) or grade 3+ neuropathy. In addition, the 
safety analysis will assess the toxicity rates that may arise related to ramucirumab-related persistent 
grade 3+ hypertension despite adequate medical management. Furthermore, presence of grade 3+ 
events which in the clinical judgment of the principal investigator are felt to be serious, unexpected, 
and a side effect likely due to with ramucirumab and trastuzumab, will give evidence to reduce the 
dose as well.  Adverse events (possibly, probably, or definitely) related to the study treatment during 
all treatment cycles will count towards the excessive toxicity boundaries below. The stopping rules 
are derived using repeated significance testing are given in the table below. 
 
Toxicity 
# of toxicities needed to stop 
the study 
Toxicity 
rate 
Probability 
boundary 
is crossed 
Gr 4+ Neutropenia 5 within the first 10 patients 
7 within the first 20 patients 
11 within 37 patients 
.19 
.11 
.45 
.98 
Gr 3+ Diarrhea 
4 within the first 10 patients 
6 within the first 20 patients 
8 within 37 patients 
.12 
.08 
.35 
.97 
Gr 3+ Neuropathy 
2 within the first 10 patients 
3 within the first 20 patients 
5 within 37 patients 
.05 
.13 
.25 
.98 
Gr 3+ persistent 
hypertension 
2 within the first 10 patients 
3 within the first 20 patients 
4 within 37 patients 
.04 
.1 
.2 
.96 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Re search Participant Re gistration 
 
 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in the section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist.  The individual signing the Eligibility Checklist is confirming 
whether or not the participant is eligible to enroll in the study. Study staff are responsible for 
ensuring that all institutional requirements necessary to enroll a participant to the study have 
been completed. See related Clinical Research Policy and Procedure #401 (Protocol 
Participant Registration). 


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16.0 
DAT A M AN AGEMENT ISSUES 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow -up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at MSKCC were approved by the National 
Cancer Institute in September 2001. The plans address the new policies set forth by the NC I 
in the document entitled ―Policy of the National Cancer Institute for Data and Safety 
Monitoring of Clinical Trials‖ which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Clinical Research Administration. The MSKCC Data 
and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center‘s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NC I cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation . 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Priv acy 
 
MSK‘s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 


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17.2 
Se rious Adverse Event (SAE) Re porting 
 
An adverse event is considered serious if it results in ANY of the following outcomes 
 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required for 30- 
days after the participant‘s last investigational treatment or intervention. Any events that occur after 
the 30-day period and that are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‗Reporting of Serious Adverse 
Events‘, the SAE report must be sent to the IRB within 5 calendar days of the event. The IRB 
requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the SAE 
Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  saegrade5@mskcc.org. 
All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  saegrade5@mskcc.org. 
All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‘s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data required to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 


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• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‘s condition 
o Indication if the subject remains on the study 
• If an amendment will need to be made to the protocol and/or consent form. 
• If the SAE is an Unanticipated Problem 
 
The PI‘s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FD A by the SAE staff through the IND office. 
 
 
 
 
 
 
 
17.2.1 
 
 
Any SAE will be reported within 24 hours of becoming aware of the event to the Eli Lilly Global 
Product Safety Fax Number for all Cyramza (ramucirumab) Studyies at 866-644-1697 or 317-453- 
3402. 
 
 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 


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4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
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