Conditions: Esophageal Cancer Gastric Cancer
Keywords: pembrolizumab trastuzumab capecitabine cisplatin Stage IV HER2-positive esophagogastric cancer 16-937 Oxaliplatin 5-Fluorouracil (5-FU)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out what effects, good and/or bad, pembrolizumab in combination with trastuzumab and chemotherapy, has on the patients' esophagogastric cancer.

Detailed description:

Arms:
arm 1: Pembrolizumab 200 mg IV every 3 weeks, trastuzumab (8 mg/kg loading dose; 6 mg/kg maintenance) IV every 3 weeks with cisplatin IV every 3 weeks with oral capecitabine 2 weeks on/1 week off. Each cycle consists of 21 days. Treatment will be administered on an outpatient basis. In Cycle 1, patients will initiate therapy with trastuzumab 8 mg/kg IV with pembrolizumab 200 mg IV. CT/MRI scan will be performed after the initial 3 weeks (1 cycle) to determine response to pembrolizumab and trastuzumab combination. With subsequent cycles, all patients will begin systemic chemotherapy with the capecitabine/cisplatin regimen in addition to pembrolizumab 200 mg IV with trastuzumab 6 mg/kg maintenance. Patients will receive cisplatin 80 mg/m2 IV on Day 1, and capecitabine 850mg/m2 twice a day on Days 1 through 14, every 3 weeks.

Interventions: intervention 1: pembrolizumab intervention 2: trastuzumab intervention 3: capecitabine intervention 4: cisplatin intervention 5: Oxaliplatin intervention 6: 5-Fluorouracil
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: Oxaliplatin may be administered instead, at a dose of 130 mg/m2/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 progression or until other withdrawl criteria are met. Patients may begin with reduced dose of oxaliplatin 104 mg/m2 as starting dose if deemed necessary per the treating physician discretion. Oxaliplatin will be administered after the completion of the pembrolizumab infusion. intervention 6: 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.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 1 of 50 
 
 
 
 
 
Phase II trial of pembrolizumab in combination with  trastuzumab, Fluoropyrimidine, and Platinum 
Chemotherapy in first line Stage IV HER2-positive metastatic esophagogastric (EG) cancer 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal Investigator/Department: 
Yelena Janjigian, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
David Ilson, MD, PhD 
Medicine 
Investigator(s)/Department: 
Marinela Capanu, PhD 
Marc Simmons, MD 
Kinh Gian Do, MD 
Jonathan Landa, DO 
Viktoriya Paroder, MD 
Jaclyn Hechtman, MD 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Luis Diaz, MD 
Andrew Epstein, MD 
James Harding, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Karuna Ganesh, 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 
Nitya Raj, MD 
Steven Maron, MD 
Ellen Hollywood, NP 
Jaclyn Norris, NP 
Michal Segal, RN 
Vanessa Grant, RN 
Robin Brenner, RN 
Erica Kaufmann, NP 
Natasha Pinheiro, NP 
Claudy Aime, NP 
Anthony Yu, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Rodrigo Erlich, MD 
Irina Konzelman, APN 
Janet Cogswel, RN 
Epidemiology/Biostatistics 
Radiology 
Radiology 
Radiology 
Radiology 
Pathology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
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Memorial Sloan Kettering Cancer 
Center IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Lisa Sarmasti, RN 
Nurs
Avni Desai, MD 
Medi
Stuart Lichtman, MD 
Medi
Jia Li, MD 
Medi
Lori Gofter, RN 
Nurs
Krysti O’Keefe, RN 
Nurs
Arlyn Apollo, MD 
Medi
Pamela Drullinsky, MD 
Medi
Zoe Goldberg, MD 
Medi
Tiffany Troso-Sandoval, MD 
Medi
Kenneth Ng, MD 
Medi
Oscar Lahoud, MD 
Medi
Elizabeth Won, MD 
Medi
Alice Zervoudakis, MD 
Medi
Parisa Momtaz, MD 
Medi
Melanie Albano, NP 
Nurs
Gloria Wasilewski, RN 
Nurs
Sherie Mar-Chaim, RN 
Nurs
Jacqueline Bromberg, MD PhD 
Medi
Colette Owens, MD 
Medi
Marina Shcherba, DO 
Medi
Azadeh Namakydoust, MD 
Medi
Raylene Langish, RN 
Nurs
Irene Kelly, RN 
Nurs
Maureen Kennedy, RN 
Nurs
Ofer Maimran, RN 
Nurs
Jessica Marchisotto, RN 
Nurs
Deaglan McHugh, MD 
Medi
Catherine Pires, NP 
Nurs
Megan Stasi, RN 
Nurs
Rui Wang, MD 
Medi
Matthew Matasar, MD 
Medi
Louise Ligresti, MD 
Medi
Isabel Preeshagul, DO 
Medi
Ping Gu, MD 
Medi
Neha Korde, MD 
Medi
Anuja Kriplani, MD 
Medi
Michael Mauro, MD 
Medi
Geri Arnell, RN 
Nurs
Kristen O’Hagan, RN 
Nurs
Consenting  Professional(s)/Department: 
Ghassan Abou-Alfa, MD 
Medi
Andrea Cercek, MD 
Medi
Andrew Epstein, MD 
Medi
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Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
 
 
 
 
 
Luis Diaz, MD 
Medicine 
James Harding, MD 
Medicine 
David Ilson, MD, PhD 
Medicine 
Yelena Y. Janjigian, MD 
Medicine 
David Kelsen, MD 
Medicine 
Nancy Kemeny, MD 
Medicine 
Geoffrey Ku, MD 
Medicine 
Karuna Ganesh, MD 
Medicine 
Eileen O’Reilly, MD 
Medicine 
Diane Reidy-Lagunes, MD 
Medicine 
Leonard Saltz, MD 
Medicine 
Neil Segal, MD, PhD 
Medicine 
Kenneth H. Yu, MD 
Medicine 
Anna Varghese, MD 
Medicine 
Rona Yaeger, MD 
Medicine 
Nitya Raj, MD 
Medicine 
Steven Maron 
Medicine 
Ellen Hollywood, NP 
Nursing 
Jaclyn Norris, NP 
Nursing 
Erica Kaufmann, NP 
Nursing 
Natasha Pinheiro, NP 
Nursing 
Claudy Aime, NP 
Nursing 
Anthony Yu, MD 
Medicine 
Han Xiao, MD 
Medicine 
Sree Chalasani, MD 
Medicine 
Afsheen Iqbal, MD 
Medicine 
Rodrigo Erlich, MD 
Medicine 
Avni Desai, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 
Jia Li, MD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Elizabeth Won, MD 
Medicine 
Alice Zervoudakis, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Colette Owens, MD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Irene Kelly, RN 
Nursing 


Page 4 of 50 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
 
 
 
 
 
Maureen Kennedy, RN 
Nursing 
Ofer Maimran, RN 
Nursing 
Jessica Marchisotto, RN 
Nursing 
Deaglan McHugh, MD 
Medicine 
Catherine Pires, NP 
Nursing 
Megan Stasi, RN 
Nursing 
Rui Wang, MD 
Medicine 
Matthew Matasar, MD 
Medicine 
Louise Ligresti, MD 
Medicine 
Isabel Preeshagul, DO 
Medicine 
Ping Gu, MD 
Medicine 
Neha Korde, MD 
Medicine 
Anuja Kriplani, MD 
Medicine 
Michael Mauro, MD 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK  Sites 
Roles 
Westchester 
All Protocol Activities 
Rockville Centre 
All Protocol Activities 
Commack 
All Protocol Activities 
Basking Ridge 
All Protocol Activities 
Monmouth 
All Protocol Activities 
Manhattan 
All Protocol Activities 
Bergen 
All Protocol Activities 
Nassau 
All Protocol Activities 
 
 
Participating Institutions 
PI's Name 
Site's Role 
MD Anderson Cancer Center 
Mariela Blum Murphy, MD 
Data Collection 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 5 of 50 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ........................................................................ 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................. 6 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 14 
4.1 
Design ................................................................................................................................... 14 
4.2 
Intervention .............................................................................................................................. 14 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................. 18 
6.1 
Subject Inclusion Criteria ........................................................................................................ 18 
6.2 
Subject Exclusion Criteria ...................................................................................................... 19 
7.0 
RECRUITMENT PLAN ......................................................................................................................... 21 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 21 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................. 22 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 25 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 30 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 40 
13.0 
CRITERIA FOR REMOVAL FROM STUDY......................................................................... 41 
14.0 
BIOSTATISTICS ................................................................................................................. 41 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES43 
15.1 Research Participant Registration ............................................................................................. 43 
15.2 
Randomization ........................................................................................................................ 44 
16.0 
DAT A M ANAGEMENT ISSUES .......................................................................................... 44 
16.1 
Quality Assurance ................................................................................................................. 44 
16.2 
Data and Safety Monitoring .................................................................................................... 45 
17.0 
PROTECTION OF HUMAN SUBJECTS .............................................................................. 45 
17.1 
Privacy .................................................................................................................................. 45 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................... 45 
17.2.1  ........................................................................................................................................ 47 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 47 
19.0 
REFERENCES ........................................................................................................................... 48 
20.0 
APPENDICES ..................................................................................................................... 50 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 6 of 50 
 
 
 
 
1.0     PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single-arm, open-label, non-randomized multi-institution Phase II study of pembrolizumab in 
combination with capecitabine/-FU and a platinum and trastuzumab as first line therapy in patients with 
metastatic HER2 positive esophagogastric (EG) adenocarcinoma. The goal of the study is to determine the 
efficacy of the drug combination as measured by 6 month progression free survival (PFS). The central 
hypothesis of this trial is that dual HER2 and PD1/2 blockade will result in enhanced antibody-dependent cell- 
mediated cytotoxicity (ADCC), NK cell degranulation, and synergistic activity in combination with 
fluoropyrimidine,  and platinum. 
 
 
2.0     OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary: 
 
To determine the efficacy of pembrolizumab in combination with trastuzumab and capecitabine/5-FU and 
oxaliplatin/cisplatin and in patients with Stage IV HER2-positive EG adenocarcinoma as measured by 6 
month progression free survival (PFS). 
Secondary: 
 
• To establish the safety of pembrolizumab in combination with capecitabine/5-FU, oxaliplatin/cisplatin, and 
trastuzumab in patients with metastatic HER2-positive metastatic EG adenocarcinoma. 
• To observe other measures of efficacy of pembrolizumab in combination with capecitabie/5-FU, 
oxaliplatin/cisplatin, and trastuzumab, including response rate, overall and 1-year survival in patients with 
Stage IV EG adenocarcinoma. 
 
• Determine overall clinical benefit defined as stable disease (SD), complete response rate (CR), or partial 
response (PR) safety and tolerability. They will be summarized using binomial proportions along with exact 
95% CI. 
 
• Median PFS, overall and 1-year survival in patients with HER2+ Stage IV esophageal, gastric or GEJ 
adenocarcinoma will be estimated using the Kaplan-Meier method 
Exploratory: 
 
• To utilize PMBC and cell-free tumor DNA (cfDNA) from blood specimens collected during the course of 
treatment to explore mechanism of primary and acquired resistance to pembrolizumab and trastuzumab 
therapy. 
• To explore tumor PD-L1 as predictive biomarker. 
• To bank tumor material for future correlative analysis, including but not limited to whole exome analysis 
to determine mutation load and specific neoantigen landscape with strong association with regimen 
efficacy and survival. 
• To explore changes in 89Zr-trastuzumab PET with trastuzumab and pembrolizumab treatment. 
• To explore response rate of pembrolizumab with trastuzumab in patients with HER-2 positive metastatic 
esophagogastric cancer 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 7 of 50 
 
 
 
 
 
 
 
3.0     BACKGROUND AND RATIONALE 
 
3.1 HER2-Positive Esophagogastric Cancer 
 
Esophagogastric (EG) cancer is the second most common cause of cancer-related death worldwide, and 
represents an enormous global health burden.1  In 2015, an estimated 22,220 people will be diagnosed 
and 10,990 people will eventually die of their disease in 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 EG 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 EG 
cancer patients have primary chemotherapy refractory disease. For these patients there is a need for 
development of new therapeutic options.6 
 
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.7 Approximately 20-30% of gastric and GEJ 
adenocarcinomas harbor HER2 overexpression.7,8 
 
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 HER2.9 The ToGA study is the first randomized, 
prospective, multicenter, phase III trial to evaluate the efficacy and safety of trastuzumab in HER2-positive 
EG adenocarcinoma in combination with cisplatin and a fluoropyrimidine.7 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 months (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 
group (HR 0.71, 95% CI 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 EG cancer when 
combined with a chemotherapy regimen consisting of a fluoropyrimidine (5-FU or capecitabine) and 
cisplatin. 
 
3.2 Pembrolizumab Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been 
known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes 
(TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ 
T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. The programmed death (PD)-1 receptor-ligand 
interaction is a major pathway hijacked by tumors to suppress immune control.  The normal function of PD- 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 8 of 50 
 
 
 
 
 
1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted 
or excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an 
Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1 has 
been resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable- 
type (V-type) domain responsible for ligand binding and a cytoplasmic tail whichis responsible for the binding 
of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition  motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM). Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules which are involved in 
the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins. PD- 
1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B- 
cells, T regs and Natural Killer cells. Expression has also been shown during thymic development on CD4- 
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including non- 
hematopoietic tissues as well as in various tumors. Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions 
with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T- 
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor- 
specific T-cell expansion in subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
KeytrudaTM (pembrolizumab) is approved in the United Stated for the treatment of patients with unresectable 
or metastatic melanoma and metastatic non-small cell lung cancer. 
 
 
3.3 Rationale for anti-PD-1/2 therapy 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 9 of 50 
 
 
 
 
 
PD-L1 is expressed in a broad range of cancers with a high 
frequency, up to 88% in some types of cancer. In a number 
of these cancers, including lung10, renal11, pancreatic12, and 
ovarian13, the expression of PD-L1 is associatedwith reduced 
survival and unfavorable prognosis. Several recent studies, 
however, suggest that high PD-L1 expression is a “positive” 
prognostic factor (i.e., better prognosis) among metastatic 
melanoma14,15, NSCLC16,17, and gastric cancer patients.18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 Dramatic and durable response from PD-1 
inhibitor in 4th line of therapy of chemotherapy 
Pembrolizumab is able to achieve a dual blockade (PD-L1 
and PD-L2). It shows no cytotoxic (ADCC/CDC) activity. 
Pharmacokinetics support dosing every 2 weeks (Q2W) or 
every 3 weeks (Q3W). Pembrolizumab demonstrated a 
clinical activity in multiple tumor types.The levels of tumor- 
infiltrating lymphocytes (TILs), and more specifically cytotoxic 
T cells, have been correlated to improved prognosis in a 
number of cancers including colorectal, melanoma, and 
lung19, suggesting that an antitumor immune response is 
beneficial to patients. It has been shown in vitro that an 
antibody  that blocks the interaction between PD-L1 and its 
receptors can relieve PD-L1-dependent immunosuppressive effects and 
enhance the cytotoxic activity of antitumor T cells.20 Results of several preclinical studies using mouse tumor 
models support this hypothesis. In these studies, antibodies directed against PD -L1, or its receptor PD-1, 
showed antitumor activity.21-24 
 
Results from the studies of pembrolizumab in advanced tumors, including gastric, show promising activity 
and tolerability from this novel monoclonal antibody. The phase I KEYNOTE-012 trial investigated the safety, 
tolerability, and antitumor activity of pembrolizumab in gastric cancer pts.25 Only patients with distinctive 
stromal or ≥1% tumor nest cell PD-L1 staining were included. Of 162 pts screened, 65 (40%) were PD-L1+ 
and 39 enrolled. Median age was 63 y, and 72% of pts were men. 66% of pts were heavily pretreated (≥2 
prior therapies). Median follow-up duration was > 6 mo. The most common AEs deemed treatment related 
by investigators were hypothyroidism and fatigue (n = 5 each). Grade ≥3 AEs deemed treatment related 
occurred in 3 pts (n = 1 each for hypoxia, peripheral neuropathy, and pneumonitis). ORR was 30.8%. 
Responses were ongoing for 11/12 pts (median response duration not reached; range 8+ to 20+ wk). 41% 
of patients with heavily pretreated disease experienced a decrease in tumor burden. Evidence of an 
association between PD-L1 expression and PFS (P = 0.032) and ORR (P = 0.071) was observed.While 
comparison of results between different trials is imprecise, the response rate compared favorable to single- 
agent irinotecan or paclitaxel in the second-line setting.26 Keynote 059 is a recently initiated Phase II, 3 cohort 
trial exploring activity of pembrolizumab alone or in combination with 5-Fu and cisplatin in 1) patients who 
have progressed on at least 2 prior systemic therapies,  2)first line therapy pembrolizumab + chemotherapy 
in PD-L1 unselected population, 3) pembrolizumab monotherapy in PD-L1 selected patients. A Phase III trial 
(NCT02267343), not limiting patient enrollment by PD-L1 biomarker status, was initiated in October 2014 to 
compare another PD1 directed antibody nivolumab versus placebo in 480 previously treated Japanese 
patients with Stage IV esophageal, gastric and gastroesophageal junction cancer. 
 
MSK GI oncologists in collaboration with Immunotherapy Group have led accrual of Stage IV 
esophagogastric cancer patients on immunotherapy trials.  PD-1 directed antibody (nivolumab) is well 
tolerated and has demonstrated dramatic single agent activity in chemotherapy refractory Stage IV 
esophagogastric cancer not selected based on PD-L1 status. Response images from patients treated by 
Dr. Janjigian with similar PD1 inhibitor, nivolumab 3 mg/kg shown in Fig 1 (Confidential, unpublished 
data). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 10 of 50 
 
 
 
 
 
 
3.4 Rationale for Combination Therapy 
Trastuzumab is the standard of care for patients with metastatic HER2+ gastric cancer. However, the 
response rate in first line setting is only 47% with trastuzumab in combination with chemotherapy and 
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. Some anticancer agents, in addition to their direct 
cytotoxic effects on tumor cells, feature the ability to promote the activation by inducing hypermutated status 
in the tumor, activation of the immune system of the host, resulting in enhanced antitumor responses.27 
Capecitabine and cisplatin may have twofold immunogenic effects. Fluropyrimidine demonstrates T-cell- 
dependent antitumor effects through T-cell activation, reduction of tumor-associated Myeloid-derived 
suppressor cells (MDSCs) and increase of CD8 tumor-infiltrating lymphocytes as well as target destruction 
through increased heat shock protein (HSP) production.27,28 Cisplatin induces immunogenic cell death 
through pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group 
box 1 protein (HMGB1), which are required for immunogenic cell death.29,30 
 
Treatment with trastuzumab results in beneficial, yet limited, clinical improvement for patients with HER2 
positive EG cancer. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the 
efficacy of trastuzumab.31,32 Upon encountering trastuzumab-coated, HER2-overexpressing breast cancer 
cells, human NK cells become activated and express the costimulatory receptor CD137. Kohry, et al. 
demonstrated that stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for 
CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently 
both in vitro and in vivo in xenotransplant models of human breast cancer.32 The co-stimulatory molecule 
CD137 (4-1BB) is expressed following NK and memory T cell activation also enhances activity of EGFR 
monoclonal antibody (cetuximab) and anti-CD137 mAb administration has shown synergism in combination 
with cetuximab.31 Junttila et al. demonstrated that combining a trastuzumab-based bispecific antibody HER2- 
TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, 
increasing the rates and durability of therapeutic response.33 
 
Phase Ib data from ongoing KN014-PANACEA trial (NCT02129556) indicate that the combination of 
pembrolizumab and trastuzumab is safe. The Phase Ib part was completed without any safety concerns 
and the study has entered the Phase II part (confidential data from Merck). 
 
Based on these data showing synergistic effect, we hypothesize that enhanced NK cell degranulation and 
cytotoxicity using PD-1 blockade will result in synergistic activity of pembrolizumab in combination with 
trastuzumab. We further hypothesize that using a dual antibody strategy, combining a tumor-targeting 
antibody with a second antibody that activates the host innate immune system, in combination with 
standard cytotoxic chemotherapy will improve the therapeutic effects of antibodies against metastatic 
HER2-expressing EG tumors. 
3.5 Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical activity of 
single agent MK-3475 (pembrolizumab). The dose escalation portion of this trial evaluated three dose levels, 
1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. 
All three dose levels were well tolerated and no dose-limiting toxicities were observed. This first in human 
study of MK-3475 showed evidence of target engagement and objective evidence of tumor size reduction 
at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date.   Recent data 
from other clinical studies within the MK-3475 program has shown that a lower dose of MK-3475 and a less 
frequent schedule may be sufficient for target engagement and clinical activity. 


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PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited volume 
of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days). This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q2W and Q3W dosing schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time data from 476 
patients. Within the resulting population PK model, clearance and volume parameters of MK-3475 were 
found to be dependent on body weight. The relationship between clearance and body weight, with an 
allometric exponent of 0.59, is within the range observed for other antibodies and would support both body 
weight normalized dosing or a fixed dose across all body weights. MK-3475 has been found to have a wide 
therapeutic range based on the melanoma indication. The differences in exposure for a 200 mg fixed dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose 
regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that 
there was no significant impact of tumor burden on exposure. In addition, exposure was similar between the 
NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumors is 
based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W 
in melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both efficacy and 
safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or 
indication on distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) the 
assumption that the dynamics of pembrolizumab target engagement will not vary meaningfully with tumor 
type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switchto fixed dosing is based on simulations 
performed using the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 
weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose 
every 3 weeks, 2) will maintain individual patient exposures in the exposure range established in melanoma 
as associated with maximal efficacy response and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to reduce 
potential for dosing errors. A fixed dosing scheme will also reduce complexity in the logistical chain at 
treatment facilities and reduce wastage. 
 
3.6 Rationale For Correlative Studies 
 
3.6.1 Exploration of Neoantigens 
 
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.34 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 


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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 MSKCC next 
generation sequencing and gene copy number analysis is routinely performed on all advanced gastric 
tumors. Whole exome sequencing is also routinely done on site at MSK for biomarker development in setting 
of clinical trials. 
 
Immune checkpoint blockade has led to durable antitumor effects in patients with metastatic melanoma, non– 
small-cell lung cancer, and other tumor types, but the factors determining whether a patient will have a 
response remain elusive. The relationship among the genomic landscape of the tumor, the mutational load, 
and the benefit from treatment has been under investigation at MSK in laboratory of Timothy Chan and 
recently published in NEJM40. Whole-exome sequencing was performed on melanoma tumors and matched 
blood samples. Somatic mutations and candidate neoantigens generated from these mutations were 
characterized. Snyder et al reported that mutational load was associated with the degree of clinical benefit 
(P=0.01) but alone was not sufficient to predict benefit. Using genome wide somatic neoepitope analysis and 
patient-specific HLA typing, MSK investigators identified candidate tumor neoantigens for each patient and 
elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 
blockade. 
 
We hypothesize that among gastric tumors, MSI and EBV positive subtypes are the most likely to benefit to 
anti-PD1 blockage. Samples will be banked for future correlative analysis after the trial enrollment is 
complete. In collaboration with MSKCC immune monitoring core facility we will conduct whole exome and 
neopeptide analysis on samples banked on the trial to explore a specific signature predictive of strong 
response to anti-PD1 therapy. 
 
 
3.6.2 Cell-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. Janjigian’s clinic, as summarized in the table below. Cell- 
free DNA (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 identify 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) 


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Zr-trastuzumab PET of a patient withheavily pretreated EG 
e and 5 days after single agent afatinibtherapy. B. 
ngpre and post afatinib liver biopsy showing persistent high 
nohistochemistry expression(IHC 3+) in Segment 2 liver lesion 
ntly high SUV uptake post afatinibindicatedin Table 3. 
 
 
 
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 
 
 
 
3.6.3 Collection of peripheral blood mononuclear cells (PBMC) and plasma for immunologic analyses 
To explore whether therapy will restart T cell activation and function, peripheral blood mononuclear cells  
will be isolated and cryo preserved analysis may include, but not necessarily be limited to, the proportion of 
T, B and NK cells, proportion of memory and affect are T cells, and expression levels of PD–1, PD L1, 
ICOS, and Ki 67.  Approximately 32 ml of whole blood per visit (baseline and wks 1, 2, 3, 6, 10, 13 post- 
dosing. 
 
 
 
3.6.4 89Zr-trastuzumab PETs as PD and predictive biomarker 
 
 
Table 1 
Primary 
M1 
M2 
M3 
ERBB2  CNV 
16.5 
8.9 
9.2 
2.5 
89Zr-PET  SUV 
Baseline 
21 
9 
16 
0 
Post afatinib 
24 
7 
16 
0 
 
 
 
 
 
 
Figure 1 A 89 
cancer befor 
Correspondi 
HER2 immu 
w ith persiste 
Our group in collaboration with Drs. Lewis 
and Weber implemented functional 
imaging with89Zr-trastuzumab  PET to 
characterize the extent of response 
heterogeneity to HER2 directed therapy 
between primary tumor and metastases in 
HER2+ gastric cancer. 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.41-43  Our preliminary data in 20 patients imaged thus far demonstrates that 
89Zr-trastuzumab PET is feasible and provides  exceptional image quality in HER2+ gastric cancer 
patients. 89Zr-trastuzumab was well tolerated with ideal imaging interval of 5 days post injection. Figure 1 
shows preliminary 89Zr-Trastuzumab PET images of a patient with heavily pretreated HER2 + EG cancer 
which demonstrate the selective and high accumulation 89Zr-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 metastases obtained during rapid autopsy of a patient treated with afatinib (Figure 1), where 
high 89Zr 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 


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noted in liver lesions and primary esophageal mass.  Post-afatinib liver biopsy showed persistently high 
HER2 expression (IHC3+ Figure 1).The patient had radiographic tumor response on 8 week CT, 27% 
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.  Thus far imaging HER2+ 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 pembrolizumab + 
trastuzumab will provide key pilot data on activity on targeted therapy without chemotherapy in first line 
HER2+ esophagogastric cancer. In select patients baseline and early assessment 89Zr-trastuzumab-PET 
will be performed under IRB 13-165 (co-PI Janjigian) 
with CT/MRI scan performed after the initial 3 
weeks (1 cycle). All patients will receive capecitabine and cisplatin with subsequent cycles together with 
pembrolizumab and trastuzumab. 
3.6.5 PD-L1 as Biomarker for Anti–PD-1 Immunotherapy 
The complexity of PD-L1 expression leads to variations in the thresholds for positivity and differences in the 
interpretation of test results. Furthermore, narrowing treatment down to PD-L1-positive patients could 
exclude patients who benefit from these treatments. PD-L1 is a very dynamic marker—it can fluctuate over 
the course of the disease and treatment. Until more is learned, it remains problematic to use PD-L1 as a 
biomarker. If PD-L1 is not the best marker, there may be another T-regulatory cell that can be measured. 
There needs to be a strategy for selecting patients who will not benefit from treatment. An important aspect 
of development program for pembrolizumab in esophagogastric cancer is identification of a biomarker for 
patient selection. PD-L1 expression in tumor tissue will be characterized by immunohistochemistry (IHC) to 
explore the relationship between PD-L1 expression and response to pembrolizumab. Other exploratory 
biomarkers including but not limited to PD-1 expression, markers of T-cell phenotype may also be 
evaluated. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is an open-label, non-randomized, single-arm, multi-institution phase II study of pembrolizumab 
in combination with fluorpyrimidine, platinum, and trastuzumab as first line therapy in patients with 
metastatic HER2 positive esophagogastric adenocarcinoma.  The primary endpoint of the study is 
to determine the six months progression free survival (PFS) in the first-line treatment of patients with 
Stage IV HER2 positive esophagogastric adenocarcinoma. With a total of 37 esophagogastric 
adenocarcinoma patients, we have 80% power to detect an improvement in the 6-month progression 
free survival (PFS) from a historical control of  55% to  75% with type I error rate of 5%. 
4.3 
Intervention 
 
Pembrolizumab 200 mg IV every 3 weeks, trastuzumab (8 mg/kg loading dose; 6 mg/kg 
maintenance) IV every 3 weeks with cisplatin IV every 3 weeks with oral capecitabine 2 weeks 
on/1 week off. 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. If the 
patient is not a good candidate for induction pembrolizumab/trastuzumab, capecitabine/5-FU and 
cisplatin/oxaliplatin can be added during cycle 1 of treatment. Oxaliplatin may also be considered 
for patients who cannot be administered cisplatin for any specific reason. Oxaliplatin 130 


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mg/m2/day will be administered on Day 1 beginning with cycle 2. Treatment will be administered on 
an outpatient basis.  In Cycle 1, patients will initiate therapy with trastuzumab 8 mg/kg IV with 
pembrolizumab 200 mg IV. CT/MRI scan will be performed after the initial 3 weeks (1 cycle) to 
determine response to pembrolizumab and trastuzumab combination. With subsequent cycles, all 
patients will begin systemic chemotherapy with capecitabine/5-FU, and cisplatin/oxaliplatin  in 
addition to pembrolizumab 200 mg IV with trastuzumab 6 mg/kg maintenance.  Patients will receive 
cisplatin 80 mg/m2 IV on Day 1, and capecitabine 850mg/m2 twice a day on Days 1 through         
14, every 3 weeks. Treatment will be performed on the scheduled day ± 7 days.  Cisplatin will be 
given in up to 6 cycles, and may be discontinued before 6 cycles for cumulative toxicity. In case of 
discontinuation of cisplatin due to cumulative toxicity, patients will be permitted to continue 
capecitabine maintenance with pembrolizumab 200 mg IV and trastuzumab every 3 weeks. CT 
scan will be performed at baseline, week 3, week 9  and every 9 weeks thereafter. CT scans 
occurring every 9 weeks will coincide with the 6 month CT scan. 15 MSK patients only  with 
disease technically amenable to biopsy will be asked to undergo an optional research biopsy for 
tissue correlative studies during week 3 of treatment. 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Pembrolizumaba 
200 mg X 
mg/kg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Trastuzumab 
8 mg/kg 
loading dose; 6 
mg/kg 
maintenance 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Cisplatinb 
80 mg/m2 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle after cycle 1, for 
up to 6 cycles 
Oxaliplatinc 
130 mg/ m2 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle  after cycle 1, for 
up to 8 cycles 
Capecitabined 
850mg/m2 
BID 
Oral 
Days 1 through 14 of 
each 3 week cycle 
after cycle 1 
5-Fluorouracile 
800mg/m2/day 
Q3W 
IV infusion 
Day 1 to Day 5 of every 
21 days 
a. 
Pembrolizumab/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 
treating investigator's  discretion, capecitabine (or 5-FU) treatment can be discontinued. 
b. 
Maintenance of satisfactory GFR and adequate hydration pre- and post-cisplatin administration should 
be performed  per local clinical practices 
c. 
As an alternative,  oxaliplatin may be considered for eligible patients who cannot be administered 
cisplatin for any specific reason. This decision should be made prior to initiation of therapy by the 
treating investigator,  switching from  cisplatin to oxaliplatin, or vice versa,  will not be allowed during  
the study. Oxaliplatin will be administered at 130 mg/m2 continuous IV infusion on Day 1every  21 day 
cycle, after completion of the first cycle. Patients may begin with reduced dose of oxaliplatin 104 


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mg/m2 as starting dose if deemed  necessary per the treating physician discretion.  Oxaliplatin may 
be stopped after 6 cycles at the treating investigator’s  discretion 
d. 
Capecitabine should be taken within 30 minutes after a meal. Total daily dose of capecitabine 
administered will be 1700 mg/m
2. 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. 
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 initiation of therapy by the treating 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/m2/day continuous IV infusion on 
Day 1-Day 5 every  21-day cycle, after completion of the cisplatin infusion. 
 
 
 
5.1.1. 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 before, during and after 
cisplatin administration. If clinically not contraindicated, patients should be advised to drink 3 liters if 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 5.1.1.1 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 pembrolizumab 
 
5.1.2. 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. Pembrolizumab Storage and Accountability 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
5.2.1 Dispensing of Pembrolizumab 


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Pembrolizumab will be provided by Merck at no charge. Pembrolizumab will be shipped by Merck directly 
to each participating site. Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
 
5.2.2 Preparation and Administration of Pembrolizumab 
 
Investigators should consult the manufacturer’s instructions for pembrolizumab for complete prescribing 
information and follow institutional procedures for the administration of pembrolizumab.  Pembrolizumab 
should be administered on Day 1 of each three week cycle after all procedures and assessments have 
been completed as detailed on the Trial Flow Chart (Section 10.0). Pembrolizumab 200mg will be 
administered as a 30 minute IV infusion every 3 weeks. Variation in infusion time is permitted; a window of 
-5 minutes and +10 minutes is permitted. 
 
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 administered as an I.V. 
infusion of 80 mg/m
2 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 pembrolizumab 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/m2/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 progression or until other 
withdrawl criteria are met. Patients may begin with reduced dose of oxaliplatin 104 mg/m2 as starting dose if 
deemed necessary per the treating physician discretion. Oxaliplatin will be administered after the completion 
of the pembrolizumab 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 willbe orally 
self-administered at 850 mg/m
2 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 


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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 treating 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. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Patient must have pathologically or cytologically MSKCC confirmed esophageal, gastric or 
gastroesophageal junction (GEJ) adenocarcinoma by the enrolling institution. 
• 
Patients must have esophageal, gastric or gastroesophageal 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 or enrolling institution 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 or the enrolling institution 
for purpose of analysis and will not impact the patient’s eligibility. 
• 
Additional available archival tumor tissue in the form of 15-20 unstained slides 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 MSK PI. 
• 
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 
• 
Patients must have disease that can be evaluated radiographically. This may be measurable 
disease or non-measurable disease per RECIST 1.1. 
• 
Patient must have a normal LVEF (>/= 53%). If a patient has a borderline LVEF (40-52%) they 
may be considered after consultation with cardiology and study PI and treated per the 
guidelines in section 11.2.2. 
• 
Age 18 years or older. 
• 
ECOG performance status 0-2. 


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• 
Demonstrate adequate  organ  function  as  defined  in  Table  1,  all  screening labs  should be 
performed within 10 days of treatment initiation. 
 
Table 1  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
(measured via 24-hour urine collection) ≥60 mL/min for 
subject with creatinine levels > 1.5 X institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN (1.5 mg/dL or 25.65 µmol/L) OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN. Except patients with Gilbert’s disease (≤3xULN) 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>3 mg/dL 
Coagulation 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
• 
Female subject of childbearing potential should have a negative urine or serum pregnancy within 
72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required. 
 
• 
Female subjects of childbearing potential should be willing to use 2 methods of birth control or 
be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 
days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from menses 
for > 1 year. 
 
• 
Male subjects should agree to use an adequate method of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy. 
 
• 
Peripheral neuropathy ≤grade 1 
 
6.3 
Subject Exclusion Criteria 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 20 of 50 
 
 
 
 
 
The subject must be excluded from participating in the trial if the subject: 
 
• 
Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 weeks of 
the first dose of treatment. 
• 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
• 
Has a known history of active TB   (Bacillus tuberculosis) 
• 
Hypersensitivity to pembrolizumab or any of its excipients. 
• 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks 
prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to a previously administered agent. 
o Note: If subject received major surgery, they must have recovered adequately  from the 
toxicity and/or complications from the intervention prior to starting therapy. 
• 
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
• 
Has known history of, or any evidence of active, non-infectious pneumonitis. 
• 
Has an active infection requiring systemic therapy. 
• 
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 
• 
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
• 
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration 
of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of 
trial treatment. 
• 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
• 
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel 
disease; systemic lupus erythematosus; Wegener  syndrome [granulomatosis with polyangiitis]; 
myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis) within the past 3 
years prior to the start of treatment. The following are exceptions to this criterion: 
o Subjects with vitiligo or alopecia 
o Subjects  with  hypothyroidism  (e.g.,  following  Hashimoto  syndrome) stable  on  hormone 
replacement or psoriasis not requiring systemic treatment. 
• 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
• 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
• 
Has received a live vaccine within 30 days of planned start of study therapy. 
o Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed;  however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
• 
Is unwilling to give written informed consent, unwillingness to participate, or inability to comply with 
the protocol for the duration of the study. 
• 
Has active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA)  > Class II. 
o Active coronary artery disease. 
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 
initiation, or myocardial infarction within 6 months before initiation. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 21 of 50 
 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by members of the patient’s treatment team, the protocol 
investigator or research team at participating institutions. If the investigator is a member of the 
treatment team, s/he will screen their patient’s medical records for suitable research study 
participants. The investigator will use information provided by the patient and/or medical record to 
confirm that the patient is eligible and contact the patient regarding study enrollment. All eligible 
patients, regardless of sex and race, will be approached for participation. No additional measures, 
e.g. advertisement, payment to patients, will be employed to recruit patients. 
 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. Participation in the study is completely voluntary. Patients will be required to 
read, agree to, and sign an IRB-approved informed consent form prior to registration on this trial. 
Patients will not receive payment for their participation on this study. Patients are free to withdraw 
from the study without consequence at any time. 
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 the Inclusion of Children as Participants in Research Involving Human Subjects. 
 
 
8.1 
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 (ECOG). 
• 
Serum or urine pregnancy test for women of childbearing potential (WOCP) 
In addition, all WOCP should be instructed to contact the MSK Prinicipal Investigator 
immediately if they suspect they might be pregnant (e.g. late or missed period) at any time 
during study participation. 
• 
Laboratory evaluation  including complete blood count, magnesium, comprehensive 
chemistry panel (includes BUN, creatinine, ALT, AST, albumin, glucose, total protein, 
calcium, bilirubin, bicarbonate, sodium, chloride, potassium, alkaline phosphatase), and 
coagulation studies (PT/PTT) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 22 of 50 
 
 
 
 
• 
Research blood  tests  including  plasma collection  for  cfDNA  analysis  and  whole  blood 
collection for PBMC. 
 
 
The following must be obtained within one month prior to starting protocol therapy: 
• 
CT scan of chest, abdomen and pelvis within 4 weeks of study entry 
• 
Electrocardiogram 
• 
Assessment of Left Ventricular Ejection Fraction (LVEF) as measured by echocardiography 
or MUGA scan. The same method of measurement has to be used throughout the study. 
 
To be completed any time prior to starting therapy: 
• 
Histological confirmation of esophageal, gastric or GE junction adenocarcinoma at MSKCC 
prior to study enrollment. 
 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Treatment will be administered on an outpatient basis. Pembrolizumab 200 mg IV every 3 weeks, 
trastuzumab (8 mg/kg loading dose; 6 mg/kg maintenance) IV every 3 weeks with cisplatin IV every 3 
weeks with oral capecitabine 2 weeks on/1 week off. Each cycle consists of 21 days. Treatment will be 
administered on an outpatient basis.  In Cycle 1, patients will initiate therapy with trastuzumab 8 mg/kg IV 
with pembrolizumab 200 mg IV. CT/MRI scan will be performed after the initial 3 weeks (1 cycle) to 
determine response to pembrolizumab and trastuzumab combination. With subsequent cycles, all patients 
will begin systemic chemotherapy with the capecitabine/5-FU, and a cisplatin/oxaliplatin  regimen in 
addition to pembrolizumab 200 mg IV with trastuzumab 6 mg/kg maintenance.  Patients will receive 
cisplatin 80 mg/m2 IV on Day 1, and capecitabine 850mg/m2 twice a day on Days 1 through 14, every 3 
weeks.  Treatment will be performed on the scheduled day ± 7 days.  Cisplatin will be given in up to 6 
cycles, and may be discontinued before 6 cycles for cumulative toxicity. In case of discontinuation of 
cisplatin due to cumulative toxicity and administration as a single agent during the study, patients will be 
permitted to continue capecitabine maintenance with pembrolizumab 200 mg IV and trastuzumabevery 3 
weeks. CT scan will be performed at baseline, week 3, week 9 and every 9 weeks thereafter. CT scans 
occurring every 9 weeks will coincide with the 6 month CT scan. 
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. 
 
 
9.2 Correlative Studies Research 
 
9.2.1 Sample Acquisition and DNA Preparation 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 23 of 50 
 
 
 
 
 
Available archival tumor samples will be obtained and stored for future correlative analysis including but not 
limited to the below. For the discovery set, we will plan conduct whole-exome sequencing of DNA from 
tumors and matched normal blood from patients that responded to trial therapy (PR or prolonged SD) and 
compare to the analysis of ‘non-responders’.. DNA will be extracted, and exon capture will be performed 
with the use of the SureSelect Human All Exon 50-Mb kit (Agilent Technologies). Enriched exome libraries 
were sequenced on the HiSeq 2000 platform (Illumina) to provide mean exome coverage of more than 100× 
(Memorial Sloan Kettering Cancer Center Genomics Core and Broad Institute). 
Immunogenicity Analysis  of Somatic Mutations 
MSK investigators (Chan and Snyder) created a bioinformatic tool to translate all mutations in exomes and 
then evaluate binding with major histocompatibility complex (MHC) class I molecules. The neoantigen 
signature was generated from the nonamers containing four amino acid strings of peptides that are common 
to tumors from patients with a long-term benefit from therapy. 
Intracellular Cytokine Staining 
Candidate neoantigen peptides will be synthesized (GenScript), cultured with autologous peripheral-blood 
mononuclear cells (PBMCs), and then analyzed by means of intracellular cytokine staining for interleukin-2, 
CD107a, macrophage inflammatory protein 1β, tumor necrosis factor α, and interferon-γ on restimulation of 
cells with the candidate peptides. 
9.2.2 Functional Imaging with 89Zr-trastuzumab PET 
In select patients, 89Zr-trastuzumab PETs will be performed on IRB 13 -165. The patients willing to  
undergo additional imaging on protocol 13-165 and that meet eligibility criteria for both protocols will be 
approached for IRB 13-165.  We will assess 89Zr-trastuzumab PET uptake as a predictor of tumor 
response. We will compare the proportion of patients with a drop in 89Zr-trastuzumab tumor uptake on PET 
(pre-therapy and at 3-wk) of 30% or greater in the responder versus in the nonresponder groups. Fisher's 
exact test will be used to determine the significance of the association. 89Zr-trastuzumab PET imaging will 
be an exploratory study, with only a select subset of MSK patients on this trial with measurable disease 
undergoing imaging with 89Zr-trastuzumab PET.  If deemed appropriate, MSK patients will be approached 
for participation in the Pilot imaging trial with 89Zr-trastuzumab PET  in HER2+ EG tumors, MSKCC 
protocol IRB13 -165. 
9.2.3 Collection of peripheral blood mononuclear cells (PBMC) and plasma for immunologic 
analyses 
Whole blood will be used for isolation of peripheral blood mononuclear cells (PBMCs). Flow cytometry will 
be performed on PBMCs at baseline and during treatment to assess changes in composition/activation 
status of lymphocyte subsets, including CD8+ and CD4+ T-cell subsets (activated; effector/memory; 
regulatory) and populations of those cells as defined by the expression of activation, exhaustion, or 
signaling markers such as ICOS, HLA-DR, PD-1, CTLA-4, and/or intracellular IFNγ. 
 
Approximately 32 ml of whole blood per visit (baseline and wks 1, 2, 3, 6, 10, 13, and EOT post-dosing) 
will be collected at ambient temperature into 4 x 8-ml BD sodium heparin Cell Preparation Tubes (CPT) for 
density gradient centrifugation and isolation of PBMC and plasma for banking according to institutional 
procedures at the Memorial Sloan-Kettering Cancer Center Ludwig Center for Cancer Immunotherapy 
Immune Monitoring Core Facility.  After centrifugation, the plasma supernatant will be collected and then 
the PBMC monolayer isolated and washed.  PBMC will resuspended at ~6-8 million cells per vial in cell 
freezing medium, frozen at –80 degrees C in controlled rate cooling containers, and then cryopreserved in 
liquid nitrogen freezers.  Plasma will be frozen in 1.5 ml aliquots and stored at –20 degrees C. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 24 of 50 
 
 
 
 
9.2.4 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 
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. 
9.2.5 PD-L1 testing of archival tissue 
 
An important aspect of development program for pembrolizumab in esophagogastric cancer is 
identification of a biomarker for patient selection. PD-L1 expression in tumor tissue will be characterized 
by immunohistochemistry (IHC) to explore the relationship between PD-L1 expression and response to 
pembrolizumab. Other exploratory biomarkers including but not limited to PD-1 expression, markers of T- 
cell phenotype may also be evaluated. Testing will be done at QualTek Laboratories, the recommended 
laboratory to perform this work.  MSKCC will contract with QualTek directly for this work.  Tumor tissue for 
biomarker analysis from archival tissue samples will be batched and shipped to QualTek for testing. 
9.2.6 Biopsies of tumor 
 
15 MSK patients only with disease technically amenable to biopsy will be asked to undergo an optional 
research biopsy at week 3 after the start of therapy for correlative studies evaluating the biologic effects of 
pembrolizumab and trastuzumab. In addition, patients will be asked to consent to tumor banking such that 
both frozen and fixed tumor cores can be utilized for future investigations. 
Pre- and post-treatment tumor biopsies will be used to evaluate biomarker expression and target inhibition 
(described below). In addition, archived tissue from prior tumor biopsies obtained at the time of cancer 
diagnosis, and prior to initiation of trastuzumab will be analyzed, when available. Our primary aims are to 
identify changes in expression of specific biomarkers or in the genomic HER2 sequence as a result of 
pembrolizumab and trastuzumab therapy in patients with HER2-overexpressed esophagogastric cancer. 
After obtaining informed consent, a diagnostic biopsy will be performed either by radiologic guidance 
(sonogram guided core biopsy or stereotactic biopsy) or endoscopy. The appropriate type of diagnostic 
biopsy will be determined by the treating physician based on the tumor location most amenable to biopsy. 
The biopsy specimen will be accessioned and sent to pathology for routine analysis (histology, tumor, 
grade, HER2 by immunohistochemistry (IHC), and HER2 by fluorescence in situ hybridization (FISH)). 
Where possible, multiple cores will be obtained. When only one core is obtained, half the core will be snap 
frozen using liquid nitrogen with a selection evaluated for the presence of invasive carcinoma by a 
participating pathologist and stored for later analysis. The second and larger sample will be formalin fixed 
and used for IHC studies. 
• 
The number of biopsies taken will be based on the clinical judgement of the endoscopist, 
sugergeon, or intervential radiologist, but ideally will be less than or equal to four. 
• 
Tumor DNA (post-treatment) will be isolated for whole exome sequencing and compared to 
genomic DNA from PBMC in order to identify tumor-specific mutations. Candidate neo- 
epitopes will be predicted using epitope-prediction algorithms, such as SYFPEITHI. 
Candidate neo-epitopes will be validated by RNA transcription and protein expression, if 
possible. 
• 
Changes in the tumor microenvironment will be evaluated comparing baseline and on- 
treatment biopsies.  We will perform immunohistochemistry for PD-L1 expression, IHC for 
immune cell subsets (including CD4, CD8, regulatory T-cells, macrophages and myeloid 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 25 of 50 
 
 
 
 
derived suppressor cell populations) and RNA expression analyses (RNAseq) for immune- 
related genes. 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
 
 
Procedure 
Screena, p 
Cycle 1 (21 days)p 
Cycle 2g, p 
Cycle 3-p 
subsequent  cycles 
EOTc, p 
F/Ud, p 
D 
1 
D8 
D15 
D 
1 
D8 
D15 
D1 
D8 
D15 
Medical 
Hx/Demographics 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum or urine 
Pregnancy  Test 
X 
Archival  tumor 
samples 
X 
Optional research 
biopsys 
X 
Physical examb 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
Performance  status 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicities/AE 
assessmenth 
X 
Reported  from screening throughout  all subsequent 
cycles. 
X 
X 
Hematologyb 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Chemistryb 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Magnesium 
X 
X 
Xf 
X 
X 
X 
X 
X 
X 
TSH, Free T3, Free 
T4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR&APTTm 
X 
Will be monitored per treating investigator  discretion 
MRI/CT  assessmenti 
X 
X 
Every  9 weeks (3 
cycles) after  initial 
CT 
X 
X 
Concomitant 
medicationsj 
X 
All medications taken during the study will be documented 
X 
12-lead  ECG 
X 
ECHO/  MUGA0 
X 
X 
Every  12 weeks (4 
cycles) o 
89Zr- trastuzumab 
PETn 
X 
X 
Research  Test: 
PMBCl 
X 
X 
X 
X 
X 
X (weeks 10 and 
13) 
X 
Research  Test: 
cfDNAk 
X 
X 
X Every 9 weeks 
(3 cycles) 
X 
Pembrolizumab 
X 
X 
X 
Trastuzumab 
X 
X 
X 
Cisplatin or 
Oxaliplatinq 
X 
X 
Capecitabine  or 5FU 
2 weeks on/ 1 week off after cycle 1 
completion 
Capecitabine 
compliancer 
Compliance will be assessed at every  visit 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 26 of 50 
 
 
 
 
 
 
ECG = electrocardiogram;  ECHO = echocardiogram;  EOT = end of treatment; FU = follow-up;  LVEF = left ventricular 
ejection fraction; h = hour(s);  hx = history; MUGA = multiple gated acquisition scan 
Radiological imaging studies <28 days prior to start of study treatment, other screening evaluation  within 2 weeks prior 
to start of study treatment. 
 
a 
Radiological imaging studies and electrocardiogram <28 days prior to start of study treatment, other screening 
evaluation  within 2 weeks prior to start of study treatment. 
b 
Physical exam (vital signs [BP, heart rate, temperature], weight, and a review of body systems), and chemistry 
(includes BUN, creatinine, ALT, AST, albumin, glucose, total protein, calcium, bilirubin, bicarbonate, sodium, 
chloride, potassium, alkaline phosphatase)  on intended days 1 and 15 of each cycle prior to chemotherapy  or 
≤ 72 h prior to dosing. If chemotherapy is  delayed then the physical exam must be repeated weekly until 
retreatment or ≤ 72 h prior to dosing. Hematology and physical exam will be done weekly for the first 6 weeks 
and on the intended days 1 and days 15 of each cycle prior to the chemotherapy or ≤ 72 h prior to dosing 
thereafter. 
c 
Within 14 days of tumor progression or study treatment discontinuation. If permanent  discontinuation  of the 
study drug falls  on a scheduled visit, examinations as  defined for EOT should be performed instead of the 
examinations of the scheduled visit. If patient is unable to come in to see MD, a nurse phone call to evaluat e 
toxicities can be substituted. 
d 
Assessment by treating medical oncologist as clinically indicated. For those patients no longer followed by an 
MD at MSK or the participating site, a nurse will make a follow up phone call every 3 months to assess patient’s 
vital status. 
e 
A sample of archival tumor biopsy, or other available tumor biopsy, should be submitted for biomarker analysis 
during screening. Tumor biopsy samples may also be submitted for biomarker analysis at any other time during 
the course of the clinical study. 
f 
Physical exam and laboratory assessments are not required if screening assessments were  done within  72 
hours of first dose. ECG is not required if screening ECG was done within 7 days of first dose. 
g 
In cycle 2 procedures  will be performed  identical to cycle 1. Radiologic  tumor assessment  will be performed 
after the initial three weeks (only applicable to patients receiving induction pembrolizumab and trastuzumab for 
cycle 1) to determine response and every  9 weeks thereafter.   If patients experience new lesions or progression 
at the initial three week CT scan, they will remain on study and be followed by subsequent CT scans.  Decision 
to keep the patient on study will be at the discretion of the treating investigator. 
h 
AE monitoring should continue for at least 4 weeks following the last dose of study treatment. AEs that occur 
within 30 days following  the last study treatment will be followed  until resolution. 
i 
The baseline and subsequent scans to assess response must be performed using identical  technique. 
Radiological imaging studies to evaluate tumor status will be performed after the initial three weeks (1 cycle) to 
determine response, and then at week 9 and every 9 weeks thereafter while on study regardless of treatment 
delays. 
Patients 
who 
received chemotherapy upfront and 
did 
not 
have an 
induction 
period 
with 
pembrolizumab/trastuzumab, do not need the 3 week scan. CT scans occurring every  9 weeks will coincide 
with the 6 month CT scan. For subjects who have entered the survival follow-up period and have not yet 
experienced PD, every  effort  should be made to follow-up  for tumor evaluation  (by CT or MRI) until progression 
of their malignancy every 9 weeks, or until a new anticancer treatment is started. Window of +/ - 7 days during 
the first cycle, and +/-14 days for all subsequent  cycles for radiological  imaging studies. Patient may have  CT 
or MRI scan on an earlier or later date than allowed by the window of +/-14 days, if clinically indicated at the 
MSK Prinicipal Investigator’s   discretion. 
j 
All medication given within 2 weeks prior to the start of study treatment. 
k 
Cell-free DNA (cfDNA) will be obtained from plasma samples collected at baseline,  at week 3, every  9 weeks 
and at the time of treatment discontinuation, as the same time as the MRI/CT evaluations . Research tests may 
vary  by up to one to fourteen  (1-14 days). 
l 
PBMC will be obtained at baseline and wks 1, 2, 3, 6, 10, 13, and EOT post-dosing. Research tests will coincide 
with physician visits that may vary  by up to one to fourteen (1-14 days). 
m PT/INR assessments will be continued per treating  investigator’s  discretion 
n 
For MSK only, some patients will have 89Zr--trastuzumab PET at baseline and week 3  only  if deemed 
appropriate by MSK Principal Investigator. Patients will have to sign a written informed consent for MSK IRB#13- 
165. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 27 of 50 
 
 
 
 
 
o Baseline ECHO/MUGA must be obtained within one month prior to starting protocol therapy. ECHO with 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 performed 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 avoid deviations from the protocol, blood tests, CT/MRI scans, optional research biopsies,  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 
Upon treating investigator discretion,  Oxaliplatin (130 mg/m2 infusion on Day 1 of Cycle 2 and on) may be 
considered. Patients  may begin with reduced dose of oxaliplatin 104 mg/m2 as starting dose if deemed 
necessary per the treating physician discretion. The decision to treat with oxaliplatin or cisplatin needs to be 
made prior to treatment initiation by the treating investigator. Switching between oxaliplatin and cisplatin is not 
allowed. 
r 
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 (800 
mg/m2/day continuous infusion on Day 1 to Day 5 of Cycle 2 and on) may be considered. The decision to t reat 
with capecitabine or 5-FU needs to be made prior to initiation by the treating investigator. Switching between 5- 
FU and capecitabine is not allowed. Patients who received chemotherapy upfront and did not have an induction 
period with pembrolizumab/trastuzumab,  do not need the 3 week scan. 
s 
For 15 MSK patients only. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 28 of 50 
 
 
 
 
10.1 Future Unspecified Use of Biospecimens 
 
The protocol includes an informed consent document and research authorization that meets 
statutory guidelines. Each participating site will have its own consent form meeting the requirements 
described in this section. The consent form will inform patients of the purpose of the bank, their 
rights in relation to it, and the safeguards in place to protect the confidentiality of their health 
information. The consent will state that some of the biospecimens will be saved to use for future 
research. 
 
Type of future use 
The consent specifically describes the types of future research that may be performed, including 
use of tissues to develop new drugs with cancer-associated molecular targets, development of cell 
lines, future use of cell lines to define cancer phenotype and (somatic) genotype, DNA sequence 
analysis of tumor compared to normal and identification of tumor-associated proteins as diagnostic 
or prognostic markers. It will be stated that researchers at MSK may either keep indefinitely or 
dispose of any leftover blood or tissues or other samples, including DNA that the samples contain. 
Blood and tissues will be stored with identifiers in secure tissue or fluid banks.  It is stated that the 
samples could be lost or ruined because of mechanical failure, and that MSK cannot guarantee that 
samples will be stored indefinitely. The samples will be stored for as long as deemed useful for 
research purposes. 
 
Consent for future use and re-contact 
Patients are asked in a series of check boxes at the end of the consent if 1) they permit their 
biospecimen samples to be stored and used in future research to learn about or prevent cancer or 
side effects of treatment, or to develop new treatments; 2)  if they permit their samples to be stored 
and used in future research to learn about, prevent, or treat diseases other than cancer; or 3) if they 
permit their samples, with personal identifiers protected, to be used for research about inherited 
genetic factors, 4) if they permit their samples to be used for genetic analysis of the tumor and 
normal tissue to learn about the causes of cancer, 5) participants are asked if they agree to be 
contacted in the future as part of research studies for additional health information or to be asked to 
participate in future biospecimen research studies and 6) if they consent to be contacted to discuss 
research findings which may come from their sample. Finally, if not available (e.g. deceased), if they 
wish to have their designee designated on the consent to be contacted. 
 
Participants will not be provided with specific results of research tests performed on their collected 
human biologic specimens. 
 
Use of identifiable information for genetic studies 
In the course of this research it is possible that some patients whose tumors are analyzed through 
investigational “next-generation” profiling in a research (non-CLIA) environment will be found to 
have somatic or germline mutations in genes that are known to be associated with an increased risk 
of cancer or other diseases. It will be stated in the consent that the participants will not receive any 
specific results from research tests. The consent will tell participants that if they wish to have  
genetic testing done for personal reasons than they should make an appointment with the MSK 
Clinical Genetics Service or Clinical Genetics Service at their site. 
 
If in the course of this research a research finding is obtained that, in the opinion of the investigator, 
may be critical to the preventive care of the participant or their family, the investigator can 
communicate that finding to the MSK IRB Genomic Advisory Panel (GAP). The finding will be 
reviewed by the GAP to determine whether the incidental finding should be discussed with the 
participant. For MSK patients, in the event that the GAP determines that the finding should be 
discussed with the participant, and the participant has consented to be re-contacted, then the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 29 of 50 
 
 
 
 
 
treating/consenting physician shall be contacted by the panel and asked to refer the participant to 
the Clinical Genetics Service for further discussion of the research finding. 
 
The following information must be provided to GAP for review: 
• 
Participant Name/MRN # 
• 
Type of Biospecimen (tissue, blood, saliva) 
• 
Incidental Finding 
• 
Collection Protocol # 
• 
Contact: ocrgapirb@mskcc.org 
 
For non-MSK patients being treated at one of the participating institutions, if the GAP determines 
the finding to be reportable to the participant and the participant has consented to be re-contacted, 
results will be returned to the Site Principal Investigator via the study team.  Site policies on 
returning these research findings to the patient should be followed. 
 
We anticipate that other research assays may be incorporated into this protocol as technology 
evolves. 
 
Voluntariness of research participation 
It is stated that taking part in this tissue and blood bank is voluntary and patients have the right to 
withdraw at any time. Participation in the study will not impact on the clinical care patients receive. 
 
W ithdrawal 
Participants may decide at a later date that they do not want identified blood and tissue samples to 
be stored in the tissue bank and /or used for future research. If participants decide to withdraw from 
the study, specimens that have not yet left the specimen archive will not be used in new studies and 
any remaining portions of samples that have not been used for research will be used only for clinical 
purposes or, if requested by the patient, destroyed.  For specimens already shipped out from the 
archive, it may not be possible to locate the samples or stop already ongoing research. When a 
participant withdraws from the protocol, MSK’s Protocol Participant Registration (PPR) Office should 
be notified immediately. If a non-MSK participant withdraws from the study, the MSK study staff 
member will notify PPR. The withdrawal request will be documented in CRDB and the system 
updated accordingly. In addition, a note-to-file documenting the patient withdrew must be filed in 
his/her medical records. 
 
Rights after death 
The consent states that if the research participant dies or is unable to make his/her wishes known, 
all of their rights to decide about future uses of the blood or tissues will pass to the authorized 
representative of the estate. If there is no representative of the estate, the rights pass to the next of 
kin. 
 
Risks of research participation 
The greatest risk is release of information from health or research records in a way that violates 
privacy rights.  MSK and any participating sites will protect records so that name, address, phone 
number, and any other information that identifies the participant will be kept private.  It will be stated 
to the participant that the chance that this information will be given to an unauthorized individual 
without the participant’s permission is very small. 
 
Costs/compensation 
There is no cost to the participant to enroll in this research. Tissue or blood obtained in this research 
may be used to make a cell line, and these may be patented or licensed and thus may have 
significant commercial value.  The participant is informed that there are no plans to provide financial 


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compensation for use of their human biologic specimens, nor are there plans for the participant to 
receive money for any new products, tests, and discoveries that might come from this research. 
 
Biospecimen Privacy 
Medical information is confidential.  The participant’s personal identity will not be used in reports 
that are written about the research.  The MSK IRB/PB will review all requests for research 
performed involving biospecimens ascertained through this protocol.  Blood and tissue samples 
may be stored with a code linked to the patient’s medical record. The results of any research using 
blood or tissues will not be placed in the medical record. 
 
The consent indicates that samples and genetic information collected may be shared with other 
qualified researchers and placed in online databases. An example of an online database is the NIH 
dbGAP database, which is monitored by the National Institutes of Health, and may be made 
accessible to investigators approved by the U.S. government. Such information will not include 
identifying information such as name. It is also stated in the Research Authorization (HIPAA 
Authorization) that research data (e.g. genomic sequence) may be shared with regulators. The 
requirements for submission of genotype/phenotype data into the NIH dbGAP or any other public 
database will be followed as per the IRB SOP for Genomic Data Sharing. 
 
Use of banked samples (at MSK) 
When samples are to be analyzed, the individual investigator needs to write an IRB biospecimen 
protocol. This protocol is fast-tracked through MSK Research Council review and is reviewed at the 
MSK IRB by the expedited review process. This protocol is only for research that will be done on 
biospecimens obtained under identified protocols and their informed consent and research 
authorization that include the institutional future use questions. The consent and research 
authorization for the use of the biospecimens will be waived as per 45 CFR 46.116(d) and 45 CFR 
164.512(i)(2)(ii). 
 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
The treating investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart (see Section 10.0) and more frequently if 
clinically indicated.  Adverse experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 4.0.  Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly an event 
of clinical interest (ECI) of a potentially  immunologic etiology (termed immune-related adverse 
events, or irAEs). 
 
11.2 Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per table 2 below. 
 
Table 2: Dose Modification Guidelines for Drug-Related Adverse Events 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-13 
Toxicity does not resolve w ithin 12 w eeks of last dose. 
3-4 
Permanently  discontinue 
(see exception below )1 
Permanently  discontinue 
Type 1 diabetes 
mellitus  (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab  for new onset 
Type 1 diabetes mellitus or Grade 3- 
4 hyperglycemia associated w ith 
evidence of beta cell failure. 
Resume pembrolizumab  w hen patients are clinically and 
metabolically  stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
Hypothyroidism 
2-4 
Therapy w ith pembrolizumab  can be 
continued w hile treatment for the 
thyroid disorder is instituted 
Therapy w ith pembrolizumab  can be continued w hile 
treatment for the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently  discontinue 
Permanently  discontinue 
Pneumonit is 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
3-4 
Permanently  discontinue 
Permanently  discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
3-4 
Permanently  discontinue 
Permanently  discontinue 
All Other Drug- 
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve w ithin 12 w eeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day w ithin 12 w eeks. 
4 
Permanently  discontinue 
Permanently  discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients w ith liver metastasis w ho begin treatment w ith Grade 2 AST or ALT, if AST or ALTincreases by greater than or equal to 50% relativ e 
to baseline and lasts for at least 1 w eek then patients should be discontinued. 
2 Patients w ith intolerable or persistent Grade 2 drug-related AEmay hold study medication at treating physician discretion. Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment w ith study drug has been held, that do not recover to Grade 
0-1 w ithin 12 w eeks of the last dose. 
3 For patients w ith history of gilberts disease and there is an isolated grade 2 elevation of increased bilirubin, patients do not need to be held and 
can be treated. 
 
 
11.1.1 Supportive Care 
 
• 
Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 


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• 
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
o Pembrolizumab can be held until the patient is off corticosteroids. 
 
• 
Type 1 diabetes mellitus (DM) (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
 
o For Type 1 DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
• 
Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
• 
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, 
non-selective 
beta-blockers (e.g. 
propranolol)  are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism 
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 


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• 
Hepatic: 
o For Grade 2 events,  monitor liver  function  tests more frequently  until  returned  to 
baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
 
Treat with IV methylprednisone 1-4 mg/kg at investigator’s discretion 
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade  1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
 
 
 
 
 
 
 
 
 
 
Table 3: Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
treating investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV f luids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusionand monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV f luids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
treating investigator. 
If symptoms resolve w ithin one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). 
Otherw ise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK- 
3475) w ith: 
Diphenhydramine 50 mg PO (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
antipyretic). 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Subjects w ho develop Grade 2 toxicity 
despite adequate premedicationshould 
be permanently discontinuedfrom further 
trial treatment administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms follow ing initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV f luids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
treating investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinuedfrom 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 
11.2 Trastuzumab 
Principal adverse effects include cardiac dysfunction, infusion associated symptoms, potentiation of 
chemotherapy related hematologic side effects. A complete listing of toxicities can be found in the 
trastuzumab package insert. 
11.2.1 Trastuzumab Dose Delays or Modifications 
There will be no dose modifications of trastuzumab. Trastuzumab dose delays are permitted for 
Grade 3/4 clinical toxicity or at treating 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 Heart 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 a normal LVEF (>/= 53% 
are elgible for entry into the study. Patients with a borderline decreased LVEF (40-52%) and with no 
signs of clinical heart failure may still be considered for inclusion in the study after consultation with 
cardiology and MSK Principal Investigator. Patients with decreased LVEF should be optimized on heart 
failure medical therapy (E.g ACE inhibitors, β-blockers, diuretics, and/or cardiac glycosides), as 
recommended by the cardiology consultant prior to entry in the study.  All patients will undergo regular 


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cardiac monitoring throughout the study, including at baseline, 6 and 12 weeks after initiation of 
trastuzumab 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, β-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 treating 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 tothe next regularly scheduled LVEF measurement maybe performed at the treating 
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. Closefollow-up of suchpatients is recommended. Patients withan 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 shouldhave 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 treating 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 treating investigator or 
consulting cardiologist, will resume per the standard schedule.  Additional LVEF 
 
Assessmentsprior tothe next regularly scheduled LVEF measurement maybeperformed at the treating 
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 treating investigator 
after consultation with a cardiologist and discussion with the patient concerning the risks and benefits 
of continued therapy. 


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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 pembrolizumab. Pembrolizumab should be discontinued in the event of any Grade 3 or 4 events 
consistent with CHF. 
 
 
11.2.3 Infusion-Related Reactions 
Any treatment-related infusion-related reactions are defined according to the NCI-CTCAE Version 4.0 
definition (General disorders and administration siteconditions). 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 investigationaltherapy, 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 treating 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 treating 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). 
 
 
 
11.3 Capecitabine, 5-FU, Cisplatin, and Oxaliplatin Dose Delays and Modifications 
For hematologic laboratory abnormalities as an initial step, the dose of capecitabine/5-FU/cisplatin/oxaliplatin 
should be reduced first before any dose reductions for pembrolizumab are considered. capecitabine/5- 
FU/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 


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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 oxaliplatin 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 the treating 
investigator’s discretion and the patient may continue with capecitabine or 5-FU without treatment 
delay. If capecitabine 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. 
 
Tables 11.4.1, 11.4.2, 11.4.3, 11.4.4, 11.4.5, 11.4.6, and 11.4.7 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/m2 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/m2 
Dose Level -1 
Cisplatin 60 mg/m2 
Dose Level -2 
Cisplatin 40 mg/m2 
 
Table 11.4.3 Oxaliplatin dose levels 
Starting dose 0 
Oxaliplatin 130 mg/m2* 
Dose Level -1 
Oxaliplatin 104 mg/m2 
Dose Level -2 
Oxaliplatin 65 mg/m2 
*Patients may begin with reduced dose of oxaliplatin 104 mg/m2 as starting dose if deemed necessary per the 
treating physician discretion. 
 
 
Table 11.4.4 Dose-modification guidelines for cisplatin, oxaliplatin,capecitabine or 5-FU for 
thrombocytopenia, neutropenia, febrile neutropenia, and infectiona. 
 
ANC Count (x 109/L) 
Platelet Count (x 109/L) 
Dose adjustment for cisplatin, oxaliplatin, 
5-FU or capecitabine 
>1.5 and 
>75 
Maintain dose level without interruption 


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<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 109/L, reduce by 1 dose level if 
permissiblec. 
<1.0  and 
Fever >38.5oC (101oF) or 
infection of any duration 
Reduce by 1 level on recovery of ANC >1.0 x 
109/L 
Abbreviations: ANC = Absolute Neutrophil Count. 
a. 
No chemotherapy should be administered if ANC <1.0 x 109/L and platelet count <75 x 109/L 
b. 
If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops 
<1.0 x 109/L or that the platelet count drops <75 x 109/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 treating 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 11.4.5 Dose-modification guidelines for nonhematologic adverse events thought to be 
related to capecitabinea 
Toxicity CTCAE Grades 
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 treating 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 for reduced glomerular filtration rate 


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IRB Number: 16-937 A(13) 
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Page 39 of 50 
 
 
 
 
 
 
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 permanently 
 
 
Table 11.4.7 Dose-modification guidelines for cisplatin and oxaliplatin related for nonrenal and 
nonhematologic adverse events 
 
Toxicity 
Grade 
Dose adjustment for cisplatin 
Nausea/vomiting/diarrhea 
(either on its own or in 
combination) 
>3 
Reduce 1 dose level, if 
permissible, on recovery to 
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 


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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 
 
 
 
11.4 General Dose-Modification Guidelines for Chemotherapy 
• 
Treatment for the first cycle should only commence if all the inclusion and exclusion criteria are 
met and patient has been enrolled. For subsequent cycles, dose delay/modification is permitted 
as described in sections specific for pembrolizumab, trastuzumab, capecitabine, 5-FU, cisplatin, 
and oxaliplatin. All study treatment will be discontinued in case of disease progression. 
• 
The dose of capecitabine or 5-FU should be determined at the start of each treatment cycle. 
Based on treating investigator's discretion, full dose of capecitabinecan 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 2 (50% 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 treating 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 canbe delayed up to 63 days (9 weeks). If the toxicity 
does not resolve within 63 days (9 weeks), that component will be discontinued unless it is 
determined by the treating investigator that the patient might benefit from continuation of the 
component. 
If at least six months have elapsed since oxaliplatin discontinuation, oxaliplatin may be reinitiated at the 
last dose level for this patient at the investigator’s  discretion for clinical progression concern. 
 
12.0   CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
All patients who receive at least one dose of pembrolizumab and began trastuzumab therapy will be 
evaluable for toxicity and response. Patients who are did not begin pembrolizumab therapy will not be 
evaluated for toxicity or response and will be replaced by a new patient. 
The primary endpoint of this study is to determine the six months progression free survival (PFS) in 
the first-line treatment of patients with Stage IV HER2 positive esophagogastric adenocarcinoma. The 
same imaging modality performed at baseline (CT or MRI) will be repeated at subsequent imaging. 


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Page 41 of 50 
 
 
 
 
 
Secondary endpoints include toxicity, overall survival, median PFS, response to pembrolizumab + 
trastuzumab, best overall RECIST 1.1 response (CR+PR) to capecitabine/5-FU, cisplatin/oxaliplatin, 
pembrolizumab 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 NCI Common Toxicity 
Criteria, version 4.0. Toxicity during cycle 1 and subsequent cycles will be reported. 
 
13.0     CRITERIAFOR REMOVAL FROM STUDY 
 
• 
If at any time the patient develops progressive disease on combination of trastuzumab, 
pembrolizumab, and chemotherapy he/she will be taken off study unless the treating 
investigator determines that it is of clinical benefit, defined as improvement in quality of life, 
function, or general well-being, for the patient to continue on trial therapy. If at least six months 
have elapsed since oxaliplatin discontinuation, oxaliplatin may be reinitiated at the last dose 
level for this patient at the investigator’s discretion for clinical progression concern. 
If after nine weeks of continued treatment a second scan shows additional disease progression, 
treatment will be discontinued and the patient will be taken off of study. If at any time the patient 
develops unacceptable toxicity that fails to resolve after a maximum treatment delay of 9 weeks, 
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 treating 
investigator’s reason for a patient’s removal must be recorded in CRDB. 
● Patient withdrawal of consents or election to discontinue participation in the trial 
● Significant deviation from the protocol or eligibility criteria; such patients will be considered 
protocol violations and removed from study 
● Non-compliance with study or follow-up procedures 
● Drug related AE(s) have not resolved after 9 weeks of treatment interruption. Exception to 
this in patients who derive obvious clinical benefit according to the investigator’s judgment 
could be considered upon discussion with Principal Investigator. 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 treating investigator judges it to be 
of clinical benefit for the patient to continue on trial therapy. 
14.0     BIOSTATISTICS 


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IRB Number: 16-937 A(13) 
Approval date: 28-Jul-2020 
Page 42 of 50 
 
 
 
 
The phase III ToGA study established the benefit of trastuzumab in combination with cisplatin and 
fluoropyrimidine (CF) chemotherapy in HER2-positive metastatic EG 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 patients were progression free at 6 months. The hypothesis is that addition of 
pembrolizumab to fluorpyrimidine and platinum and trastuzumab will improve outcome in previously 
untreated patients with HER2 gastric, esophageal or GE junction gastric adenocarcinoma. 
The primary endpoint is 6-month progression free survival (PFS), as measured from the start of the 
treatment with trastuzumab and pembrolizumab  to the date of either documentation of disease 
progression on fluoropyrimidine and platinum with trastuzumab and pembrolizumab or death. 
Patients with disease progression on pembrolizumab and trastuzumab will be removed from study 
per the rules described in section 13.0.. We will define progression of disease to capecitabine/5-FU, 
and a cisplatin/oxaliplatin with trastuzumab and pembrolizumab 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  esophageal, 
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%. After week 9, CT/MRI scans occurring every 9 weeks will 
coincide with the 6 month CT/MRI scan, and if necessary, an additional scan will be done at 6 
months. If there is a delay in treatment for a patient the 6 month scan will not be delayed. If 26 or 
more patients are progression free at 6 months, capecitabine/5-FU, cisplatin/oxaliplatin  and 
trastuzumab + pembrolizumab 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. We anticipate enrollment to be 1-2 patients/months 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. 
The patients who completed at least one cycle of trastuzumab + pembrolizumab will be considered 
evaluable. 
Secondary and exploratory endpoints include: 
 
• 
Calculation of the rate of best RECIST 1.1. response (CR+PR) estimated using binomial 
proportions along with 95% confidence intervals; median PFS, overall and 1-year survival in 
patients with HER2+ Stage IV esophageal, gastric or GEJ adenocarcinoma will be measured 
from the start of treatment to death or last follow-up. 
• 
Perform correlative analyses including whole exome analysis in order to determine mutation 
load and specific neoantigen landscape with strong association in patients with regimen 
efficacy (PR, CR or prolonged SD). The Mann–Whitney test will be used to compare 
mutational loads. 


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Page 43 of 50 
 
 
 
 
• 
Correlate the change in uptake on 89Zr-trastuzumab PET with changes in tumor size on CT in 
patients receiving study therapy. We will compare the proportion of patients with a drop in 
89Zr-trastuzumab tumor uptake on PET (pre-therapy and at 3-wk) of 30% or greater in the 
responder versus in the nonresponder groups. Fisher's exact test will be used to determine 
the significance of the association. This will be conducted for MSK patients only. 
• 
Determine overall clinical benefit defined as stable disease (SD), complete response rate (CR), 
or partial response (PR) safety and tolerability. They will be summarized using binomial 
proportions along with exact 95% CI. 
• 
Generalized estimating equations (GEE) will be used to look at associations between 
response and PBMC and cfDNA while Cox regression with time dependent covariate will be 
used to associate survival with PBMC and cfDNA. 
 
• 
PD-L1 will be associated with response using Fisher's exact test while log-rank test will be 
used to compare survival curves between PD-L1 positive and negative patients. 
 
Previous clinical trials have reported the frequency of adverse events attributable to treatment with 
capecitabine, cisplatin, and trastuzumab. A similar frequency of adverse events will be considered 
attributable to the capecitabine, cisplatin and trastuzumab plus pembrolizumab 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 pembrolizumab 
persistent grade 3+ hypertension despite adequate medical management. Furthermore, presence of 
grade 3+ events which in the clinical judgment of the MSK Principal Investigator are felt to be 
serious, unexpected, and a side effect likely due to pembrolizumab , 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 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 


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IRB Number: 16-937 A(13) 
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Confirm eligibility  as defined in the section entitled  Inclusion/Exclusion  Criteria. Obtain 
informed consent, by following  procedures  defined in 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). 
 
 
15.3 
Randomization 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA), or equivalent at each participating site, will be assigned to 
the study. The responsibilities of the MSK RSA include project compliance, data collection, 
abstraction 
and entry, data reporting, regulatory monitoring, problem resolution and 
prioritization, and coordinate the activities of the protocol study team. 
The data collected for this study will be entered into a secure database, Clinical Research 
Database (CRDB) Source documentation will be available to support the computerized patient 
record. Anonymization will take place at the point of entry into the database. Subsequent 
laboratory analysis will take place on the anonymized samples. 
MSK will be the data coordinating center under the guidance of the Multicenter Protocol 
Executive Committee (MPEC). MSKCC will be responsible for reporting to the funding source 
(as applicable) and governing agencies. 
Tumor slides from MSK and the participating sites will be stored in the MSK pathology 
laboratory. Results from laboratory studies will include computer files of sequencing data, and 
analyses. These files will be stored on the Department of Medicine server. Documentation 
linking patient identifiers and patient samples results will be securely maintained in the secure 
Clinical Research Database (CRDB) with access limited to study investigators. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 


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IRB Number: 16-937 A(13) 
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Page 45 of 50 
 
 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI 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 Office of Clinical Research. 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, NCI cooperative group, etc.) Will be addressed and the monitoring 
procedures will be established at the time of protocol activation. 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be reviewed 
with the participant, including a discussion of the possible toxicities and side effects. Alternative,  non- 
protocol, treatment options will be discussed with the patient. It will be reviewed that participation in 
this clinical trial is voluntary  and that the patient may withdraw consent at any time. The study is 
designed with careful safety monitoring for toxicity including physician visits and serial cardiac 
monitoring. Specific guidelines for symptom management are in place to protect the study participant. 
The financial costs of the study will be discussed; pembrolizumab will be provided free of charge. 
Biopsy cost may be covered by the patient’s insurance if it is required for confirmation of metastatic 
disease, if not covered will be covered by research funds. The patient will be responsible for the cost 
of standard medical care and all hospitalizations, even for complications of treatment. 
 
No incentives will be offered to patients/subjects to participate in this study. 
 
17.2 
Privacy 
 
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). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 


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Page 46 of 50 
 
 
 
 
• 
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 and is registered.  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. 
 
An SAE must be reported to the IRB/PB within 5 calendar days of the event. The IRB/PB 
requires a Clinical Research Database (CRDB) SAE report will 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. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSK) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
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 


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IRB Number: 16-937 A(13) 
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Page 47 of 50 
 
 
 
 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above.  If appropriate, the report will be 
forwarded to the FDA by the SAE staff through the IND Office. 
17.2.1 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study that occurs to any subject from the time the consent 
is signed through 90 days following cessation of treatment, or the initiation of new anti-cancer therapy, 
whichever is earlier, whether or not related to Merck product, must be reported within 2 working days 
to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in 
the same manner as SAEs. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to 
be related to Merck product that is brought to the attention of the investigator at any time outside of 
the time period specified in the previous paragraph also must be reported immediately to the Sponsor 
and to Merck. 
 
SAE reports and anyother relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
18.1 
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. 


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IRB Number: 16-937 A(13) 
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Page 48 of 50 
 
 
 
 
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.) 
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 
REFERENCES 
 
 
2015 
1. 
Siegel RL, Miller KD, Jemal A: Cancer statistics, 2015. CA Cancer J Clin 65:5-29, 
 
2. 
van Hagen P, Hulshof MC, van Lanschot JJ, et al: Preoperative chemoradiotherapy 
for esophageal or junctional cancer. N Engl J Med 366:2074-84, 2012 
3. 
Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus 
surgery alone for resectable gastroesophageal cancer. New England Journal of Medicine 355:11-20, 
2006 
4. 
Roth AD, Fazio N, Stupp R, et al: Docetaxel, cisplatin, and fluorouracil; docetaxel and 
cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric 
carcinoma: A randomized phase II trial of the Swiss group for clinical cancer research. Journal of 
Clinical Oncology 25:3217-3223, 2007 
5. 
Van Cutsem E, Moiseyenko VM, Tjulandin S, et al: Phase III Study of Docetaxel and 
Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for 
Advanced Gastric Cancer: A Report of the V325 Study Group, 2006, pp 4991-4997 
6. 
Cunningham D, Starling N, Rao S, et al: Capecitabine and oxaliplatin for advanced 
esophagogastric cancer. New England Journal of Medicine 358:36-46, 2008 
7. 
Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or 
gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 
Lancet, 2010 
8. 
Tafe LJ, Janjigian YY, Zaidinski M, et al: Human epidermal growth factor receptor 2 
testing in gastroesophageal cancer: correlation between immunohistochemistry and fluorescence in 
situ hybridization. Arch Pathol Lab Med 135:1460-5, 2011 
9. 
Hudis CA: Trastuzumab--mechanism of action and use in clinical practice. N Engl J 
Med 357:39-51, 2007 
10. 
Mu CY, Huang JA, Chen Y, et al: High expression of PD-L1 in lung cancer may 
contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating 
dendritic cells maturation. Med Oncol 28:682-8, 2011 
11. 
Thompson RH, Kuntz SM, Leibovich BC, et al: Tumor B7-H1 is associated with poor 
prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 66:3381-5, 2006 
12. 
Nomi T, Sho M, Akahori T, et al: Clinical significance and therapeutic potential of the 
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20.0 
APPENDICES 
Appendix 1: Multicenter Addendum 
Appendix 2: Laboratory Manual 
Appendix 3: Pill Diary