Clinical trial NCT01522768
Conditions: Esophageal Cancer Gastric Cancer
Keywords: ESOPHAGUS STOMACH Afatinib paclitaxel trastuzumab 11-166
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2012-03-01; Completion date: 2023-02-20
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out what effects, good or bad, the combination of standard chemotherapy agent paclitaxel with the investigational (experimental) drug afatinib that targets HER2, has on HER2-positive esophagogastric cancer that started to get bigger despite previous treatment with trastuzumab. The doctors will also study the tumor to understand why it grew while on trastuzumab treatment and to see the effects afatinib and paclitaxel has on the tumor.

Detailed description:

Arms: arm 1: This is a multi-institution, open-label, non-randomized, Phase II evaluation of oral afatinib daily and intravenous paclitaxel (weekly, 3 weeks on, 1 week off) in patients with trastuzumab refractory HER2-positive metastatic or recurrent esophagogastric adenocarcinoma. An initial biopsy prior to the start of therapy is required for the correlative studies evaluating the biologic effects of afatinib. It will be obtained for all patients whose tumors are feasible to biopsy. At the site investigator's discretion, a second biopsy will also be obtained. At the discretion of the MSK Principal Investigator, select participants who show response on this study and then progress may be asked to have an optional third biopsy.
Interventions: intervention 1: Afatinib and Paclitaxel
Intervention descriptions: intervention 1: All patients receiving therapy on trial with afatinib and trastuzumab will continue on afatinib and trastuzumab until disease progression or intolerable toxicity. All additional patients will be enrolled on afatinib and paclitaxel. Patients will be treated with afatinib and paclitaxel combination. Patients will receive oral afatinib 40 mg daily plus paclitaxel 80 mg/m\^2 intravenously on day 1, 8, and 15 of a 28-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Page 1 of 69 
 
 
Approval date: 13-Sep-2018 
 
 
 
A Phase II Study of Afatinib and Paclitaxel in Patients with A 
Trastuzumab Refractory Advanced Esophagogas 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROT 
 
 
Principal Investigator/Department: 
Yelena Y. Janjigian, MD 
dvanced HER2-Positive 
tric Cancer 
OCOL 
Medicine 
Co-Principal  Investigator(s)/Department: 
David Ilson, MD 
Medicine 
Investigator(s)/Department: 
David P. Kelsen, MD 
James Harding, MD 
Anna Varghese, MD 
Geoffrey Ku, MD 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
David Ilson, MD 
Nancy Kemeny, MD 
Eileen O‟Reilly, MD 
Leonard Saltz, MD 
Zsofia Stadler, MD 
Diane Reidy, MD 
Neil Segal, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Andrew Epstein, MD 
Elizabeth Won, MD 
Armin Shahrokni, MD 
Nitya Raj, MD 
Karuna Ganesh, MD 
Luis Diaz, MD 
Danny Khalil, MD 
Ellen Hollywood, NP 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
Jaclyn Rosenthal Norris, NP 
Natasha Pinheiro, NP 
Robin Brenner, RN 
Michal Segal, RN 
Pamela Raasch, RN 
Vanessa Grant, RN 
Claudy Aime, NP 
 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Curtis Chong, MD 
Loren Michel, MD 
Rodrigo Erlich, MD 
Janet Cogswell, RN 
Jennifer Howgate-Klingaman, RN 
Medicine 
Medicine 
Medicine 
Medicine 
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 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Nursing 
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Page 2 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
 
 
 
 
 
 
Lisa Sarmasti, RN 
Nursing 
Irina Konzelmann, APN 
Nursing 
Avni Desai, MD 
Medicine 
John Fiore, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 
Jia Li, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Juliana Eng, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Krysti O‟keefe, RN 
Nursing 
Lori Gofter, RN 
Nursing 
Barbara Ferrara, NP 
Nursing 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Erin Scansarole, RN 
Nursing 
Alice Zervoudakis, MD 
Medicine 
Chung-Han Lee, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Min Yuen Teo, MD 
Medicine 
Melanie Albano, NP 
Nursing 
Sherie Mar-Chaim, RN 
Nursing 
Gloria Wasilewski, RN 
Nursing 
Jason Konner, MD 
Medicine 
Serena Wong, MD 
Medicine 
Jacqueline Bromberg, MD, PhD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Isidore Tepler, MD 
Medicine 
Colette Owens, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Raylene Langish, RN 
Nursing 
Karen Brown, MD 
Radiology/Interventional 
Mark Schattner, MD 
Radiology/Interventional 
Marinela Capanu, PhD 
Epidemiology/Biostatistics 
Robert Lefkowitz, MD 
Radiology 
Marc Simmons, MD 
Radiology 
Mario E. Lacouture, MD 
Medicine 
Liang Deng, MD 
Medicine 
Christine A Iacobuzio-Donahue 
Pathology 
MD PhD 
Matthew Matasar, MD 
Medicine 


Page 3 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
 
 
 
 
 
 
Louise Ligresti, MD 
Michael Mauro, MD 
Neha Korde, MD 
Ping Gu, MD 
Daniel Danila, MD 
Rui Wang, MD 
Isabel Preeshagul, MD 
Anuja Kriplani, MD 
Kristen O‟Hagan, NP 
Geri Arnell, RN 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Consenting  Professional(s)/Department: 
Yelena Y. Janjigian, MD 
Medicine 
David P. Kelsen, MD 
Medicine 
James Harding, MD 
Medicine 
Anna Varghese, MD 
Medicine 
Geoffrey Ku, MD 
Medicine 
Ghassan Abou-Alfa, MD 
Medicine 
Andrea Cercek, MD 
Medicine 
David Ilson, MD 
Medicine 
Nancy Kemeny, MD 
Medicine 
Eileen O‟Reilly, MD 
Medicine 
Leonard Saltz, MD 
Medicine 
Zsofia Stadler, MD 
Medicine 
Diane Reidy, MD 
Medicine 
Neil Segal, MD 
Medicine 
Rona Yaeger, MD 
Medicine 
Kenneth Yu, MD 
Medicine 
Andrew Epstein, MD 
Medicine 
Elizabeth Won, MD 
Medicine 
Armin Shahrokni, MD 
Medicine 
Nitya Raj, MD 
Medicine 
Karuna Ganesh, MD 
Medicine 
Luis Diaz, MD 
Medicine 
Danny Khalil, MD 
Medicine 
Ellen Hollywood, NP 
Nursing 
Erica Kaufmann, NP 
Nursing 
Jaclyn Rosenthal Norris, NP 
Nursing 
Patricia Gabriel, NP 
Nursing 
Natasha Pinheiro, NP 
Nursing 
Claudy Aime, NP 
Nursing 
Han Xiao, MD 
Medicine 
Sree Chalasani, MD 
Medicine 
Afsheen Iqbal, MD 
Medicine 
Curtis Chong, MD 
Medicine 
Loren Michel, MD 
Medicine 
Rodrigo Erlich, MD 
Medicine 
Avni Desai, MD 
Medicine 
John Fiore, MD 
Medicine 
Stuart Lichtman, MD 
Medicine 


Page 4 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
 
 
 
 
 
 
Jia Li, MD 
Medicine 
Jahan Aghalar, MD 
Medicine 
Juliana Eng, MD 
Medicine 
Wanqing Iris Zhi, MD, PhD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Alice Zervoudakis, MD 
Medicine 
Chung-Han Lee, MD 
Medicine 
Parisa Momtaz, MD 
Medicine 
Min Yuen Teo, MD 
Medicine 
Melanie Albano, NP 
Nursing 
Jason Konner, MD 
Medicine 
Serena Wong, MD 
Medicine 
Jacqueline Bromberg, MD, PhD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Isidore Tepler, MD 
Medicine 
Colette Owens, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Matthew Matasar, MD 
Medicine 
Louise Ligresti, MD 
Medicine 
Michael Mauro, MD 
Medicine 
Neha Korde, MD 
Medicine 
Ping Gu, MD 
Medicine 
Daniel Danila, MD 
Medicine 
Rui Wang, MD 
Medicine 
Isabel Preeshagul, MD 
Medicine 
Anuja Kriplani, MD 
Medicine 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Basking Ridge 
All Protocol Activities 
Commack 
All Protocol Activities 
Rockville Centre 
All Protocol Activities 
Westchester 
All Protocol Activities 
Monmouth 
All Protocol Activities 
Bergen 
All Protocol Activities 
Manhattan 
All Protocol Activities 


Page 5 of 69 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
 
 
 
 
 
 
Participating  Institutions 
PI's Name 
Site's Role 
University of Southern California 
Syma Iqbal, MD 
Data Collection 
Dana-Farber Cancer Institute 
Peter Enzinger, MD 
Data Collection 
Massachusetts General Hospital 
Janet Murphy, MD 
Data Collection 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 6 of 69 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 7 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 24 
4.1 Design ................................................................................................................................ 24 
4.2 Intervention .............................................................................................................................. 24 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 26 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 28 
6.1 Subject Inclusion Criteria .................................................................................................... 28 
6.2 Subject Exclusion Criteria ................................................................................................... 29 
7.0 
RECRUITMENT PLAN ................................................................................................................... 30 
8.0 
PRETREATMENT EVALUATION...................................................................................... 31 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 31 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 39 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 45 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 47 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 48 
14.0 
BIOSTATISTICS ............................................................................................................... 48 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES51 
15.1 Research Participant Registration ......................................................................................... 51 
15.2 
Randomization ................................................................................................................... 52 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 52 
16.1 
Quality Assurance ........................................................................................................ 53 
16.2 
Data and Safety Monitoring .............................................................................................. 54 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 57 
17.1 
Privacy .......................................................................................................................... 60 
17.2 
Serious Adverse Event (SAE) Reporting ......................................................................... 60 
17.2.1.........................................................................................................................................61 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 63 
19.0 
REFERENCES ...................................................................................................................... 64 
20.0 
APPENDICES ................................................................................................................... 69 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 7 of 69 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
This is a Phase II study of afatinib with paclitaxel in patients with HER2-positive advanced 
esophagogastric cancer with progression following at least one trastuzumab-containing 
regimen. The goal of this study is to determine the efficacy of combined inhibition of 
epidermal growth factor receptor (EGFR) super family with an oral, specific, irreversible 
inhibitor of the ErbB family receptor tyrosine kinases (IC50: EGFR, 0.5 nM; HER2, 14 nM; 
HER4, 1 nM) with paclitaxel in patients with HER2-positive trastuzumab-refractory advanced 
esophagogastric cancer. Eligible patients ≥ 18 years of age must have histologically proven 
HER2-positive esophagogastric cancer (immunohistochemistry 3+ or FISH≥2.0) with at least 
one site of measurable metastatic disease. Correlative tissue will be done to determine the 
molecular profile that may predict response to afatinib with paclitaxel. We anticipate the 
majority of the patients enrolled will have pre- and post-treatment biopsies (if clinically safe). 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective 
 
1) The primary objective of this study is to determine toxicity, safety and tolerability of 
afatinib with paclitaxel in patients with metastatic HER2-positive esophagogastric 
cancer. 
 
 
Secondary objectives 
 
2) To estimate secondary efficacy endpoints of afatinib and paclitaxel, including overall 
clinical benefit defined as response rate (ORR) = stable disease (SD), complete 
response (CR) or partial response (PR), median overall survival and progression free 
survival (PFS). 
 
Exploratory objectives 
 
1) To perform exploratory analysis on available archival, pre- and post-treatment tumor 
specimens to determine predictive biomarkers for afatinib response. 
2) To utilize cell-free tumor DNA (cfDNA) from  blood specimens  collected during the 
course of treatment to explore the mechanism of primary and acquired resistance to 
afatinib therapy. 
3) To explore changes in 89 Zr-trastuzumab PET with afatinib treatment. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Esophagogastric  adenocarcinoma 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 8 of 69 
 
 
 
 
World-wide, esophagogastric cancer is diagnosed in nearly one million individuals each year 
and is the second most common cause of cancer-related death.
1,2  Most patients with 
esophagogastric cancer present with stage IV disease, which is incurable. Despite this, 
systemic chemotherapy can lead to a decrease in cancer-related symptoms and prolongs 
survival.3-6  However, even with treatment, most patients with advanced gastric cancer have a 
median survival of less than 1 year. More specific molecularly targeted therapies are 
anticipated to improve the current status of systemic treatment beyond conventional cytotoxic 
therapy. 
 
3.2 
Human Epidermal Growth Factor Receptor (HER2) in esophagogastric 
adenocarcinoma 
Human Epidermal Growth Factor Receptor (HER2) is a validated treatment target in 
esophagogastric cancer, based on results of the trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric 
or gastro-esophageal junction cancer (ToGA): a Phase III, open-label, randomized controlled 
trial demonstrating improved response and survival when trastuzumab is added to 
chemotherapy (see section 3.3 for study results). Approximately 30% of stomach 
cardia/gastroesophageal junction (GE junction) tumors harbor HER2 gene amplification 
(assessed by fluorescent in situ hybridization [FISH] and/or HER2 oncoprotein 
overexpression (assessed by immunohistochemistry [IHC]).7-9  The rise in the incidence of 
gastroesophageal junction tumors in Western countries10,11  underscores the significance of 
this new target in esophagogastric cancer and opens a new drug development strategy for 
this disease. 
 
The ErbB2/HER2 oncogene encodes a transmembrane tyrosine kinase receptor that belongs 
to the epidermal growth factor receptor (EGFR) family and plays an essential role in 
promoting cell growth, migration, differentiation, proliferation, and survival. The family 
comprises ErbB1 (EGFR/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). 
Each receptor has an extracellular domain, a lipophilic transmembrane domain, and an 
intracellular tyrosine kinase domain. Activation of the kinase occurs with ligand binding and 
hetero- or homodimerization of these receptors. Ligand-independent activation of HER2 may 
occur due to mutations in HER2 or receptor overexpression.12  HER2 activation plays a  
pivotal role in cell proliferation and survival which has been shown to be mediated largely 
through activation of the phosphatidylinositol 3‟-kinase-AKT-mammalian target of rapamycin 
(PI3K-AKT-mTOR) pathway.
13  However, HER2 and HER3 are not autonomous since HER2 
has no known ligand, and the kinase activity of HER3 is defective. 13 These two receptors can 
form heterodimeric complexes with each other as well as other HER receptors to generate 
potent signals.14 
 
3.2.1 
HER2 as prognostic factor 
 
The role of HER2 as a prognostic factor in esophagogastric cancer remains controversial. A 
number of retrospective studies have demonstrated that HER2 positivity (IHC and/or FISH) is 
a prognostic factor associated with worse survival15-17  and in patients with resected disease  
is the second poorest prognostic variable after nodal status.
18,19  We evaluated the prognostic 
significance of HER2 gene amplification or protein overexpression in 338 advanced gastric 
cancer patients from six prospective first-line therapeutic trials of chemotherapy without 
trastuzumab performed in the U.S. and Europe. The impact of HER2 status was correlated 
with patient outcome using univariate and multivariate analysis. Interestingly, median overall 
survival was longer in HER2-positvie patients (13.4 vs. 11.6 mos, HR 0.74; p=0.048) on 
univariate analysis. This prognostic value disappeared in multivariate analysis (p=0.3). In 
addition, HER2-positive disease was not prognostic in subgroup analysis based on tumor 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 9 of 69 
 
 
 
 
histology.20  Also worthy of mention is that in the phase III ToGA study, the median overall 
survival of HER-2 positive patients on the control arm (i.e., non-trastuzumab arm) was similar 
to the historic comparison with Phase III studies of 5FU/Cisplatin in metastatic gastric cancer. 
 
HER2 mediates the transformed phenotype, and HER2 is a validated therapeutic target in 
esophagogastric adenocarcinoma, based on the results of the Phase III ToGA study (see 
section 3.3 for details). The study demonstrates improved survival when trastuzumab is 
added to chemotherapy.21  MSKCC data and similar data presented at ASCO 2011 
demonstrate that unlike breast cancer where HER2-positive disease carries an adverse 
prognostic value, HER2-positivity is not an independent prognostic factor in advanced or 
resectable esophagogastric cancer.22-24 
3.2.2 
HER2 testing in esophagogastric cancer 
 
All esophagogastric cancer patients are now routinely tested for HER2 at MSKCC. HER2 
testing by IHC has been reported to be distinct from breast cancer IHC testing.25 
Esophagogastric tumors, because of the secretory nature of gastric epithelium, can have 
higher frequence of incomplete membranous staining (basolateral only). As a result, these 
tumors would be scored “negative” by IHC while in fact they may be FISH positive.25 Based 
on these findings, in 2008, Hofmann et al. proposed a HER2 scoring system modified from 
breast cancer guidelines, which was later used in the ToGA trial. The new ASCO/CAP HER2 
scoring guidelines (www.cap.org) specify that IHC score 0 should be reserved for tumors  
with no staining, which would avoid underscoring the majority of gastric tumors. We recently 
published results of a validation study of HER2 scoring (by IHC and FISH) in 135 cases with 
paired IHC and FISH results using the new ASCO/CAP HER2 scoring guidelines for breast 
cancer and the gastric cancer criteria proposed by Hofmann et al. We recognize that the 
basolateral pattern of immunoreactivity in some gastric cancers can result in difficulty 
assigning a definitive IHC score. Reliable separation of IHC 1+ and IHC 2+ patterns can be 
particularly challenging in small biopsy specimens, which frequently show crush and edge 
artifacts. Having a simple and straightforward interpretation method can significantly reduce 
testing variation. We conclude that HER2 assessment in gastric cancer can be accurately 
performed using standard breast cancer procedures and the ASCO/CAP scoring criteria. 
While IHC 0 and IHC 3+ provide clear stratification, reliable separation of IHC 1+ and IHC 2+ 
may be difficult, especially in biopsy. The latter two groups are best referred to FISH for 
definitive classification.7  For the purposes of this protocol, and in accordance with standard 
MSKCC HER2 testing algorithm for esophagogastric adenocarcinoma, patients that are IHC 
1+ or 2+ will undergo FISH testing to confirm HER2 positivity. Patients with IHC 3+ or FISH+ 
(>2 HER2:CEP17) will be eligible to receive treatment with afatinib on this study. 
 
3.3 
ToGA study: Trastuzumab in HER2-positive esophagogastric adenocarcinoma 
 
Trastuzumab (Herceptin), a humanized, recombinant monoclonal antibody that binds to the 
extracellular domain of HER2 has been shown to exert antitumor effects and is a key 
component in the treatment of early and metastatic HER2-positive breast cancer. 26-28  With 
the results of the Phase III ToGA study, the benefit of trastuzumab in combination with 
cisplatin and fluoropyrimidine (CF) chemotherapy in HER2-positive metastatic 
esophagogastric adenocarcinoma has been established.
21  This study comprised 584 patients 
with HER2-positive gastric or GE junction tumors. Patients were randomly assigned to 
receive cisplatin and capecitabine (fluorouracil infusion was given to patients who were 
unable to take oral medication) alone or with trastuzumab, a humanized monoclonal antibody 
against the extracellular region of HER2. Patients assigned to receive trastuzumab with 
chemotherapy had a significant improvement in all measures of efficacy, including overall 
survival (13.8 vs. 11.1 months, HR 0.74 [0.6-0.91], p = 0.0046), progression-free survival (6.7 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 10 of 69 
 
 
 
 
vs. 5.5 months), and overall response rate (CR+PR) (47 vs. 35%). Notably, patients with 
strongly HER2-positive tumors (IHC 2+/FISH+ or IHC3+) derived the greatest overall survival 
benefit with the addition of trastuzumab to chemotherapy (16.0 vs. 11.8 months, HR 0.68 
[0.5-0.83]).
21
 
 
Trastuzumab is the first biological strategy to show a survival benefit in advanced 
esophagogastric adenocarcinoma. Trastuzumab is now approved by the FDA and European 
Union (EMA) for treatment of patients with HER2-positive advanced gastric cancer in 
combination with systemic chemotherapy. 
 
3.4 
Trastuzumab: mechanism of action and the emergence of resistance 
 
Trastuzumab is approved by the FDA and is the standard of care for patients with HER2- 
positive advanced gastric cancer in combination with systemic chemotherapy. Resistance to 
trastuzumab is now emerging in HER2-positive esophagogastric cancer. There is no 
standard of care treatment at this time that has been shown to reliably induce a second 
response in these patients. 
 
Whereas anti-HER2 therapy with trastuzumab has shown efficacy in some HER2-positive 
esophagogastric cancer, limitations to this approach can include coincident activation of 
downstream signaling pathways. In HER2-positive breast cancer, both de novo and acquired 
resistance to trastuzumab are now recognized.29  Similar mechanisms of resistance in 
esophagogastric cancer are expected, the nature of which remains to be investigated. There 
are several proposed mechanisms of action of trastuzumab.30  By binding to the 
juxtamembrane domain of HER2, trastuzumab inhibits homo- and heterodimerization and 
activation of the kinase, leading to downregulation of the MAPK and PI3K signal-transduction 
pathways. With cleavage of the extracellular domain of HER2, the phosphorylated p95 
domain may still activate cellular proliferation; trastuzumab binding inhibits this cleavage 
event. Laboratory models suggest that trastuzumab recruits immune cells and may inhibit 
angiogenesis leading to tumor regression when combined with chemotherapy.30 
 
Elucidating the molecular mechanisms of trastuzumab resistance will aid in the development 
of new targeted therapies, and a number of putative models of resistance have been 
described in HER2-positive breast cancer (reviewed by Gajria and Chandarlapaty
31). In 
breast cancer, one of the best characterized mechanisms of trastuzumab resistance involves 
increased signaling from other EGFR members of EGFR family of receptors (see section 
3.4.1). 
 
Activation of the PI3K-AKT-mTOR pathway by two genetic mechanisms, loss of the PTEN 
tumor suppressor, and mutational activation of PI3K has been demonstrated to confer 
resistance to trastuzumab in animal models and a small series of clinical tumor samples in 
breast cancer.32  Increased insulin-like growth factor-1 receptor (IGF-1R) signaling is also 
associated with PI3K-AKT activation and trastuzumab resistance.33,34  In gastric cancer 
tumors, IGF-1R is most commonly overexpressed in HER2-positive tumors and correlates 
with poor prognosis and increased propensity to metastasize. 35-37  Lastly, another 
mechanism of resistance to trastuzumab is the accumulation of a truncated form of HER2 
(p95-HER2), which lacks the extracellular domain needed for trastuzumab binding. This 
truncated receptor maintains kinase activity independent of ligand binding and is able to 
activate downstream signaling pathways.38 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 11 of 69 
 
 
 
 
Through a better understanding of these models of resistance, new targeted therapies will be 
developed to improve response rates in HER2-positive esophagogastric cancer patients. An 
approach to overcome trastuzumab-refractory HER2 activity is to block the kinase activity of 
this receptor. 
 
3.4.1 
Increased signaling from HER family receptors 
 
EGFR plays a significant role in trastuzumab resistance. Work by Ritter and colleagues 
demonstrated that trastuzumab resistant cell lines and xenograft models overexpress 
phosphorylated EGFR (p-EGFR), EGFR, EGFR/HER2 heterodimers, and HER family ligands 
EGF, heparin-binding EGF and heregulin.39  Furthermore, the addition of dual EGFR/HER2 
tyrosine kinase inhibitors led to diminished HER2 phosphorylation and cellular proliferation.
39
 
 
The role of EGFR/HER2 cross-talk in transformation and tumor progression is supported by 
multiple examples in mouse models and primary human tumors. For example, coexpression 
of the EGFR ligand TGFα and Neu in the mammary gland of transgenic mice markedly 
accelerates tumor onset and progression compared with mice expressing Neu or TGFα 
transgenes alone. In this model, TGFα x Neu bitransgenic mice exhibited increased tyrosine 
phosphorylation of both EGFR and HER2,40  and tumor latency was markedly delayed by 
administration of the EGFR TKI.41  Analysis of breast tumor specimens revealed that the 
majority of breast tumors with phosphorylated HER2 at Y1248 exhibited detectable EGFR, 
and the combination of Y1248 phosphorylated HER2 together with co-overexpression of 
HER2 and EGFR is associated with the shortest patient survival.42  In esophagogastric 
cancers, EGFR is commonly overexpressed (IHC) and may signify worse prognosis.43,44 
Although EGFR overexpressing MKN7 gastric cancer cells are insensitive to trastuzumab, in 
these cells, submicromolar concentrations of an EGFR TKI, gefitinib, inhibit p-EGFR and 
restore sensitivity to trastuzumab.39  These data support the rationale for combined blockade 
for EGFR and HER2 in HER2-driven tumors. 
 
3.5 
EGFR/HER2 Tyrosine Kinase Inhibitors (TKIs) 
 
3.5.1 
Reversible EGFR/HER2 TKI- Lapatinib 
 
Lapatinib is a reversible tyrosine kinase inhibitor of EGFR and HER2 that blocks receptor 
activation by binding to the intracellular ATP binding site of these kinases. This reversible, 
ATP-competitive kinase inhibitor has shown modest activity in HER2-positive breast cancer 
Phase II and III clinical trials and causes responses in some patients refractory to 
trastuzumab, suggesting that suppression of HER2 continues to be useful in this patient 
population.
45,46  In a number of studies of single agent lapatinib in esophagogastric 
adenocarcinomas, modest activity has been documented. The South Western Oncology 
Group (SWOG) reported a study in unselected patients with advanced gastric cancer where 
lapatinib had a 9% (4 of 47 patients) confirmed partial response (PR) rate, one patient had 
an unconfirmed PR, and 23% (10 of 47) had stable disease. HER2 overexpression was not 
required for participation in this study, which affected the potential efficacy of the drug. 
Evaluation of EGFR or HER2 status of the treated patients was not mandated and not 
reported and, therefore, hindered the interpretation of the study results.47 
 
A second study of single agent lapatinib in patients with previously treated esophagogastric 
adenocarcinomas was reported in the abstract form by Hecht et al.48  Presence of either 
EGFR overexpression (IHC) or HER2 overexpression (IHC) or HER2 gene amplification 
(FISH) were required for study entry. EGFR overexpression is not a predictor of response to 
HER2 directed therapy. Notably, HER2 FISH positivity was unusually high in this study, 43% 


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(9 of 21 patients) in this small sample, which leaves the accuracy of diagnostic molecular 
analysis of the cohort in question. Both of these factors may have affected the efficacy 
results of the study. No objective responses were reported; 2 patients had durable stable 
disease (SD). One patient with SD for 5 months had HER2 FISH-positive/IHC 3+, EGFR 3+ 
gastroesophageal junction adenocarcinoma; the other patient with SD for 9 months had 
HER2 FISH negative/IHC 2+, EGFR 1+ esophageal adenocarcinoma. Another study of 
lapatinib in patients with HER2-positive (FISH) solid tumors included esophagogastric 
patients. One of 16 patients achieved durable complete response for over 1 year and one 
other patient had disease stabilization for 9 months.49 
 
Lapatinib is currently being tested in two Phase III trials in gastric cancer. TYTAN is an open- 
label, randomized Phase III study comparing paclitaxel with paclitaxel plus lapatinib in 
patients with HER2 FISH-amplified gastric cancer as a second-line therapy. The primary end 
point is overall survival, and 260 patients will be enrolled (clinicaltrials.gov NCT00486954). 
As regards the first-line setting, the LOGiC trial will compare capecitabine and oxaliplatin with 
or without lapatinib in advanced gastric cancer and GE junction with HER2 amplification by 
FISH; overall survival is the primary end point (clinicaltrials.gov NCT00680901). 
 
 
3.5.2 
Irreversible EGFR/HER2 TKIs 
In vitro data suggest that second-generation irreversible inhibitors that covalently bind HER2 
and EGFR (unlike lapatinib, which compete with ATP in a reversible manner) may be able to 
overcome trastuzumab resistance. In HER2-positive breast cancer patients with trastuzumab 
resistance, the reported efficacy profile seen with one such irreversible, dual EGFR/HER2 
inhibitor (neratinib) compares favorably with the monotherapy experiences with other anti- 
HER2 agents.50 Neratinib demonstrates 16-week PFS rates of 59% for HER2-positive breast 
cancer patients with prior trastuzumab treatment and 78% for patients with no prior 
trastuzumab treatment. Objective response rates were 24% among patients with prior 
trastuzumab treatment and 56% in the trastuzumab-naïve cohort.
50
 
3.6 
Afatinib: clinical experience 
 
Afatinib (BIBW 2992) is a highly selective and potent low molecular weight, irreversible 
inhibitor of the erbB-family tyrosine kinase receptors EGFR, HER2, and HER4. The potency 
of afatinib was determined in enzymatic assays using recombinant human wild type EGFR, 
HER2, and HER4 that revealed IC50 values of 0.5 nM, 14 nM, and 1nM, respectively.51,52 
 
On July 12, 2013, the U.S. FDA approved afatinib for the first-line treatment of patients with 
metastatic non-small cell lung cancer (NSCLC) whose tumors had specific EGFR gene 
mutations (exon 19 deletions or exon 21; i.e., L858R substitution mutations) as detected by 
an FDA approved test. Afatinib is currently in Phase III in NSCLC, colorectal cancer, 
trastuzumab-pretreated HER2-positive breast cancer, and head and neck squamous cell 
carcinoma (HNSCC). 
 
Afatinib is well tolerated and has been shown to provide meaningful response and 
progression free survival (PFS) benefit as a single agent in patients with metastatic NSCLC 
and acquired resistance to EGFR TKIs gefitinib or erlotinib. In a Phase IIb/III trial of afatinib + 
best supportive care (BSC) vs. placebo + BSC in patients failing 1–2 lines of chemotherapy 
and erlotinib/gefitinib (LUX-Lung 1), a subgroup analysis demonstrated a 3.5 month benefit in 
PFS; 1 vs. 4.5 months, HR=0.35 (95% CI 0.24, 0.497) in patients with clinically defined 
acquired resistance (defined by Jackman and colleagues53) treated with afatinib.54  Two 


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Phase III trials of afatinib as first line therapy in EGFR mutation positive NSCLC patients are 
currently ongoing. 
 
Data generated in Dr. William Pao‟s laboratory in the Human Oncology and Pathogenesis 
Program at MSKCC using a mouse model of lung cancer expressing both L858R and T790M 
in lung epithelia under the control of doxycycline, revealed that the combination of afatinib 
and cetuximab overcomes T790M- 
mediated resistance by targeting the 
mutant receptor more effectively than 
either agent alone. Based on these data, 
a Phase Ib trial of afatinib with 
cetuximab in patients with acquired 
resistance to erlotinib is open and 
accruing patients at MSKCC, Vanderbilt 
Cancer Center, and international sites. 
In this patient population recommended 
Phase II dose is afatinib 40 mg daily and 
cetuximab 500 mg/m2  every 2 weeks. 
The combination was well tolerated. 
Most patients in the study (>90%) 
(Figure 1) derived clinical benefit from 
afatinib + cetuximab therapy. In this 
ongoing trial, objective responses were 
observed in T790M-positive and T790M- 
Figure 1 Afatinib/cetuximab at MTD 
negative tumors, with a confirmed 
objective response rate of 30%.55 
 
Objective responses observed with afatinib monotherapy in Phase II trials in patients with 
NSCLC having HER2 mutations56  and HER2 positive breast cancer are indicative of the 
direct anti-tumor effects of afatinib in patients with HER2-driven tumors. Four partial 
responses and prolonged disease stabilization have been observed in HER2-positive breast 
cancer patients failing trastuzumab57, which has led to a Phase III trial in this setting. 
 
In a randomized Phase II trial in HNSCC, afatinib-treated patients had a higher objective 
response rate compared to cetuximab-treated patients, leading to Phase III development in 
this indication. In HNSCC patients 60 patients have been treated in either arm of the trial, 
comparing afatinib to cetuximab (EGFR monoclonal antibody) monotherapy. Partial 
responses were observed in 13 patients (21.7%) of afatinib treated patients vs. 8 (13.3%) of 
cetuximab treated patients. Maturation of PFS data is currently ongoing.58  In other Phase I 
trials to date, objective responses have been observed in patients with esophageal cancer, 
cholangiocarcinoma in monotherapy and combination treatment. These indicate direct 
antiproliferative/anti-tumor effects of afatinib in EGFR over expressing tumors. 
 
The Adverse Events (AEs) observed with afatinib are of a nature expected from HER2/ 
EGFR tyrosine kinase inhibitors with diarrhea and skin toxicity including rash and acne being 
the most commonly reported adverse events. 
 
3.7 
MSKCC  preclinical  data  of  afatinib  in  HER2  esophagogastric  cancer  and 
rationale for current study 
MSK preclinical data shows potent antitumor activity of single agent afatinib in HER2-positive 
esophagogastric cancer xenografts.59 The efficacy of afatinib, trastuzumab and the 
combination  of  afatinib  and  trastuzumab  were  examined  in  HER2-amplified  NCI-N87 


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xenograft model. 10 mice per group were treated over a course of 4 weeks with vehicle 
alone ip daily x5 (Mon-Fri), afatinib 25 mg/kg po daily x5 (Mon-Fri), trastuzumab 20 mg/kg 
IV once a week and combination of afatinib 25 mg/kg po daily x5(Mon-Fri) with 
trastuzumab 20 mg/kg IV once a week. Figure 2 demonstrates that treatment with single 
agent afatinib resulted in near complete resolution of HER2-positive esophagogastric 
tumors. Figure 3 demonstrates by Western blot analysis that afatinib induces 
downregulation of total Erb2 (HER2), p-Erb2 (p-HER2), total EGFR, p-EGFR and results 
in apoptosis in HER2-positve xenografts. Figure 4 demonstrates that a single dose of 
afatinib results in decrease in total HER2 as assessed by standard immunohistochemistry 
(IHC, DAKO). 
 
 
Figure 2. Antitumor activity of afatinib, trastuzumab and combination of afatinib with trastuzumab in 
HER2-positive NCI-N87 xenografts 
 
 
 
 
Figure 3 Afatinib induces inhibition of EGFR and Erb2 tyrosine cases activity, downregulation of total 
EGFR and Erb2 and apoptosis in HER2-positive NCI-N87 xenografts. Western blot analysis of tumors 
harvested from HER2-positive NCI-N87 gastric xenografts treated with afatinib 25 mg/kg PO x 1 dose, specimen 
collected 8 h, 24h, 48h and 72h post single dose of afatinib. EGFR and Erb2 tyrosine kinase inhibition causes 
dephosphorylation of its downstream targets p-Erb2, p-EGFR. Decrease in total Erb2, p-ErB2, total EGFR and p- 
EGFR is most pronounced after 24-48hr of treatment with afatinib. Induction of apoptosis is shown by elevated 
cleaved PARP and β-actin. 


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Figure 4 Single dose of afatinib induces inhibition downregulation of total Erb2 (HER2) in HER2-positive 
NCI-N87 xenografts. Immunohistochemistry analysis of tumors harvested from HER2-positive NCI-N87 gastric 
xenografts treated with afatinib 25 mg/kg PO x 1 dose, specimen collected 24h and 48h post single dose of 
afatinib. Total HER2 assessed by conventional immunohistochemistry (IHC, DAKO). Decrease from total HER2 
from baseline IHC 3+ (panel A, untreated) is most pronounced after 24 hours of treatment with afatinib (panel B, 
24 hours), HER2 IHC begins to recover to baseline at 48hours (panel C). 
 
Simultaneous targeting of EGFR/HER2 kinase activity is beneficial in oncogene addicted 
tumors
60,61  and may be an effective strategy in patients with metastatic, trastuzumab resistant 
HER2 positive esophagogastric cancer via potent EGFR/HER2 signaling inhibition. This 
protocol is focused on improving the efficacy of HER2 targeted therapy and on 
understanding the mechanisms of HER2 resistance in gastric cancer. 
 
3.8 
Rationale for trastuzumab and afatinib combination 
 
Since enrollment began in March 2012 fourteen patients have been treated with single agent 
afatinib. The following treatment emergent adverse events were observed: nausea/vomiting 
(Grade 1/2: 22%), diarrhea (Grade 1/2:67%), fatigue (Grade1/2: 33%), rash (Grade  
1/2:44%), anorexia (Grade 1/2:33%, Grade 3:11%), mucositis (Grade1/2: 11%), 
paronychia/nail loss (Grade 1/2:11%). To date, 13 pts evaluable for response , 3 of 13 
patients (23%) derived clinical benefit; 1 patient with RECIST 1.1 confirmed PR - a durable 
75% regression of biopsy proven metastases in lung and lymph nodes for 12 months. This 
patient has trastuzumab refractory gastric cancer with progression on trastuzumab in 
combination with multiple chemotherapy regimens, including taxanes, irinotecan, 5FU and 
platinum. A second patient had 20% tumor regression in biopsy proven liver metastasis, 3.6 
mos disease stabilization. This patient had previously demonstrated progression of disease 
on four prior trastuzumab containing chemotherapy regimens. A third patient experienced 4.7 
mos disease stabilization and regression of biopsy proven skin metastasis. 
 
Afatinib has single agent activity in HER2-positive esophagogastric cancer. With one PR, the 
study met the criteria for expansion of the accrual based on original Simon‟s minimax two- 
stage design. In EGFR addicted lung adenocarcinoma only the combination of dual afatinib 
and cetuximab together induced dramatic shrinkage of tumors, because together they 
efficiently depleted both phosphorylated and total EGFR.
60  A Phase II trial of afatinib in 
combination with cetuximab in lung cancer patients with acquired resistance to erlotinib 
demonstrated a 40% partial response (PR) rate, with clinical benefit (PR + SD) observed in 


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>90% of study patients (PI:Janjigian, 2009 ASCO YIA, MSK IRB 10-078), while another 
study of single afatinib in same patient population resulted in 8% PR rate. The MSKC IRB 10 
078 afatinib 40 mg and cetuximab 500 mg/m2 study shows that this combination has 
acceptable safety profile. 
 
The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitors have 
complementary mechanisms of action and synergistic antitumor activity in HER2- 
overexpressing breast cancer supports the rational for afatinib and trastuzumab given 
together will be better than single-agent therapy. In patients with HER2-positive early stage 
breast cancer Baselga et al demonstrated that pCR rate is significantly higher in the group 
given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1–59·5]) than in the 
group given trastuzumab alone (44 of 149 patients [29·5%; 22·4–37·5]; difference 21·1%, 
9·1–34·2, p=0·0001). No major cardiac dysfunctions occurred in this study. Frequency of 
Grade 3 diarrhea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus 
trastuzumab (32 [21·1%]) than with trastuzumab (three [2·0%]). Similarly, Grade 3 liver- 
enzyme alterations were more frequent with lapatinib (27 [17·5%]) and lapatinib plus 
trastuzumab (15 [9·9%]) than with trastuzumab (11 [7·4%]).62  Blackwell et al showed that 
despite disease progression on prior trastuzumab-based therapy, lapatinib in combination 
with trastuzumab significantly improves PFS and clinical benefit rate versus lapatinib alone, 
thus offering a chemotherapy-free option with an acceptable safety profile to patients with 
HER2-positive metastatic breast cancer. The most frequent adverse events were diarrhea, 
rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The 
incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 
2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). 
63  Similarly, toxicity data on file 
from Boehringer Ingelheim suggests that combination with afatinib and trastuzumab will result 
in increased incidence and severity of diarrhea, which will be carefully managed with 
prophylactic loperamide and monitored with weekly clinic visits with afatinib dose reductions 
per Section 9. No major cardiac dysfunctions have been reported with combination of afatinib 
and trastuzumab. Continuation of trastuzumab beyond progression is standard clinical 
practice for HER2 positive esophagogastric cancer based on the breast cancer standard. 
 
In vivo studies in HER2-positive gastric cancer showed that the combination of lapatinib and 
trastuzumab had greater antitumor efficacy than either drug alone. 64  In addition, second- 
generation irreversible EGFR/HER2 TKIs may be more attractive drugs than lapatinib. These 
TKIs covalently bind the tyrosine kinase domain and initial studies compare favorably with  
the monotherapy experiences with lapatinib (which competes with ATP in a reversible 
manner).
50  Although the combination of lapatinib and trastuzumab is highly synergistic
64, 
emerging data from our group suggest that afatinib, an irreversible TKI against HER2, EGFR 
and HER4, was sufficient to induce tumor shrinkage in vivo in gastric cancer xenografts 
59, 
mirroring the effects of trastuzumab and lapatinib combination. 65 
Combination strategies are the future in HER2-positive esophagogastric cancer. In breast 
cancer, lapatinib therapy resulted in shorter survival and more toxicity compared with 
trastuzumab66  and the paradigm has already shifted to dual HER2 blockade using multiple 
agents.62 Trastuzumab, due to its favorable toxicity profile and efficacy, will likely continue to 
play a major part in the HER2-directed treatment algorithm. By binding the extracellular 
domain of HER2 and preventing the ligand activation of the receptor, trastuzumab provides 


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additional antitumor effect via activation of antibody-dependent cellular cytotoxicity67  and 
inhibition of the autocrine loop of the cancer cell.
68  In preclinical studies performed by our 
group at MSKCC in patient derived xenograft (PDX) established form a skin metastasis of a 
patient with HER2 positive esophagogastric cancer (IRB 10-018 PI: Janjigian), showed that 
the combination of afatinib and trastuzumab had greater antitumor efficacy than either drug 
alone (Figure 5). Preclinical data in gastric cancer and clinical experience in lung and breast 
cancers suggest that we can improve response rate to single agent afatinib by continuing 
trastuzumab beyond progression and adding afatinib. On the basis of these promising 
preclinical data and the clinical data outlined above, the Phase 2 study will be amended to 
add afatinib to trastuzumab in refractory HER-positive esophagogastric cancer. Amending 
the current study, will give us a quicker read out and help us plan for future registration 
strategy in gastric cancer. Waiting for the afatinib single agent study to accrue and doing a 
separate study to test afatinib + trastuzumab combination in gastric cancer will lead to 
unnecessary delays. 
 
 
 
Figure 5 Afatinib and trastuzumab therapy in HER2-positive PDX. 
 
 
 
Continuous once daily dosing of afatinib was combined with weekly trastuzumab infusions (4 
mg/kg loading dose; 2 mg/kg maintenance weekly dose) in study 1200.68.
69  In trial 1200.68, 
18 patients with advanced or metastatic HER2 positive breast cancer which may have been 
pretreated with trastuzumab and/or lapatinib, were treated with concomitant administration of 
weekly trastuzumab 2 mg/kg once weekly after a loading dose of 4 mg/kg IV and oral daily 
afatinib at escalating doses of 20-50 mg with 10 mg increments between dose cohorts. 
 
Afatinib PK data was found to be consistent with afatinib PK monotherapy data evaluated in 
the PK meta-analysis. Trastuzumab exposure was within the range of what was observed in 
a published PK analysis. This data suggested that there was no PK interaction between 
afatinib and trastuzumab in the applied treatment schedule. 


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Diarrhea had been the DLT observed in 1/6 patients at the 20 mg afatinib dose level and in 
2/2 patients at 30 mg afatinib. The MTD was determined to be 20 mg daily in combination 
with standard dose of trastuzumab. However, when the MTD cohort was expanded, and a 
further 8 patients were treated with 20 mg afatinib daily plus weekly trastuzumab, the overall 
incidence of DLTs was 4 out of 13 evaluable patients (31%). All DLT events reported during 
the first treatment cycle were cases of CTCAE Grade 3 diarrhea. Since 20 mg daily was the 
lowest afatinib dose planned and available, no lower dose of afatinib could be assessed in 
this study and further recruitment into the 1200.68 trial was stopped. All DLT events reported 
during the first treatment cycle were cases of CTCAE Grade 3 diarrhea. The most frequently 
reported AEs were diarrhea, rash, decreased appetite, fatigue, and nausea. Prophylactic 
loperamide was not used on this study; the diarrhea was treated after Grade 2 or 3 diarrhea 
developed. 
 
Another Phase I trial of afatinib with trastuzumab (8 mg/kg loading dose; 6 mg/kg 
maintenance every 3 weeks) determined the MTD of afatinib 20 mg with trastuzumab, with 1 
of 6 patients experiencing Grade 3 diarrhea. Prophylactic anti diarrheal agents were not used 
on this study. 
 
Diarrhea is a result of direct exposure of intestinal epithelial cells to EGFR inhibition via oral 
administration of afatinib. Diarrhea develops within first 10 days on therapy. On the prior 
afatinib with trastuzumab trials the patients were managed with anti-diarrheal agents only 
after significant diarrhea developed. 
 
Based on available toxicity and efficacy data, on the present trial, a starting dose of afatinib 
30 mg will be used in order to optimize the efficacy/toxicity balance. Prophylactic loperamide 
will be mandatory on this study, with weekly toxicity assessments and MD visit. Variability is 
expected in the incidence and severity of adverse events and dose de-escalation to 20 mg is 
planned, if required. 
 
Three patients will be treated with Afatinib 30 +trastuzumab q2wks with loperamide 
prophylaxis. If no patients experience Grade ≥3 diarrhea with prophylactic loperamide, a new 
cohort of patients will be enrolled at dose Afatinib 40 mg +trastuzumab. If however 1 of 3 
patients have Grade ≥3 diarrhea at dose 30 mg, the cohort will be expanded to 6. If no 
further DLT occurs, patients will be enrolled at dose Afatinib 40 mg +trastuzumab. If 2 of 6 
patients experience Grade ≥3 diarrhea, the MTD will be defined as the dose-level below 
which this occurred. If 2 of 3 or 2 of 6 subjects experience DLT at 30 mg then Afatinib will be 
deescalated to 20 mg. 
 
3.8.1 
Correlative  science:  determinants  of  resistance  to  trastuzumab  and 
sensitivity to afatinib and trastuzumab 
Members of the ErbB family of receptor tyrosine kinases have proven critical in oncogenesis, 
and in the case of esophagogastric cancer, ErbB2/HER2 overexpression is seen in up to 
30% of adenocarcinomas. Effective targeted therapy against the HER2 receptor was initially 
achieved with the monoclonal antibody, trastuzumab though there are patients who do not 
respond or eventually progress on therapy. Several models of trastuzumab resistance have 
been proposed and a better understanding of the mechanisms that underlie resistance will 
aid in the development of rational therapies.70 The PI3K-AKT-mTOR signaling pathway, 


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activated by growth factor receptors HER2 and IGF1-R, mediates aberrant cell growth and 
proliferation in many breast cancers. Moreover, dysregulation of this pathway has been well 
described in models of trastuzumab resistance. For instance, the PTEN tumor suppressor 
antagonizes PI3K function and absence of PTEN expression has been identified and is 
associated with trastuzumab resistance. Nagata and colleagues conducted an 
immunohistochemical analysis of 39 patient tumor samples from HER2-overexpressing 
breast cancer for the presence or absence of PTEN and correlated these findings with 
response; those tumors which lack PTEN expression had significantly fewer responses to 
trastuzumab than those with normal PTEN expression. Using human breast cancer cells 
lines these researchers demonstrated that knockdown of PTEN resulted in increased AKT 
activity and diminished growth inhibition by trastuzumab.71 Loss or reduced expression of 
PTEN protein is associated with tumorigenesis and metastasis in gastric cancer. Yang et al 
examined 184 cases of gastric carcinoma. Their adjacent normal mucosa and dysplasia 
were evaluated for PTEN protein expression by SABC immunohistochemistry. PTEN 
expression was compared with tumor stage, lymph node metastasis, Lauren's and WHO's 
histological classification of gastric carcinoma. The positive rates of PTEN protein were 
100% (102/102), 98.5% (65/66), 66.7% (4/6) and 47.8% (88/184) in normal mucosa, IM, 
dysplasia and carcinoma of the stomach, respectively. The positive rates in dysplasia a nd 
carcinoma were lower than in normal mucosa and IM (P<0.01). Advanced gastric cancers 
expressed less frequent PTEN than early gastric cancer (43 % vs. 68%, P<0.0172 Loss of 
PTEN expression commonly occurs in HER2 expressing esophagogastric tumors 73Taken 
together, these results suggest that PTEN status in HER2-overexpressing esophagogastric 
tumors may be used as a predictor of trastuzumab response. 
 
 
In addition to PTEN status, activating mutations in the gene encoding the catalytic subunit of 
PI3K (PI3KCA) have been identified and may contribute to trastuzumab resistance through 
increased PI3K signaling and AKT phosphorylation. Berns and colleagues used 
immunohistochemical analysis and gene sequencing to determine PTEN and PI3KCA 
mutational status in 55 trastuzumab-refractory tumor samples; reduced PTEN expression 
was seen in 22% of tumors, while mutations of PI3KCA were seen in 25% of tumors. Kaplan- 
Meier survival curves demonstrate shorter progression-free survival among patients with 
PI3KCA mutations, and taken together with PTEN loss, these factors may serve as  
predictors for the development of trastuzumab resistance. 
 
 
Recognizing that aberrations in the PI3K pathway may mediate resistance to trastuzumab, 
the growth factor receptor tyrosine kinase IGF1 receptor (IGF1-R), that plays a role in 
activation of this signaling pathway, has come under investigation. HER2-overexpressing 
human breast cancer cells lines transfected with IGF1-R and treated with trastuzumab had 
diminished inhibition of cell proliferation. With the addition of an inhibitor of IGF1-R signaling, 
sensitivity to trastuzumab was restored.34 Further studies in trastuzumab-refractory cell lines 
have shown that HER2 and IGF1-R interact and mediate trastuzumab resistance likely 
through PI3K pathway activation.34 


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Another mechanism of resistance to trastuzumab therapy is the accumulation of truncated 
forms of the HER2 receptor lacking the trastuzumab-binding domain. Truncation of HER2 at 
the amino terminal leads to p95HER2 receptor which maintains kinase activity in the  
absence of ligand binding; cell lines transfected with p95HER2 are resistant to trastuzumab. 
These cell lines maintain sensitivity to lapatinib, suggesting that these tumors retain their 
dependence of HER2. Retrospective analysis of tumor samples has confirmed that p95HER2 
expression is strongly associated with trastuzumab resistance while tumors expressing full- 
length HER2 maintained sensitive to trastuzumab.74 
 
 
Given the use of trastuzumab in esophagogastric cancer and the emergence of resistance, 
delineation of the mechanisms of resistance are paramount. Although the mechanisms 
described above have been described in breast cancer, in esophagogastric cancer 
characterization the mechanisms of resistance to HER2-derected therapies are very limited. 
In breast cancer the mechanisms of resistance are observed in cell lines, xenograft models, 
and in selected archival breast cancer samples, it has not been possible to observe 
sequential changes that lead to resistance as patients generally do not have repeat biopsies 
after trastuzumab resistance has been observed. Moreover, evaluation of multiple 
mechanisms of resistance within the same samples has never taken place so the possibility 
of multiple concurrent “mechanisms of resistance” has not been excluded. 
 
By analyzing the baseline pre-trastuzumab (when tissue is available) and resistant tumor for 
mutational changes in HER2 and PI3K and for expression changes in p95-HER2, PTEN, 
EGFR, HER3, and IGF1-R, further validation of mechanisms of resistance to trastuzumab 
and other anti-HER2 therapy may occur. By correlating the efficacy of afatinib with the 
molecular changes observed in post-treatment biopsies, we may be able to predict and 
select patients for this or other therapies. We will correlate these profiles with clinical 
response to afatinib therapy. Tissue can be used for future studies to characterize 
trastuzumab resistance. 
 
 
We will profile genomic alterations in key cancer-associated genes found to drive 
trastuzumab resistance in preclinical studies using the IMPACT assay developed at MSKCC. 
This bait capture, next generation sequencing assay is capable of identifying point mutations, 
small insertion/deletion events (indels), and large gene level and intragenic copy number 
aberrations in 410 cancer-associated genes. The research IMPACT testing in the Center for 
Molecular Oncology will be done for participants from both MSK and participating sites. In 
brief, DNA from each patient is sheared, and then both tumor DNA and normal DNA is end- 
repaired and ligated to adapters, minimally amplified with bar-coded primers, and the exons 
corresponding to the genes of interest are captured using Agilent SureSelect beads.75,76  We 
have validated the robustness of this assay using DNA derived from formalin-fixed, paraffin 
embedded (FFPE) tumor tissue. For specimens in which <70% of the tissue comprises viable 
tumor, macrodissection will be performed to minimize stromal contamination. Normal DNA  
will be derived from blood using QIAGEN PAXgene Blood DNA Tubes or comparable tubes. 
Tumor DNA will be prepared from frozen section when available, and if not, from formalin- 
fixed paraffin-embedded (FFPE) blocks using the DNEasy tissue kit (Qiagen). In parallel, p- 
AKT, IGF1-R, HER3, HER4, c-MET and p95-HER2 levels in ERRB2- amplified EG tumor 


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samples collected at the time of disease progression and pretreatment tumors from the same 
patient will be quantitated using a proteomics-based CEER (Collaborative Enzyme Enhanced 
Reactive-immunoassay, Prometheus Labs) assay. In prior studies, CEER has showed 
superior accuracy when compared with IHC.77 
Expected Outcomes/Statistical Considerations. Our preliminary data in trastuzumab 
refractory breast cancer studies and the published literature on EG cancer suggest that many 
of the actionable alterations such as PIK3CA, ERBB2, PTEN mutation, presence of p95- 
HER2 or loss of PTEN are likely to be found in 5%-15% of ERBB2-amplified EG cancer 
tumors. Clinical data such as magnitude of response to trastuzumab-based therapy (stable 
disease, partial response, complete response) and time to development of trastuzumab 
resistance will be collected on all patients to compare differences in outcome as a function of 
mutational status. We will generate a multivariate model incorporating mutational status and 
clinical predictors of outcome such as age, performance status, and stage. Given the sample 
size, this will be an exploratory analysis of correlative biomarkers. Presence of mutations 
(categorized as a binary variable) in pre- and post-treatment tissue samples will be  
correlated with overall clinical benefit to afatinib using Fisher‟s exact test. 
3.9 
Update on Second-line Therapies in HER2 EG Cancers 
 
In second-line settings, several recent Phase III studies exploring lapatinib (EGFR/HER2 
reversible tyrosine kinase inhibitor) or trastuzumab emtansine (or T-DM1; an antibody-drug 
conjugate consisting of the trastuzumab linked to the cytotoxic agent DM1) failed to meet the 
primary endpoint and therefore no standard exists for HER2 directed therapy after 
trastuzumab progression. 
T-DM1 
 
The Phase II/III GATSBY study examined the efficacy and safety of T-DM1 compared to 
paclitaxel alone in second-line advanced gastric cancer and failed to show a primary 
endpoint efficacy benefit of T-DM1 over paclitaxel (Median OS 7.9 vs. 8.6 mos.; HR 1.13 
p=0.31).78 
Failure of T-DM1 does not eliminate HER2 as a target in second-line esophagogastric 
cancer. HER2-positive esophagogastric cancer in second-line therapy is a clinically and 
biologically aggressive disease. The Phase II/III GATSBY trial failed because the cytotoxic 
agent DM1 was unsuccessful in inducing response in platinum and fluropyrimidine refractory 
gastric tumors.  Much remains to be learned about ERBB2 as a driver in esophagogastric 
cancer. As our understanding of the genomic subtypes of gastric cancer deepens, it is 
becoming clear that co-occurring genomic aberrations impact the efficacy of HER2 targeted 
agents. According to the Cancer Genome Atlas analysis of the four distinct molecular gastric 
cancer subtypes
79, HER2-positive tumors are characterized by chromosomal instability (CIN), 
marked aneuploidy, and dependency on receptor tyrosine kinase signaling. It is therefore 
possible that recurrent amplification in key tyrosine kinases (such as EGFR80, HER365,  
HER4) contributed to T-DM1 resistance. 
Ramucirumab 


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Page 22 of 69 
 
 
 
 
Lapatinib and TDM-1 failed in second-line settings, and a combination of paclitaxel with 
ramucirumab (monoclonal antibody against vascular endothelial growth factor receptor 2 
[VEGFR2]) remains the standard second-line therapy for HER2-positive esophagogastric 
cancer patients. The RAINBOW trial demonstrated an improved survival and response rate 
for the combination of ramucirumab with paclitaxel compared to placebo with paclitaxel in 
second-line therapy of metastatic gastric adenocarcinomas (median OS 9.6 vs. 7.4 months, 
Median PFS was 4.4 and 2.9 months).81 
 
 
3.10 
Preliminary toxicity and efficacy of afatinib and trastuzumab 
 
Initially, this was a single-agent afatinib study in trastuzumab refractory patients. We 
subsequently amended the study to treat patients with afatinib/trastuzumab based on 
possibly higher efficacy of afatinib/trastuzumab as demonstrated in the preclinical model. 
 
We treated 12 patients with afatinib and trastuzumab with prophylactic loperamide and 
frequent toxicity assessments due to the concerns of excessive diarrhea. Despite lowering 
the starting dose of afatinib to 30 mg from 40 mg, afatinib 30 mg and trastuzumab was 
associated with a higher rate of Grade 3 treatment-related toxicity with afatinib/trastuzumab 
compared with single agent afatinib 40 mg daily. Intolerable Grade 2 diarrhea required dose 
reductions in 42% of patients. Diarrhea was difficult for patients to tolerate despite the use of 
loperamide and Lomotil. Grade 3 toxicities attributable to afatinib/trastuzumab included 
creatinine increase, dehydration, hypokalemia, and hypophosphatemia despite aggressive 
management and frequent follow up visits. The tables 3.1.1 and 3.1.2 summarize the efficacy 
data, dose reductions and toxicity data to date from the two cohorts. 
Table  3.1.1 
 
Cohort 
N 
Responders 
Dose reductions 
Afatinib 40 mg 
20 
3 
3 of 20 patients (15%) 
Afatinib 30 mg + trastuzumab 
12 
1 
5 of 12 patients (42%) 
 
 
Table 3.1.2 
 
No. (%) 
Afatinib Arm, n=20 
Afatinib/Trastuzumab 
Arm, n=12 
Toxicity 
Grad 
e 2 
Grad 
e 3 
Grad 
e 4 
Toxicity 
 Gra 
de 2 
Grad 
e 3 
Grade 4 
Activated 
partial 
thromboplastin 
time prolonged 
Anemia 
Anorexia 
1 (5) 
0 
0 
Creatin
increas
ine 
ed 
0 
1 (8) 
0 
0 
1 (5) 
0 
Dehydr ation 
0 
2 (17) 
0 
0 
1 (5) 
0 
Diarrhea 
8 
0 
0 
(75) 


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Dehydration 
0 
1 (5) 
0 
Fatigue 
1 (8) 
2 (17) 
0 
Diarrhea 
6 (30) 
0 
0 
Gastritis 
1 (8) 
0 
0 
Dry skin 
1 (5) 
0 
0 
Hypokalemia 
1 (8) 
2 (17) 
0 
Fatigue 
1 (5) 
0 
0 
Hypophosphate 
0 
1 (8) 
0 
mia 
Nausea 
2 (6) 
0 
0 
Mucositis oral 
1 (8) 
0 
0 
Papulopustula 
1 (5) 
0 
0 
Nausea 
1 (8) 
0 
0 
r rash 
Rash 
2 (10) 
0 
0 
Paronychia 
2 
0 
0 
acneiform 
(17) 
Vomiting 
2 (10) 
0 
0 
Rash acneiform 
1 (8) 
0 
0 
Rash maculo- 
papular 
1 (8) 
0 
0 
Vomiting 
1 (8) 
 
These data suggest that the combination of afatinib and trastuzumab results in a higher rate 
of toxicity. Despite use of prophylactic loperamide in all patients, 75% of patients experience 
significant diarrhea needing dose reductions. Lower afatinib doses and poor absorption due 
to diarrhea may have contributed to limited efficacy of this regimen. Given that only 1 
response was observed out of 12 patients treated, the probability of observing 4 or more 
responses out of the remaining 14 patients treated with afatinib and trastuzumab and 
determine is regimen promising is very low. Furthermore, the emerging data from the 
negative TDM1 Phase II/III GATSBY study leaves second-line therapy in HER2-positive 
esophagogastric cancer as an unmet therapeutic need. 
 
The negative T-DM1 trial suggests that there may be minimal benefit to trastuzumab beyond 
progression.  To help shed light on mechanisms of trastuzumab resistance, we analyzed 
samples from 80 patients had Stage IV HER2-positive (IHC 3+, IHC2+/FISH+) EG 
adenocarcinoma using a NGS assay -MSK-IMPAC. Seventy-one samples were collected 
pre-trastuzumab, 38 post-trastuzumab, and 28 with paired pre/post samples. In the paired 
samples, we observed post-therapeutic loss of HER2 amplification (16%); gain of new AMP 
of MET (7%), EGFR (4%), and IGF1R (4%); MUT in ERBB4 (14%), KRAS (11%), PIK3CA 
(7%), MTOR (7%). These data highlight the secondary alterations in the RTK/RAS/PI3K 
pathway in patients with acquired trastuzumab resistance (Janjigian submitted ESMO 2016). 
This molecular data and the clinical data from the GATSBY trial -showing failure of T-DM1 - 
suggests that HER2 monoclonal antibody will be insufficient to induce responses and 
questions the utility of trastuzumab beyond progression in trastuzumab refractory gastric 
cancer. Paclitaxel is standard therapy in second-line settings in gastric cancer. The 
hypothesis is that the combination of afatinib and paclitaxel will result in an overall survival 
improvement compared to standard therapy with paclitaxel and ramucirumab in second-line 
patients with HER2-positive esophagogastric cancer. 
 
 
3.11 Development Plan for Afatinib with Paclitaxel in HER2-positive EG Cancer 


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IRB Number: 11-166 A(14) 
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Page 24 of 69 
 
 
 
 
Afatinib demonstrates clinical activity in heavily pretreated patients with metastatic HER2- 
positive esophagogastric cancer after disease progression on trastuzumab with 
chemotherapy warranting further investigation in trastuzumab refractory gastric cancer. The 
combination of afatinib with trastuzumab was not dramatically better and is associated with 
higher toxicity; therefore we plan to develop afatinib in combination with paclitaxel. A Phase 
II/III trial of afatinib with paclitaxel vs. ramucirumab with paclitaxel in second-line settings in 
HER2-positive EG cancer was proposed by Yelena Janjigian and is supported by the  
Alliance and Boehringer Ingelheim. This trial was well received and supported by the NCI EG 
task force as an intergroup trial, with the request to generate toxicity data for afatinib with 
paclitaxel in second-line patients with HER2-positive EG cancer. We plan to amend the 
current trial to stop accrual to the afatinib/trastuzumab combination and treat the remaining 
14 patients with afatinib and paclitaxel. The enrollment plan is outlined in the section below. 
3.12 Safety of Paclitaxel with Afatinib 
 
The randomized LUX-Lung 582  study demonstrated in 202 patients with afatinib refractory 
tumors that the combination of afatinib with paclitaxel is safe, and treatment-related adverse 
events were consistent with those previously reported with each agent. In this trial, 48% of 
patients receiving afatinib plus paclitaxel and 30% of patients receiving single-agent 
chemotherapy  experienced drug-related Grade 3/4 adverse events. Afatinib plus paclitaxel 
improved PFS and ORR compared with single-agent chemotherapy  in patients EGFR 
mutant NSCLC (median 5.6 vs. 2.8 months, hazard ratio [HR] 0.60, P=0.003) and ORR 
(32.1% versus 13.2%, P=0.005) significantly improved with afatinib plus paclitaxel. There  
was no difference in OS, due to cross-over design and overall favorable prognosis of patients 
with EGFR mutant lung carcinoma. Global health status/quality of life was maintained with 
afatinib plus paclitaxel over the entire treatment period.
82  Several randomized trials 
demonstrated no benefit for addition of EGFR TKIs (erlotinib or gefitinib) to chemotherapy in 
non-enriched patient population including EGFR wild-type and KRAS mutant tumors. 
Although no benefit was detected, these treatments are not detrimental. KRAS mutations do 
not occur in HER2-positive esophagogastric cancer. There is no data to suggest that the 
combination of an EGFR TKI and chemotherapy is antagonistic. Riely et al. demonstrated 
that the combination of erlotinib, carboplatin, and paclitaxel is safe and well tolerated with 
response rates and survival similar to those reported for carboplatin, paclitaxel, and 
bevacizumab in lung cancer patients.83 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a multi-institution, open-label, non-randomized, Phase II evaluation of oral afatinib 
(daily) and intravenous paclitaxel (weekly, 3 weeks on, 1 week off) in patients with 
trastuzumab refractory HER2-positive metastatic or recurrent esophagogastric 
adenocarcinoma. Patients are eligible if they experience progression of disease on 
trastuzumab-based therapy; other chemotherapy regimens may have been administered 
between the time of progression on the prior trastuzumab-containing regimen and the start of 
this protocol therapy. All patients with disease technically amenable to biopsy will be asked 


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IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 25 of 69 
 
 
 
 
to undergo a biopsy for tissue correlative studies during pretreatment. Per the investigator‟s 
discretion, MSK patients only will be asked to undergo a second biopsy after one week of 
therapy (with a +7 day window). The pretreatment biopsy can occur any time prior to initiation 
of afatinib, following consent (see section 9.0). At the discretion of the MSK Principal 
Investigator, select participants who show response on this study and then progress may be 
asked to have an optional third biopsy. 
 
 
All patients must be able to provide informed consent prior to enrollment. 
See Section 10 for treatment table. 
 
 
4.3 
Intervention 
 
All patients receiving therapy on trial with afatinib and trastuzumab will continue on afatinib 
and trastuzumab until disease progression or intolerable toxicity. All additional patients will 
be enrolled on afatinib and paclitaxel cohort.. 
 
Fourteen patients will be treated with afatinib and paclitaxel combination. Patients will receive 
oral afatinib 40 mg daily plus paclitaxel 80 mg/m2 intravenously on day 1, 8, and 15 of a 28- 
day cycle. 
 
Up to two 10 mg dose reductions of afatinib will be permitted if patients encountered any 
Grade ≥3 drug-related adverse events (AEs; assessed according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI-CTCAE]), or Grade 2 diarrhea lasting 
≥2 days despite antidiarrheal agents, or nausea or vomiting for ≥7 consecutive days despite 
best supportive care. The paclitaxel dose will be reduced by 10 mg/m2 for the following cycle 
when NCI-CTCAE Grade 4 hematological toxicity or Grade 3 paclitaxel-related non- 
hematological toxicity (except for alopecia) is observed. If the dose of paclitaxel is reduced 
because of potentially related AEs, subsequent dose increases are not permitted. Paclitaxel 
will be permanently discontinued if dose reduction to less than 60 mg/m 2 would be required, 
or in case of any paclitaxel-related event that is deemed life threatening, regardless of grade. 
AE assessments will be performed day 1, 8 and 15 and will coincide with treatment 
appointments. 
Patients must have measurable disease and will undergo a computerized tomography (CT) 
or magnetic resonance imaging (MRI) scan of the chest and abdomen within 14 days of start 
of therapy, at eight weeks, and every eight weeks thereafter (every 2 cycles), with a 
scheduling window of up to one to fourteen (1-14) days. Response assessment will be by 
RECIST 1.1 criteria84. The same imaging modality performed at baseline (CT or MRI) will be 
repeated at subsequent imaging. 
 
 
Therapy will be administered in the outpatient setting, with each cycle consisting of 28 days 
of continuous therapy. The cycle start date will coincide with the physician visit date. If a 
patient is held or unable to come in at the cycle start date, a new pill diary will be provided at 


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Page 26 of 69 
 
 
 
 
the previous visit. A study diary will be completed by patients to ensure compliance with the 
study drug (see APPENDIX A). 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Afatinib 
 
Pharmaceutical form: Film-coated tablets 
 
Source: Boehringer Ingelheim Pharma GmbH & Co. KG 
 
Unit strength: 40 mg, 30 mg and 20 mg film-coated tablets (dose of afatinib in the film- 
coated tablets is free-base equivalent of afatinib) 
 
Daily dose: 40 mg, 30 mg or 20 mg 
 
Duration of use: Continuous daily dosing; one course consists of 28 days. Patients are 
eligible for repeated treatment cycles in the absence of disease progression and undue 
adverse events (as per criteria in Section 9). 
 
Route of administration: Oral (swallowed) 
 
Posology: Once daily 
 
5.2 Trastuzumab 
Pharmaceutical form: Trastuzumab is commercially available, and is a recombinant DNA- 
derived humanized monoclonal antibody that selectively binds with high affinity in a cell- 
based assay (Kd = 5 nM) to the extracellular domain of the human epidermal growth factor 
receptor 2 protein, HER2. The antibody is an IgG1 kappa that contains human framework 
regions with the complementarity-determining regions of a murine antibody (4D5) that binds 
to HER2. 
The humanized antibody against HER2 is produced by a mammalian cell (Chinese Hamster 
Ovary) [CHO] suspension culture in a nutrient medium containing the antibiotic gentamicin. 
Gentamicin is not detectable in the final product. Trastuzumab is a sterile, white to pale 
yellow, preservative-free lyophilized powder for intravenous (IV) administration. Each vial of 
trastuzumab contains 400 mg of trastuzumab, 9.9 mg of L-histidine HCl, 6.4 mg of 
L-histadine, 400 mg of ,-trehalose dihydrate, and 1.8 mg of polysorbate 20, USP. 
Reconstitution with 20 mL of the supplied Bacteriostatic Water for Injection (BWFI) USP, 
containing 1.1% benzyl alcohol as a preservative, yields 21 mL of a multidose solution 
containing 21 mg/mL trastuzumab, at a pH of ~6. 
 
Source: For this study, locally obtained commercial supplies of trastuzumab will be used. 
 
Dosage and Administration: Trastuzumab will be administered on an every 2 week dosing 
schedule, 4 mg/kg every 2 weeks over 30 mintues. Patients who were off trastzumab for at 
least 4 weeks prior to study enrollment will require initial loading dose of trastuzumab 6 
mg/kg over 90 minutes, followed by trastuzumab 4 mg/kg every 2 weeks over 30 mintues . 
 
 
Preparation and Storage: Trastuzumab will be prepared and administered as per MKSCC 
guidelines. Please refer to the FDA-approved package insert for additional information. 


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Route of administration: every 2 weeks 
 
Cardiac Dysfunction: Signs and symptoms of cardiac dysfunction were observed in a 
number of women who received trastuzumab alone or in combination with chemotherapy, 
most often anthracycline based treatment. Cardiac dysfunction was observed most 
frequently among patients who received trastuzumab plus AC chemotherapy (28%), 
compared with those who received AC alone (7%), trastuzumab plus paclitaxel (11%), 
paclitaxel alone (1%), or trastuzumab alone (7%). Severe disability or fatal outcome due to 
cardiac dysfunction was observed in ~1% of all patients. The signs and symptoms of cardiac 
dysfunction usually responded to treatment. All patients must have a baseline evaluation of 
cardiac function including a measurement of LVEF by either MUGA or ECHO prior to entry 
into the study. Only patients with normal LVEF should be entered into this study. All should 
have regular cardiac monitoring throughout the study per the site investigator‟s discretion. It 
is suggested that the first evaluation occur 4 months after the initiation of trastuzumab 
therapy. 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). The diagnosis must be confirmed 
using the same method used to measure LVEF at baseline (either ECHO or MUGA). 
 
Management of Symptomatic Cardiac Changes. Patients who develop signs and symptoms 
of CHF should have trastuzumab held and should receive treatment for CHF as prescribed  
by the HFSA (e.g., ACE inhibitors, angiotensin-II receptor blockers, β-blockers, diuretics, and 
cardiac glycosides, as needed; HFSA guidelines). Consideration should be given to obtaining 
a cardiac consultation. 
 
If the symptoms of CHF resolve with treatment, and cardiac function improves, Trastuzumab 
may be continued after discussion with the patient concerning the risks and benefits of 
continued therapy. If the patient is benefiting clinically from Trastuzumab, the benefit of 
continued treatment may outweigh the risk of cardiac dysfunction. If Trastuzumab is 
restarted, continued surveillance with noninvasive measures of LVEF (MUGA or ECHO) is 
strongly recommended until cardiac function has normalized. 
 
Management of Asymptomatic Decreases in LVEF. Trastuzumab may be continued in 
patients experiencing an asymptomatic absolute decrease in LVEF of <20 percentage points 
from baseline, when the ejection fraction remains within the imaging center‟s range of normal 
limits. Per the site investigator‟s discretion, srepeat measures of LVEF should be obtained 
using the methodology selected at baseline. Close follow-up of such patients is 
recommended. Patients with an asymptomatic absolute decrease in LVEF of >20 percentage 
points or an ejection fraction below the range of normal limits, should have trastuzumab held 
and be considered for treatment of incipient CHF as prescribed by the HFSA (e.g., ACE 
inhibitors, angiotensin-II receptor blockers, β-blockers, diuretics, and cardiac glycosides, as 
needed; see HFSA guidelines). In light of the variability inherent in the assessment of  
ejection fraction, consideration should be given to repeating the study to confirm an observed 
decline. Repeat measures of LVEF should be obtained using the same methodology  
selected at baseline. If trastuzumab has been discontinued for an asymptomatic decline in 
LVEF, a repeat measure of LVEF will be obtained in 1 month to determine if the decline has 
resolved. 
 
If cardiac function improves, trastuzumab may be restarted after discussion with the patient 
concerning the risks and benefits of continued therapy. If the patient is benefiting clinically 
from Trastuzumab, the benefit of continued treatment may outweigh the risk of cardiac 
dysfunction. If trastuzumab is restarted, continued surveillance with noninvasive measures of 


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Approval date: 13-Sep-2018 
Page 28 of 69 
 
 
 
 
LVEF (MUGA or ECHO), using the methodology selected at baseline, is strongly 
recommended until cardiac function has normalized. 
 
5.3 Paclitaxel 
 
Please refer to the FDA-approved package insert for paclitaxel for product information, 
extensive preparation instructions, and list of adverse events. 
 
Administration 
 
Paclitaxel will be administered intravenously on day 1, 8, and 15 of a 28-day cycle in 
accordance with standard institutional clinical practice. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Pathologically or cytologically confirmed esophagogastric cancer. 
• 
HER2 overexpression and/or amplification as determined by 
immunohistochemistry (3+) or FISH (≥2.0) 
• 
Previously received trastuzumab as part of a regimen in the perioperative or 
metastatic setting with evidence of progression. 89 Zr-trastuzumab use as imaging 
agent for 89 Zr-trastuzumab PET permitted. 
• 
May have previously received lapatinib as part of a regimen in the perioperative or 
metastatic setting with evidence of progression of disease. Washout period for 
lapatinib of 14 days. 
• 
Completion of previous chemotherapy regimen ≥2 weeks prior to the start of study 
treatment. 
• 
Other chemotherapy regimens may have been administered between the time of 
progression on prior trastuzumab containing regimen and protocol therapy. No 
restriction on prior chemotherapy regimens for advanced stage disease. 
• 
At least one measurable metastatic lesion according to RECIST 1.1 criteria. 
Ascites, pleural effusions, and bone metastases are not considered measurable. 
Minimum indicator lesion size = 10 mm by helical CT or = 20 mm by conventional 
techniques. Pathological nodes must be = 15 mm by the short axis to be 
considered measurable. 
• 
Patients aged 18 years or older, as no dosing or adverse event data are currently 
available on the use of afatinib in patients <18 years of age, children are excluded 
from this study. 
• 
Life expectancy of at least three (3) months. 
• 
Karnofsky performance status ≥60% 
• 
All patients with disease technically amenable to biopsy will be asked to undergo 
a biopsy. Patient must agree to allow 2 biopsies of any malignant lesion that can 
be accessed by endoscopy or with the aid or radiology (i.e. CT guided). 
• 
Patients who have previously provided samples at any time after trastuzumab 
resistance will be exempt from biopsy at the start of therapy. 
• 
Consent to preservation of frozen and fixed samples of tumor cores for evaluation 
• 
Able to swallow and retain oral medication. 


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• 
Negative serum HCG pregnancy test for premenopausal women of reproductive 
capacity and for women less than 12 months after menopause. 
• 
Willingness to use birth control while on study. 
• 
Asymptomatic, central nervous system metastases are permitted. 
6.3 
Subject Exclusion Criteria 
 
• 
Patients receiving any concurrent anticancer therapy or investigational agents 
with the intention of treating esophagogastric cancer.89 Zr-trastuzumab uses as 
imaging agent for 
89 Zr-trastuzumab PET permitted. 
• 
Prior disease progression on docetaxel or paclitaxel in metastatic setting. 
 
• 
Patients who are unwilling to consent to mandatory tumor biopsy. Patients with 
archival tissue permitted to enroll on study per MSK Principal Investigator 
discretion. 
• 
Women who are pregnant or breast feeding. 
• 
Concurrent radiotherapy is not permitted for disease progression on treatment on 
protocol (except in the context specified in section 9.0), but might be allowed for 
pre-existing non-target lesions with approval from the principal investigator of the 
trial. 
• 
Concurrent medical conditions which may increase the risk of toxicity, including 
ongoing or active infection, history of significant bleeding disorder unrelated to 
cancer (congenital bleeding disorders, acquired bleeding disorders within one 
year), HIV-positive. 
• 
Subjects with acute Hepatitis B are not eligible. Subjects with chronic hepatitis are 
eligible if their condition is stable and in the opinion of the investigator, if 
consulted, would not pose a risk to subject safety. 
• 
History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure NYHA classification of 3, 
unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 
months prior to study entry. 
• 
Baseline (< 1 month before treatment) cardiac left ventricular function with resting 
ejection fraction of less than 50% measured by echocardiogram. 
• 
Known pre-existing interstitial lung disease. 
• 
Significant or recent acute gastrointestinal disorders with diarrhea as a major 
symptom e.g., Crohn‟s disease, malabsorption, or CTCAE Grade >2 diarrhea of 
any etiology. 
• 
Unwillingness to give written informed consent, unwillingness to participate, or 
inability to comply with the protocol for the duration of the study. 
• 
Active hepatitis B infection, active hepatitis C infection. 
• 
Known HIV carrier 
• 
Known or suspected active drug or alcohol abuse. 
Restricted Therapies 
• 
Additional experimental anti-cancer treatment and/or standard chemo-, 
immunotherapy, hormone treatment (with the exception of megestrol acetate), or 
concurrent radiotherapy is not allowed concomitantly with the administration of 


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study treatment (with the exception listed in section 9.0). 89 Zr-trastuzumab use as 
imaging agent for 
89 Zr-trastuzumab PET permitted. Afatinib is a substrate of P-gp 
and its plasma concentrations can be affected by the use of P-gp inhibitors (data 
on file) and it is also likely that P-gp inducers could also influence afatinib plasma 
concentrations. 
 
• 
The use of potent P-gp inhibitors (including cyclosporine, erythromycin, 
ketoconazole, itraconazole, quinidine, Phenobarbital salt with quinidine, ritonavir, 
valspodar, verapamil) and potent P-gp inducers (including St John's wort, 
rifampicin) has to be avoided during treatment with afatinib. Any exemptions to 
this have to be discussed with the principal investigator. 
 
7.0 
RECRUITMENT PLAN 
 
This will be a multi-institution, Phase II study. Patients with metastatic or recurrent 
esophageal, gastric and gastroesophageal (GE) junction cancer that are eligible will be 
identified for enrollment from MSKCC clinical practice and clinic lists. No additional 
measures, e.g. advertisement, payment to patients, will be employed to recruit patients. 
Patients will be accrued to this study without regard for gender or minority status. 
 
Similar recruitment procedures will be followed at participating institutions. 
 
Participating site recruitment will be conducted as outlined within the protocol. Any 
participating sites that require a limited waiver must obtain it from their own site IRB/Privacy 
Board (PB) via a separate protocol addendum or request.  It is the responsibility of the MSK 
staff to confirm the participating data collection sites have a limited waiver approved by their 
local IRB(s)/PBs. 
 
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. 
 
 
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. 


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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. 
• 
Serum pregnancy test for women of childbearing potential (WOCP) 
In addition, all WOCP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant (e.g. late or missed period) at any time during 
study participation. 
• 
CT scan or MRI of all relevant disease sites within 2 weeks of study entry. 
• 
Laboratory evaluation including complete blood count, magnesium and 
comprehensive chemistry panel (includes BUN, creatinine, ALT, AST, albumin, 
glucose, total protein, calcium, bilirubin, bicarbonate, sodium, chloride, potassium, 
alkaline phosphatase) 
 
The following must be obtained within one month prior to starting protocol therapy: 
• 
Electrocardiogram 
• 
Assessment of Left Ventricular Ejection Fraction (LVEF) as measured by 
echocardiography or MUGA scan will be assessed at screening. The same method of 
measurement has to be used throughout the study. 
• 
Biopsies of tumor: An initial biopsy prior to the start of therapy (specific tumors that 
have progressed on trastuzumab will be biopsied if at all possible) for the correlative 
studies for all patients whose tumors are feasible to biopsy is required. Patients with 
tumor not technically amenable to be safely biopsied may be allowed to participate in 
the study (see section 9 for exceptions). 
• 
When available, primary tumor samples of the patients will be obtained and analyzed. 
 
To be completed any time prior to starting therapy: 
• 
Histological confirmation of esophagogastric adenocarcinoma at enrolling institution 
prior to study enrollment. Patients without histological confirmation of recurrence or 
metastasis will undergo a biopsy to confirm recurrence, unless the risk of such a 
procedure outweighs the benefits of confirming recurrent disease. 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 Afatinib Administration 
 
Afatinib will be self-administered by the study subjects in the outpatient setting. The starting dose of 
afatinib is 30 mg orally once daily for 28 days (continuously). Three patients will be treated with 
Afatinib 30 +trastuzumab q2wks with loperamide prophylaxis. If no patients experience Grade ≥3 
diarrhea with prophylactic loperamide, a new cohort of patients will be enrolled at dose Afatinib 40 
mg +trastuzumab. If however 1 of 3 patients have Grade ≥3 diarrhea at dose 30 mg, the cohort will 
be expanded to 6. If no further DLT occurs, patients will be enrolled at dose Afatinib 40 mg 
+trastuzumab. If 2 of 6 patients experience Grade ≥3 diarrhea, the MTD will be defined as the dose- 


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Page 32 of 69 
 
 
 
 
level below which this occurred. If 2 of 3 or 2 of 6 subjects experience DLT at 30 mg then Afatinib 
will be deescalated to 20 mg. 
 
 
1) Afatinib is supplied as 40 mg, 30 mg and 20 tablets. There is no planned interruption between 
treatment cycles unless clinically indicated. The cycle start date will coincide with the physician 
visit date. Because of the potential need for physician visit scheduling to vary (due to both 
physician and patient issues), to avoid violation of, and deviation from, the protocol, physician 
visits may vary by up to one to fourteen (1-14) days from a strict 28 day schedule. Afatinib will 
be taken on Days 1 to 28 of each 28-day cycle. Afatinib should be taken at approximately the 
same time each day. It is advised that patients take their medication at least one hour before 
food intake and at least three hours after food intake, but patients may deviate from this 
following consultation with the Principal Investigator and treating physician. Treatment may 
be held and doses skipped in the event of a clinically necessary procedure, such as EGD or 
CT scan, and after consultation with the Principal Investigator and treating physician. 
Additionally, treatment may be held or skipped in the event of a protocol related biopsy. The 
tablet should be swallowed with a glass of water (~250 mL). Afatinib tablets are film-coated 
and therefore should not be chewed or crushed, but may be administered via G-tube after 
dispersing the afatinib tablets according to the following procedure: Place the tablet into a 
glass containing 50 mL isotonic sodium chloride solution. Stir until the tablet is broken up into 
very fine particles (about 15 minutes). Drink the suspension immediately or administer via a 
gastric tube. Rinse the glass with another 50 ml of isotonic sodium chloride solution and drink 
or administer the supplementary solution via the gastric-tube again (to pick up any drug 
remaining in the glass/gastric-tube). Patients with emesis should not take a replacement 
dose. If a dose of afatinib is missed, it should be taken during the same day as soon as the 
patient remembers. However, if the next scheduled dose is due within 8 hours then the 
missed dose must be skipped. A study diary will be completed by patients to ensure 
compliance with afatinib (see APPENDIX A). Missed doses should be recorded on the pill  
diary but will not be considered violations of the protocol 
 
 
If a patient develops intolerable toxicity that meets criteria for dose limiting toxicity (DLT) other than 
hypomagnesemia (for DLT definition refer to Section 9.2) regardless of treatment cycle, treatment 
with afatinib must be paused. If all drug-related toxicities recover to CTCAE version 4 Grade 1 or 
baseline (whichever is higher) within 14 days of stopping treatment with afatinib, treatment may be 
resumed with dose modifications according to Section 9.2. 
 
 
9.3 Afatinib Dose Delays or Modifications 
 
Intrapatient afatinib dose reduction will be allowed to 30 mg and 20 mg depending on the type 
and severity of toxicity encountered provided that criteria for patient withdrawal from study 
treatment have not been met. Once afatinib is dose reduced, the patient should not go back to 
the starting dose. 
 
 
ILD 


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Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary 
symptoms (dyspnea, cough, fever) should be performed to exclude ILD. Study drug should be 
interrupted pending investigation of these symptoms. If interstitial lung disease is diagnosed, study 
drug should be permanently discontinued and appropriate supportive treatment instituted as 
necessary. 
 
 
9.4 Paclitaxel  Administration 
 
Paclitaxel 80 mg/m2 will be administered intravenously on day 1, 8, and 15 of a 28-day cycle in 
accordance with standard institutional clinical practice. 
 
 
9.5 Paclitaxel Dose Delays and Modifications 
Table 9.4.1 Paclitaxel Dose Levels 
 
 
 
Table 9.4.2 Dose-modification guidelines for paclitaxel for thrombocytopenia, neutropenia, 
febrile neutropenia, and infectiona. 
 
ANC Count (x 109/L) 
Platelet Count (x 109/L) 
Dose adjustment for  paclitaxel 
>1.5 
and 
>100 
Maintain dose level without interruption. 
<1.5 
and/or 
<100 
Wait for counts to recoverb. If within 7 days of 
interruption, ANC >1.5 x 109/L and platelets 
>100 x 109/L, maintain dose level. If within 42 
days of interruption, ANC >1.0 x 109/L and 
platelets ANC >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 <100 x 109/L. 
b. 
If unscheduled laboratory assessments during a treatment cycle show that the ANC drops <1.0 x 10
9/L 
or that the platelet count drops <75 x 109/L, treatment with paclitaxelshould be interrupted. 
c. 
Dose reductions of paclitaxelfor ANC <1.5 x 109/L but >1.0 x 109/L may be determined at the discretion 
of the investigator or institutional guidelines. In such situations, if administration of chemotherapy is 
prohibited, then paclitaxelmust be held until the ANC recovers to >1.5 x 109/L. 
Starting dose 0 
Paclitaxel 80 mg/m2 day 1, 8, and 15 of 28 days 
Dose Level -1 
Paclitaxel 60 mg/m2 day 1, 8, and 15 of 28 days 
Dose Level -2 
Paclitaxel 60 mg/m2 day 1 and 15 of 28 days 


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Table 9.4.3 Dose-modification guidelines for nonhematologic adverse events thought to be 
related to paclitaxel
a
 
 
 
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 
100% 
- Second appearance 
Dose level -1 
- Third appearance 
Discontinue treatment 
permanently 
Not applicable 
Grade 3 
- First appearance 
Interrupt until resolved to Grade 
0-1 or pretreatment baseline 
Dose level -1 
- Second appearance 
Dose level -2 
- Third appearance 
Discontinue treatment 
permanently 
Not applicable 
Grade 4* 
- First appearance 
Discontinue treatment 
permanently 
OR 
If the investigator deems it to 
be in the patient‟s best interest 
to continue, interrupt until 
resolved to Grade 0-1 or 
pretreatment baseline 
Not applicable 
OR 
Dose level -2 
- Second appearance 
Discontinue treatment 
permanently 
Not applicable 
*Hypersensitivity Reactions 
 
Paclitaxel treatment should be discontinued for Grade 4 hypersensitivity reactions. There are 
no dose reductions for hypersensitivity reactions. Manage mild to moderate infusion 
reactions per the institutional guidelines. 
9.6 Concomitant Therapy 
 
The use of investigational or anticancer agents is not allowed while patients are on this study. 
However, symptomatic treatment of tumor-associated symptoms is allowed, such as radiation 
therapy with palliative intent and dose for symptom control. Concomitant medication, or therapy to 
provide adequate supportive care, may be given as necessary. If concomitant therapy (e.g., 
radiation) is clinically indicated, patients may temporarily discontinue afatinib therapy and resume 
treatment following consultation with the treating physician and principal investigator. 
89 Zr- 
trastuzumab use as imaging agent for 89 Zr-trastuzumab PET is permitted. 
 
 
Antidiarrheal Treatment 


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Loperamide Antidiarrheal Therapy 
 
 
 
Prophylactic use of antidiarrheal medication is not mandatory for patients taking afatinib and 
paclitaxel. Loperamide is the recommended standard therapy to treat diarrhea as clinically indicated 
in this study. Second-line antidiarrheal treatments and adjunctive therapies (e.g., Lomotil 
(Diphenoxylate and Atropine) (or equivalent as approved by the  sponsor) are also recommended for 
use when appropriate. 
 
 
Biopsies of tumor 
 
An initial biopsy prior to the start of therapy is required for the correlative studies evaluating the 
biologic effects of afatinib. It will be obtained for all patients whose tumors are feasible to biopsy. For 
MSK patients only,  a second biopsy* (occurring after one week of therapy (+ 7 day window), see 
study calendar) will also be obtained at the investigator‟s discretion. 
 
At the discretion of the MSK Principal Investigator, select participants who show response on this 
study and then progress may be asked to have an optional third biopsy. 
 
Examples of conditions under which biopsies should not be performed include: 
 
• It is in the opinion of the treating physician that a biopsy would involve too great of risk (e.g. tumor 
near a blood vessel, significant risk of perforation). In this scenario, the treating physician must both 
document the reason for not doing the biopsy and must discuss and have permission from the 
principal investigator of the study (Yelena Janjigian, MD). 
• Platelet count is less than 60,000. 
 
• Patient is on anticoagulation therapy with either Coumadin or Heparin and are unable to be taken 
off it safely temporarily for the biopsy to be done. 
*Note: It is possible that a patient will be eligible for the first biopsy, but will not be required to have 
the second biopsy due to an unforeseen circumstance (i.e., patient does not have viable tissue). 
This will be at the discretion of the investigator. 
 
 
 
Collection of blood of cell-free DNA (cfDNA) 
 
Cell-free DNA (cfDNA) will be obtained from plasma samples collected at baseline, every 8 weeks, 
and at the time of treatment discontinuation 
Approximately 20 ml of whole blood per visit (baseline, every 8 weeks, and treatment 
discontinuation) will be collected at ambient temperature into 2x 10mL cell free DNA BCT tubes for 
plasma isolation. 


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Baseline research bloods will be collected on Cycle 1, Day 1 prior to treatment administration. A 
window of +/-7 days is permitted for research bloods completed every 8 weeks and at treatment 
discontinuation 
9.7 Dose limiting toxicity (DLT) 
 
 
 
Suggested medical management of afatinib and trastuzumab associated toxicities is outlined in 
section 9.7. Suggested afatinib dose modifications are outlined in section 9.8. A dose-limiting toxicity 
(DLT) is defined as an adverse event or laboratory abnormality that is: a) considered to be related to 
the study regimen; b) meets any of the following criteria: 
 
• CTCAE Grade 2 or higher decrease in cardiac left ventricular function 
 
• CTCAE Grade 2 diarrhea lasting for seven or more days, despite appropriate use of standard anti- 
diarrheal therapy 
• CTCAE Grade ≥3 diarrhea despite appropriate use of loperamide and standard anti-diarrheal 
therapy for at least two days 
 
• CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at 
least three days 
 
• CTCAE Grade ≥3 rash despite standard medical management . 
 
• CTCAE Grade ≥3 fatigue lasting for more than seven days 
 
• All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an 
interruption of afatinib for more than 14 days until recovery to baseline or Grade 1, whichever is 
higher. 


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‡ 
If a patient has not responded to dermatological intervention and 
permanent discontinuation of afatinib is being considered, formal 
evaluation with dermatology is suggested. 
 
Figure 5 : Dose modification for skin toxicity 
 
*Patients will be evaluated by an institutional or local dermatologist 
 
 
 
 
9.8 Suggested medical management of afatinib and trastuzumab associated toxicities 
 
 
 
9.7.1 Suggested management of diarrhea following treatment with afatinib and 
trastuzumab. 
Close monitoring and proactive management of diarrhea is essential for successful  
treatment of patients with afatinib and trastuzumab. Early and appropriate intervention can 
prevent the development of more severe diarrhea. Diarrhea is the major dose-limiting toxicity 
CTCAEv4 Grade ≥3 Skin Reaction or intolerable Grade 2 
(e.g. clinically significant or intolerable) 
Continue dermatological treatment 
Interrupt afatinib dosing for up to 14 days 
Resolves to 
CTCAEv4 Grade 
Resolves to 
CTCAEv4 Grade 2 
Remains at 
CTCAEv4 Grade ≥3 
Reinstate afatinib at 
initial dose 
and continue 
dermatological 
treatment 
Reinstate afatinib at 
reduced dose 
and continue 
dermatological treatment 
‡
Discontinue 
afatinib 
CTCAEv4 Grade 1 or 2 Tolerable Skin 
Reaction 
Initiate dermatological treatment 
Continue afatinib at current dose 


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of afatinib and trastuzumab with onset typically occurring early in the course of treatment 
(during the first few weeks of treatment). Primary prophylactic use of antidiarrheal 
medication is mandatory for patients taking afatinib and trastuzumab, unless constipation is 
present at baseline. Patients with constipation at baseline will be excluded from prophylactic 
treatment. Loperamide is the recommended standard therapy to treat diarrhea in this study. 
Alternative antidiarrheal medication proposal will be based on investigator discretion and the 
reason documented in the source documents. 
. Second-line antidiarrheal treatments and adjunctive therapies (e.g., Lomotil (Diphenoxylate 
and Atropine) (or equivalent as approved by the Sponsor) are also recommended for use 
when appropriate. 
 
Inform patients that they will experience diarrhea while taking protocol treatment. 
• 
Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first dose of 
afatinib and trastuzumab, followed by 2 mg (1 tablet/capsule) every 6- 8 hours for 1 
cycle of therapy. Patients should be given prescription of Lomotil at the initiation of 
afatinib therapy. For patients with persistent Grade 1 diarrhea (<4 stools per day 
above baseline) on loperamide, Lomotil® (diphenoxylate hydrochloride and atropine 
sulfate) 1 tablet (2.5 mg) every 6 to 8 hours should be added (or per investigator 
discretion). 
• 
Patients with baseline constipation are exempt from mandatory prophylactic 
loperamide after discussion with site PI. 
• 
Prophylactic loperamide administration may continue for subsequent cycles at the 
physician's discretion. 
• 
For Grade 2 diarrhea during Cycle 1 (4 to 6 stools per day above baseline, despite 
intensive anti-diarrheal therapy), consider adding tincture of opium or octreotide 
(short-acting) 150 µg subcutaneous [SC] injection 3 times a day, or after initial dose 
of short-acting octreotide, if well tolerated, a single dose of octreotide LAR 20 mg by 
intramuscular injection (equivalent medication may be used with approval of the 
Sponsor). 
• 
Instruct patients to promptly report diarrhea symptoms. 
• 
Instruct patient to record the number of stools per day and the dose of any anti- 
diarrheal medication taken each day for the first cycle of therapy only 
 
9.7.2 Management of nausea and vomiting following treatment with afatinib and 
trastuzumab 
Nausea and vomiting may significantly affect patients‟ adherence to the treatment and their 
quality of life. In order to reduce the occurrence and the intensity of emesis, the patients 
should be treated with an aggressive antiemetic program such as the following: 
 
CTCAE Grade 
Antiemetic treatment 
Nausea = Grade 0 
and 
Vomiting = Grade 0 
No antiemetic prophylactic treatment 
Nausea = Grade 1 
and 
Vomiting = Grade 0 
Antiemetic treatment 
Nausea = Grade 2 
and 
Antiemetic treatment1 
Pause afatinib and trastuzumab treatment if 


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1Antiemetic treatment should follow the recommendations given in the Consensus Statement of the 
Antiemetic Subcommittee of the Multinational Association of Supportive Care in cancer (MASCC): 
Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus 
Conference. 2 Baseline is defined as the CTCAE grade at the start of treatment 
 
After a treatment pause the dose of afatinib should be reduced according to the dose reduction 
scheme table. In case of nausea and/or vomiting ≥ CTCAE Grade 2, appropriate hydration (1.5 
L/m2/day plus hydration deficit) must be ensured. 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
≤2 weeks11 
prior to 
start 
≤1months 
prior to start 
Cycle 11 
Cycle 2 and 
onwards
2
 
EOT3 
Week # 
1 
2 
3 
4 
1 
2 
3 
4 
Informed consent 
X 
Pretreatment core biopsy 4 
X 
Post-treatment core biopsy5 
X 
Optional third biopsy17 
X 
Research Bloods Collection for 
IMPACT testing14,  15 
X15 
X15 
Research Bloods Collection for 
cfDNA14,  16 
X16 
X16 
X 
History, concomitant medications, 
and toxicity assessment 
X 
X 
X 
X 
X 
X 
X 
Physical exam, vital signs6, and 
performance  status6,10 
X 
X 
X 
X 
X 
X 
X 
Complete blood count, 
comprehensi ve metabolic panel, 
magnesium
10
 
X 
X 
X 
X 
X 
X 
X 
ECG6 
X 
Echo or MUGA
7
 
X 
Serum Pregnancy  Test8 
X 
Tumor  assessment
9,10
 
X 
X 
89Zr-trastuzum ab-PET13 
X 
X 
Dispense afatinib 
X 
X 
Afatinib diary/compliance revi ew 
X 
X 
X 
Paclitaxel 
X 
X 
X 
X 
X 
X 
Afatinib daily treatment12 
Continuous daily 
Termination of trial medication 
X 
Conclusion of subject 
participation 
Vomiting = Grade 0 
Nausea = Grade 0, 1 or 2 
and 
Vomiting = Grade 1 or 2 
Grade 2 
vomiting or Grade 2 nausea persist for 7 or 
more consecutive days despite optimal 
supportive care. Resume treatment when 
CTCAE Grade ≤ 1. 
Vomiting ≥ Grade 3 
or 
Nausea ≥ Grade 3 
Antiemetic treatment
1
 
Pause afatinib and trastuzumab treatment until 
return to 
CTCAE Grade ≤ 1 or baseline2. 


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1. Each treatment Cycle consists of 28 days and will be repeated until tumor progression 
(PD according to RECIST v1.1) confirmed by tumor imaging. 
2. AE assessments will be performed Day 1, 8, and 15 and will coincide with treatment 
appointments. 
3. EOT: end-of-treatment visit; within 14 calendar days after permanent termination of trial 
drug(s). If permanent discontinuation of 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 evaluate 
toxicities can be substituted. 
4. The pretreatment biopsy can occur any time prior to initiation of afatinib, following 
consent. Patients who have previously provided samples at any time after trastuzumab 
resistance will be exempt. 
5. The post-treatment biopsy will be conducted for MSK patients only and should happen 
one week (+ 7 day window) after initiation of therapy per the site investigator‟s discretion. 
The patient is to continue taking afatinib without interruption. 
6. Vital signs per institutional standard of care. 12-Lead resting digital electrocardiogram 
(ECG) will be performed at Screening. ECG will be repeated and as clinically indicated. 
7. LVEF (Echo or MUGA) should be initially assessed during screening visit. Per the site 
investigator‟s discretion, an Echo or MUGA should be repeated on Day 1 of Cycle 3 and 
every 12 weeks thereafter (Cycle 6, 9, 12 etc.) .Assessments on study may vary up to 
one to fourteen (1-14) days 
8. For women of childbearing potential. 
9. A CT or MRI will be obtained at baseline within two weeks of study enrollment. Repeat 
radiographic evaluation will be obtained after the first eight weeks, and then every eight 
weeks ±14 days thereafter. Patients with a partial/complete response require a 
confirmatory scan at least four weeks after the initial scan documenting response (see 
Section 12.0). The same imaging modality performed at baseline (CT or MRI) will be 
repeated at subsequent imaging. Patients requiring CT scans earlier than allowed 
indicated window due to physician discretion or suspicions of disease progression is 
permitted on study. 
10. Because of the potential need for blood test, CT/MRI scan, and physician visit scheduling 
to vary (due to both physician and patient issues), to avoid violation of, and deviation from 
the protocol, blood tests, CT/MRI scans, and physician visits (including physical exam, 
vitals, blood pressure, weight, performance status, and concomitant medications) may 
vary by up to one to fourteen (1-14) days from a strict 28 day schedule. The study 
treatment will not be interrupted, with the next cycle beginning before the patient is 
evaluated for toxicity. Vital signs per institutional standard of care 
11. If screening evaluations are done within 14 days of start of treatment, Cycle 1 Day 1 
evaluations need not be repeated. 
12. Afatinib should be taken continuously, but afatinib may be skipped if clinically 
indicated 
13. In select patients, 89 Zr-trastuzumab PET uptake will be evaluated pretreatment and 3 
weeks following initiation of study treatment 
14. Additional samples may be collected during different time points of the study after 
discussion with MSK PI 
15. The baseline research blood collection will occur within one month of treatment on 
Cycle 1, Day 1 (EDTA tube). Additional research blood collection for IMPACT (EDTA 
tube) will occur throughout the study dependent on MSK PI discretion. 
16. cfDNA research bloods collected: baseline (collection will occur on Cycle 1, Day 1 
before treatment is administered), every 8 weeks, and at treatment discontinuation. 
17. At the discretion of the MSK Principal Investigator, select participants who show 
response on this study and then progress may be asked to have an optional third 


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biopsy. 
 
 
10.1 Evaluations during treatment 
 
Please note, because of the potential need for blood test, CT/MRI scans, and physician 
visit scheduling to vary (due to both physician and patient issues), to avoid violation of, 
and deviation from, the protocol, all visits and corresponding evaluations may vary up to 
one to fourteen (1-14) days from a strict 28 day schedule. If screening evaluations are done 
within 14 days of start of treatment, Cycle 1 Day 1 evaluation need not be repeated. 
 
o History, concomitant medications, physical exam, vital signs, performance status assessment, 
and AE assessments will be performed Day 1, 8, and 15 and will coincide with treatment 
appointments. Vital signs per institutional standard of care. 
Complete blood count will be performed Day 1, 8 and 15 and will coincide with treatment 
appointments. Comprehensive metabolic panel on Week 1, of each cycle or as clinically indicated. 
o Afatinib diary to be collected on Week 1 of each new cycle. 
o A repeat CT or MRI of measurable disease at eight weeks, and then every eight weeks thereafter. 
The same imaging modality performed at baseline (CT or MRI) will be repeated at subsequent 
imaging. 
 
Evaluations at end-of-treatment visit 
• 
History, concomitant medications, and toxicity assessment. 
• 
Physical exam, vital signs, and performance status. 
• 
Afatinib diary to be collected. 
• 
Complete blood count, comprehensive metabolic panel, Magnesium. 
• 
Unused study medication to be returned to the local institution‟s pharmacy. 
 
 
10.2 Correlative studies 
 
 
We will profile genomic alterations in key cancer-associated genes found to drive trastuzumab 
resistance in preclinical studies using the IMPACT assay developed at MSKCC. To interrogate 
the mechanisms underlying response and resistance (de novo and acquired) to targeted therapy 
using pretreatment, on-treatment, and/or post treatment/progression tumor tissue, patients will 
be asked to provide tissue from pretreatment, post-treatment, and post-progression on 
afatinib/trastuzumab therapy, and blood (one 3mL EDTA tube) one month prior to starting 
treatment and at any time-point on study. 
 
 
Pre-treatment tissue for the correlative studies evaluating the biologic effects of afatinib and 
paclitaxel will be obtained for all patients whose tumors are feasible to biopsy. Per the site 
investigator‟s discretion, a post-treatment biopsy (within 1 week (+7 day window) of initiation of 
afatinib) will also be obtained for MSK patients only. This protocol through obtaining tissue 
specimens prior to initiation of afatinib and paclitaxel therapy in patients with trastuzumab 
resistant HER2-positive esophagogastric adenocarcinoma, will evaluate the relevance of 
putative mechanisms of trastuzumab resistance in vivo. In addition, patients will be asked to 


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Page 42 of 69 
 
 
 
 
consent to tumor banking such that both frozen and fixed tumor cores can be utilized for future 
investigations. 
 
 
The pretreatment biopsy can occur any time prior to initiation of afatinib, following consent. The 
post-treatment biopsy for MSK patients only should happen within 1 week (+ 7 day window) after 
the initiation of therapy. At the discretion of the MSK Principal Investigator, select participants 
who show response on this study and then progress may be asked to have an optional third 
biopsy. The patient will continue taking afatinib without interruption. Pre- and post-treatment 
tumor biopsies will be performed 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 afatinib and trastuzumab therapy in patients with HER2- 
overexpressed esophagogastric cancer with trastuzumab-resistant disease. All patients with 
disease technically amenable to biopsy will be asked to undergo a pre-treatment with afatinib 
biopsy of their metastatic disease or primary tumor as well as consent to evaluate their primary 
tumor biopsy or resection specimens for comparative studies. Per the investigator‟s discretion, a 
post-treatment biopsy will be obtained for MSK patients only. Specific tumors that have 
progressed on trastuzumab will be biopsied if at all possible. Patients who meet inclusion criteria 
will be assessed for a site of disease that is amenable to biopsy. 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 a 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 section 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 judgment of the endoscopist, 
surgeon or interventional radiologist, but ideally will be less than or equal to four. In the 
unlikely event that only one core specimen is obtained for local recurrenc e, priority will be 
given for use for clinically necessary studies. 
• 
For the purposes of mutational analysis, RNA isolation will be carried out after 
macrodissection using approximately 25 µg of gross tissue from the tumor specimens. RNA 
extraction will be performed using TRIZOL reagent (Gibco-BRL, Gaithersburg, MD) and the 
Qiagen RNeasy Kit (Qiagen, Valencia, CA). RNA purity and quality will be assessed by 
spectrophotometry at A260 and A280 and visualization after running on a denaturing  
agarose gel. The individual exons of the HER2 gene will be amplified by RT-PCR and 
sequenced using standard methods. Hotspot mutations in PIK3CA will be determined using a 
Sequenom prevalidated assay. These studies will test if mutations in HER2, PI3KCA, or 
PTEN are found in patients with resistance to anti-HER2 therapy. 


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Page 43 of 69 
 
 
 
 
• 
After one week (+7 day window) of therapy, MSK patients only will have a repeat biopsy per 
the investigator‟s discretion to assess target inhibition. The procedures used to obtain and 
analyze the tissue samples will be as described above for the pretreatment tissue sample. 
 
 
Participating sites will notify the Multicenter staff at MSKC when specimens are shipped 
using the study requisition form. Details regarding the collection and shipping processes are 
outlined in the Lab Manual. 
 
 
In regards to the return of genomic data, the protocol consent form asks participants for 
permission for re-contact to discuss research findings that may occur during the course of 
next generation sequencing (i.e. IMPACT assay). These incidental findings may be critical to 
the patient and/or family‟s preventative care. If an MSKCC participant agrees to be re- 
contacted, he or she will not be told the specific results of the research test, but will be 
informed that his or her samples were analyzed and a potential risk was uncovered. If the 
participant is interested in further discussion of the research findings, he or she will be asked 
to come into the MSKCC Clinical Genetics Service for counseling and specific genetic 
testing. If a participating site participant agrees to have tissue sent to MSK for our secondary 
objective with IMPACT testing and s/he wished to be re-contacted in the consent form, then 
any significant incidental findings uncovered during IMPACT testing will be relayed to the 
treating physician at the treating institution so they may carry out their institution‟s policy with 
regard to offering the patient confirmatory testing and genetic counseling. 
 
 
In the event an investigator‟s research identifies a finding that he or she believes should be 
communicated to the participant, the investigator shall communicate this to the IRB Genomic 
Advisory Panel. The finding will be reviewed by the IRB/PB Genomic Advisory Panel (GAP) 
to determine whether the incidental finding should be discussed with the participant. In the 
event that the group convened by the IRB determines that the finding should be discussed 
with the participant, and the participant has consented to be re-contacted, then the 
treating/consenting physician shall be contacted by the IRB and asked to refer the participant 
to the Clinical Genetics Service for further discussion of the research finding. 
 
 
For MSK patients, after appropriate counseling and consent, the Clinical Genetics Service 
will request permission to confirm the result in a New York DOH-approved laboratory prior to 
communication of the specific result. If the patient is not available (e.g. deceased) then the 
surrogate designated on the consent will be contacted and the above should occur. 
 
 
If the subject is not an MSK patient and is being treated at one of the participating  
institutions, the findings will be returned to the outside Principal Investigator and local policies 
on returning these research findings to the patient should be followed. 
 
 
Lastly, patients will be asked to consent to tumor banking such that both frozen and fixed 
tumor cores can be utilized for future investigations 


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When samples are to be analyzed, the individual investigator needs to write an IRB 
biospecimen protocol. This protocol is fast-tracked through Research Council review and is 
reviewed at 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). 
 
 
 
10.2.1 Cell-Free DNA (cfDNA) 
Preliminary data obtained in collaboration with MSKCC Laboratory Medicine Core (E. 
Peerschke and A. Samoila) demonstrates that cfDNA 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 (on Cycle 1, Day 1 prior to treatment 
administration), every 8 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) 
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 
 
 
 
10.2.2 MSK patients only: Functional Imaging with 89 Zr-trastuzumab PET 
In select patients, 89 Zr-trastuzumab PET uptake pretreatment and 3 weeks following initiation 
of study treatment in patients will be examined and correlated with changes in tumor size on 
CT scan at 9 weeks. We will compare the proportion of patients with a drop in 89 Zr- 
trastuzumab tumor uptake on PET (pretherapy 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. 89 Zr-trastuzumab PET imaging will be an exploratory 
study, with only a select subset of patients on this trial with measurable disease undergoing 
imaging with 89 Zr-trastuzumab PET. If deemed appropriate, the patients will be approached 
for participation in the Pilot imaging trial with 89 Zr-trastuzumab PET in HER2+ EG tumors, 
MSKCC protocol IRB13 -165. 


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11.0 
TOXICITIES/SIDE EFFECTS 
 
For definition of dose limiting toxicity and suggested medical management of afatinib associated 
toxicities refer to Sections 9.1 and 9.2 
 
Afatinib 
 
Afatinib has shown an acceptable safety profile, on the basis of results from the Phase I and Phase 
II studies conducted to date. The most commonly reported treatment-emergent adverse events 
(TEAEs) were skin and GI disorders, and included rash, diarrhea, nausea, and vomiting. Below is a 
list of TEAEs based on their likelihood of occurrence: 
 
Likely: 
 
• 
Diarrhea that could be severe and may require hospitalization and/or fluid 
replacement 
• 
Skin problems (including rash, acne, dryness, itching, redness, and infection) 
• 
Pain, irritation and swelling of the inner lining of the mouth (stomatitis), food pipe , 
and nose (nasopharyngitis) 
• 
Inflammation, cracking and pain in fingernail--paronychia 
• 
Tiredness and weakness 
• 
Loss of appetite and weight 
• 
Nausea 
• 
Vomiting 
• 
Nose bleeding, runny nose 
• 
Difficulty breathing 
• 
Cough 
• 
Dryness, irritation, and painful sensations of the eyes 
• 
Headache 
• 
Constipation 
• 
Muscle spasms 
• 
Abnormal liver tests 
• 
Sleeplessness 
• 
Back pain 
• 
Cracking, swelling of the lips 
• 
Dizziness 
• 
Chemical imbalances in the blood such as low potassium, salt (sodium) from 
diarrhea/dehydration 
• 
Chest pain 
• 
Fever 
• 
Runny nose 
 
Less Likely: 
• 
Anemia (low level of iron in your blood) 
• 
Dehydration commonly a result of diarrhea/vomiting that may affect kidney function 
• 
Abnormal taste sensations 
• 
Painful swelling of the palms of the hands and the soles of the feet 
• 
Stomach pain and heartburn 
• 
Infection in the urinary tract 
• 
Generalized swelling 
• 
Weight loss 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 46 of 69 
 
 
 
 
• 
Convulsion/seizure 
• 
Interstitial lung disease (ILD) 
• 
Kidney failure 
• 
Pulmonary embolism (blood clot to lung) 
• 
Heart failure 
 
Rare but Serious: 
• 
Septic shock (serious blood infection) 
• 
Pancreatitis (inflammation of pancreas that could be severe) 
• 
Stevens-Johnson Syndrome (a severe and possibly fatal skin condition) 
• 
Stroke (including bleeding within the brain) 
• 
Heart attack 
• 
Inflammation of the cornea 
• 
Gastrointestinal perforation 
• 
Liver failure 
 
 
Of 1717 patients who received afatinib, interstitial lung disease (ILD) or adverse events indicating 
that a patient could have ILD occurred in five patients over 75 years of age (from a total 117 treated) 
and in fourteen patients less than 75 years of age (from a total 1600 treated). 
 
Paclitaxel 
Principal adverse effects include leukopenia and thrombocytopenia, alopecia, nausea, and vomiting. 
A complete listing of toxicities can be found in the paclitaxel package insert. 
 
Trastuzumab 
Principal adverse effects include cardiac dysfunction, infusion-associated symptoms, and 
potentiation of chemotherapy-related hematologic side effects. A complete listing of toxicities can be 
found in the trastuzumab package insert. 
 
11.1 Definitions of adverse events 
 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of 
a pre-existing condition, in a patient in a clinical investigation who received a pharmaceutical 
product. The event does not necessarily have to have a causal relationship with this treatment. 
Severity of adverse event 
The severity of the AE should be judged based on the following: 
The severity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4 in the CRDB. 
 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. Assessment of 
causal relationship must be recorded for each adverse event. 
 
Causality will be reported as either “Yes” or “No”. 
 
Yes: 
There is a reasonable causal relationship between the investigational product 
administered and the AE. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 47 of 69 
 
 
 
 
No: 
There is no reasonable causal relationship between the investigational product 
administered and the  AE. 
 
11.2 Malignant disease progression 
 
Expected fluctuations or expected deterioration of the underlying disease should not be recorded as 
an AE unless at least one of the following criteria is met: 
– 
The worsening of the disease constitutes an SAE. 
– 
Additional treatment is required; i.e., concomitant medication is added or changed. 
– 
An unexpected deterioration from baseline has occurred in the opinion of the 
investigator. 
 
11.3 Worsening of pre-existing conditions 
 
A pre-existing condition present at baseline, which remains unchanged during the trial, does not 
need to be recorded as adverse event. Any worsening of any pre-existing baseline condition should 
be reported as an adverse event. Examples of worsening of a preexisting condition that should be 
recorded as an AE are given below; 
• 
Worsening of condition meets the criteria for an SAE 
• 
Action is taken with the investigational drug (i.e. dose is reduced or treatment is 
discontinued) 
• 
Treatment is required (concomitant medication is added or changed) 
• 
The investigator believes a patient has shown a clear deterioration from baseline symptoms 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
All patients who receive at least one week of afatinib and trastuzumab combination therapy will be 
evaluable for toxicity and response. Patients who are unable to complete one week of afatinib 
therapy will not be evaluated for toxicity or response and will be replaced by a new patient. 
 
The primary endpoint of the study is the efficacy of the combination of daily afatinib and trastuzumab 
in terms of the overall clinical benefit defined as response rate (ORR) = stable  disease  (SD) 
complete response (CR) and partial response (PR) at 4 months by RECIST 1.1 criteria assessed 
after every 8 weeks ±14 days of therapy. Confirmatory scans should be obtained no less than four 
weeks following initial documentation of objective response. This is defined as the percentage of 
patients who have achieved either an objective complete or partial target lesion response that is 
confirmed on the RECIST 1.1 criteria. Complete or partial responses will be confirmed with repeat 
CT evaluation after 4 weeks. Target lesions must have a minimum size of at least one diameter of 
10mm for liver, soft tissue lesions, lung, and skin. Pathological nodes must be at least 15mm in the 
short axis to be considered target lesions. The primary tumor is not considered measurable disease. 
Recurrent or metastatic lesions within a prior radiation fie ld are acceptable as long as disease has 
progressed in the radiation field by RECIST 1.1 criteria. The same imaging modality performed at 
baseline (CT or MRI) will be repeated at subsequent imaging. 
 
Secondary endpoints include toxicity, safety and tolerability, progression free survival (PFS) at 4 
months. 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. Given the small sample size, the analysis of correlative 
biomarkers will be exploratory and hypothesis generating. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 48 of 69 
 
 
 
 
Assessment of stable disease will be based on RECIST 1.1 criteria. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient develops progressive disease he/she will be taken off study and referred for 
alternative therapy. If at any time the patient develops unacceptable toxicity that fails to resolve after 
a maximum treatment delay of 4 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. If the off study scan shows SD and the patient has been on study for 
less than 3 months than the patient will be considered as non responder whereas if the patient has 
been on study for longer than 3 months and has SD at the off study scan then the patient will be 
counted as having had clinical benefit. 
 
A patient will be withdrawn from the study treatment in the following circumstances: 
 
● the patient is no longer able to participate in the study (e.g., AE, surgery, concomitant diagnoses, 
concomitant therapies or administrative reasons); in such a case the Investigator‟s reason for a 
patient‟s removal must be recorded in CRDB. 
● Patient withdrawal of 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 4 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 site Principal Investigator. The dose-reduction scheme provided 
should be followed in this case. 
● Repeated episodes of drug-related toxicity despite dose reduction to afatinib 20 mg or dose 
interruption. 
● Documented progressive disease. 
 
As soon as a patient is withdrawn from the study treatment, the end-of-treatment (EOT) visit must be 
performed (not if patient has withdrawn consent). 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 from treatment with afatinib and trastuzumab (i.e., with either an 
objective tumor response or the absence of disease progression), may continue to receive additional 
treatment courses. Patients with radiologically documented progressive disease should be removed 
from the study unless the investigator judges it to be of clinical benefit for the patient to continue on 
trial therapy. 
 
 
 
 
14.0 
BIOSTATISTICS 
 
The purpose of this Phase II study is to determine the efficacy of afatinib in patients with advanced 
HER2- positive esophagogastric cancer. The primary endpoint of the study will be measured by the 
overall clinical benefit defined as best response (ORR) = stable disease (SD), complete response 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 49 of 69 
 
 
 
 
(CR), or partial response (PR) at 4 months by RECIST 1.1 criteria following the start of therapy. 
Patients are evaluable for response if they complete at least one week of treatment. Patients who  
are unable to complete one week of therapy will not be evaluated for toxicity or response and will be 
replaced by a new patient. The patients will remain on study until excessive toxicity or disease 
progression. Patients that come off study before 4 months for excessive toxicity will be followed up 
with a scan to assess the response at 4 months. However patients that are lost to follow up without a 
4 months scan will be treated as events (non-responder). 
 
 
A Simon‟s minimax two-stage design will be used with unacceptable response rate of 5% against an 
acceptable response rate of 20%. The design chosen has a 5% type I error rate and 80% power. 
There is no standard of care treatment at the time of trastuzumab resistance that has been shown to 
reliably induce a second response in these patients. The 5% was chosen because the cohort of 
patients that will be accrued for this study will be heavily treated, with no standard of care options for 
treatment. Based on the background data presented in section 3.5.1, we have chosen a target 
response rate below 5% will not be worthy of further consideration. We plan to treat 13 patients in 
the first stage. If 1 or more responses are observed in the first stage, then another 14 patients (for 
total of 27 patients) will be treated on the study. If 4 or more objective responses are observed in 
these 27 patients, then the treatment with afatinib will be considered worthy for further investigation 
in HER2-positive gastric cancer. Probability of early termination is 51%. 
 
 
OS, PFS and PFS at 4 months will be estimated using the Kaplan-Meier method. Toxicity, safety  
and tolerability of afatinib will be assessed and summarized using descriptive statistics. The type, 
frequency, severity, timing, and relationship of each adverse event will be determined as per the NCI 
Common Toxicity Criteria, version 4. Toxicity during cycle 1 and subsequent cycles will be reported. 
Once dosed, all patients will be included in the safety analysis. 
 
 
Pre- and post-treatment (after 1 week of afatinib (+7 day window)) tissue for the correlative studies 
evaluating the biologic effects of afatinib will be obtained. An exploratory analysis of correlative 
biomarkers will be performed. Expression levels of the different biomarkers (categorized as binary) 
in pre- and post-treatment tissue samples will be correlated with overall clinical benefit to afatinib 
using Fisher‟s exact test. To evaluate whether changes in the expression level of the different 
biomarkers between pre- and post-treatment correlate with overall clinical benefit to afatinib, 
conditional logistic regression will be employed to account for the paired nature of the data. We 
anticipate that all patients on whom the biopsies are feasible will have pre- and post-treatment 
biopsies. 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. 
 
 
June 2013 amendment: 
 
 
Afatinib has single agent activity in HER2 positive esophagogastric cancer. With one PR, the study 
met the criteria for expansion of the accrual based on original Simon‟s minimax two-stage design. 
Preclinical data in gastric cancer and clinical experience in lung and breast cancers suggest that we 
can improve this response rate by continuing trastuzumab beyond progression and adding afatinib. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 50 of 69 
 
 
 
 
An exact binomial single stage design will be used with unacceptable response rate of 7% against  
an acceptable response rate of 25%. Based on recent data emerging on single agent afatinib  
activity, we have chosen a target response rate below 7% for the combination of afatinib and 
trastuzumab will not be worthy of further consideration. We plan to treat a total of 26 patients with 
afatinib and trastuzumab. If 5 or more responses are observed in these 26 patients, then this regimen 
will be considered worthy for further investigation in HER2-positive esophagogastric cancer.         
The design chosen has a 5% type I error rate and 80% power. 
 
 
Three patients will be treated with Afatinib 30 +trastuzumab q2wks with loperam ide prophylaxis. If no 
patients experience Grade ≥3 diarrhea with prophylactic loperamide, a new cohort of patients will be 
enrolled at dose Afatinib 40 mg +trastuzumab. If however 1 of 3 patients have Grade ≥3 diarrhea at 
dose 30 mg, the cohort will be expanded to 6. If no further DLT occurs, patients will be enrolled at 
dose Afatinib 40 mg +trastuzumab. If 2 of 6 patients experience Grade ≥3 diarrhea, the MTD will be 
defined as the dose-level below which this occurred. If 2 of 3 or 2 of 6 subjects experience DLT at 30 
mg then Afatinib will be deescalated to 20 mg. 
 
 
April 2016 amendment: 
 
 
Initially, this was a single-agent afatinib study in trastuzumab refractory patients. We subsequently 
amended the study to treat patients with afatinib/trastuzumab based on efficacy of 
afatinib/trastuzumab demonstrated in the preclinical model. 
 
 
We treated 12 patients with afatinib and trastuzumab with prophylactic loperamide and frequent 
toxicity assessments due to the concerns of excessive diarrhea. Afatinib 30 mg (lowered from 40 
mg) and trastuzumab was associated with a higher rate of Grade 3 treatment-related toxicity.. 
Intolerable Grade 2 diarrhea required dose reductions in 42% of patients treated with afatinib and 
trastuzumab. Diarrhea was difficult for patients to tolerate despite use of loperamide and Lomotil. 
 
 
The combination of afatinib and trastuzumab would have been deemed promising if 5 or more 
responses would have been observed out of the proposed sample size of 26 patients. Given that 
only 1 response was observed out of 12 patients treated, if the true response rate for afatinib 
+trastuzumab is 25%, the probability of observing 4 or more responses out of the remaining 14 
patients treated with afatinib and trastuzumab would be 48%. Therefore, the power of the study 
would be very low. 
 
 
This power is further diminished to 4% if the true response rate is 10%, and it‟s 15% if the true 
response rate is 15%. The probability is still low: 64% if the response rate is 30%. So the probability 
(power) of having a successful trial (having continued until the end of 26 patients) is small under 
reasonable response rates. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-166 A(14) 
Approval date: 13-Sep-2018 
Page 51 of 69 
 
 
 
 
The purpose of this amendment is to generate safety and toxicity data for a combination of afatinib 
with paclitaxel in HER2-positive EG cancer. We plan to stop accrual to the afatinib trastuzumab 
combination and treat the remaining 14 patients with afatinib and paclitaxel. 
 
 
A sample size of 14 patients will provide 90% probability to observe at least 1 AE if  the  true 
incidence of the AE in the population is 15% or more. This probability is 77% if the true underlying 
AE rate is 10% and it is 51% if the true underlying AE rate is 5%. Exact 95% confidence intervals 
will be computed for the incidence of AEs. 
 
 
Descriptive statistics will be used to calculate and tabulate for endpoints assessing safety, 
tolerability, and anti-tumor activity in each treatment cohort: 1) afatinib, 2) afatinib and trastuzumab, 
3) afatinib and paclitaxel. Progression-free and overall survival will be analyzed using Kaplan-Meier 
methodology. The biomarkers' objectives will be accomplished across all the 3 cohorts. If the 
combination of afatinib and paclitaxel is proven tolerable in this cohort of patients, we plan to further 
explore this combination in a randomized Phase II trial. 
 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
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. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
15.1.1  Registration for Participating Sites 
 
Central registration for this study will take place at MSK. 
To complete registration and enroll a participant from another institution, the site must 
contact the MSK study coordinator to notify him/her of the participant registration. 
 
The following documents must be sent to the MSK study coordinator for each enrollment 
within 24 hours of the informed consent form being signed: 
 
• 
The completed or partially completed MSK eligibility checklist 


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Page 52 of 69 
 
 
 
 
• 
The signed informed consent and HIPAA Authorization form 
• 
Supporting source documentation for eligibility questions (e.g. laboratory results, 
pathology report, radiology reports, MD notes, physical exam sheets, medical history, 
prior treatment records, and EKG report). 
 
Upon receipt, the MSK study coordinator will conduct an interim review of all documents. If 
the eligibility checklist is not complete or source documentation is missing, the participant will 
be registered PENDING and the participating site will be responsible for sending the 
completed registration documents within 30 days of the consent. 
 
If the external registration submission is complete, the participating site IRB has granted 
approval for the protocol, and the participating site is in good standing, the MSK study 
coordinator will send the completed registration documents to the MSK Protocol Participant 
Registration Office for participant enrollment as stated in the protocol. 
 
Once the participant is registered, the participant will be assigned a protocol participant 
number in the MSK Clinical Research Database (CRDB). This number will be relayed back to 
study staff at the registering participating site via e-mail and will serve as the enrollment 
confirmation.  The number is unique to the participant and must be written on all data and 
correspondence for the participant. 
. 
 
15.3 
Randomization 
 
This research study does not require randomization procedures. 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
 
The data collected for this study will be entered into a secure database. 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. 
 
 
Tumor slides will be stored in the MSKCC pathology laboratory. Results from laboratory 
studies will include photomicrographs of IHC studies, computer files of sequencing data, and 
computer files from microarray 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 CRDB with access limited to study investigators. 
 
 
16.1.1 Data and Source Documentation for Participating Sites 
 
Data 


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The participating sites will enter data remotely into electronic Case Report Forms (eCRFs) 
using the internet based system CRDBi-Multicenter. Data entry guidelines have been 
generated for this study and participating site staff will receive database training prior to 
enrolling the first participant. The participating site PI is responsible for ensuring these forms 
are completed accurately and in a timely manner. A Data and Source Document Submission 
Timeline is shown in section 16.0.2. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into eCRFs. Relevant source documentation to be submitted 
throughout the study includes: 
• 
Baseline measures to assess pre-protocol disease status (ex. CT, PSA, bone 
marrow) 
• 
Treatment records 
• 
Toxicities/adverse events that meet study reporting requirements not previously 
submitted with SAE reports 
• 
Response designation 
• 
Any other forms of source documentation required per protocol 
 
Source documentation must include a minimum of two identifiers to allow for data  
verification. MSK will maintain the confidentiality of any subject-identifiable information it may 
encounter. 
 
 
16.1.2 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSK according to 
the chart below. 
 
Table 1: Data and Source Submission Timelines 
 
Time point 
Data 
Source Documentation 
Baseline 
Within 24 hours of consent 
(see section 15. 1.1) 
Within 24 hours of consent 
(see section 15. 1.1) 
Study Visits 
Within 14 days of the study visit 
Within 14 days of the study visit 
Serious 
Adverse Events 
Within 3 days of event(see section 17.2.2); 
Updates to be submitted as available 
Within 3 days of event (see section 
17.2.2) 
 
 
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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Page 54 of 69 
 
 
 
 
16.1.1 Quality Assurance for Participating Sites 
 
Monitoring 
Each data collection site including MSK will be monitored periodically by MSK. Monitoring 
visits will be conducted every 4-8 weeks, dependent upon the protocol and patient accrual 
activity. The monitor and the participating site will identify a mutually agreeable time for each 
monitoring visit. At least 10 business days ahead of the visit, the monitor will send the site a 
notification letter that details the date and expectations of the visit. Monitoring may be 
conducted remotely or in-person. The monitor must be allowed access to all protocol 
regulatory and source documents to assess compliance with the protocol, federal regulations 
and GCPs. The monitor will assess all data for completeness of source documents and to 
confirm data being recorded in the eCRFs is accurate. If monitoring will be done remotely, 
site must agree in advance to provide source documents as required. During onsite visits,  
the monitor will also inspect and review the facilities and investigational product storage area. 
The participating site will maintain accurate records of dispensing of study drugs for drug 
accountability. Drug accountability will be reviewed at monitoring visits. Study drug and 
bottles must be retained until the monitor performs drug accountability of the study drug(s). 
 
The site Investigator(s) and/or an authorized member of the Investigator‟s staff should allow 
sufficient time during monitoring visits to discuss findings. The Investigator(s) or an 
authorized member of the Investigator‟s staff will make any necessary corrections during and 
between monitoring visits. 
 
Auditing 
Each participating site accruing participants to this protocol may be audited by MSK for 
protocol and regulatory compliance, data verification and source documentation. Audits of 
selected participant records may be conducted on-site or remotely. 
 
Audits will be summarized and a final report will be sent to the PI at the audited participating 
site within 30 days of the audit. The report will include a summary of findings, participant- 
specific case review, recommendations on any performance and/or shortcomings and 
request for corrective action, when necessary. When corrective action is required, the 
participating site must reply within 45 days of receipt of the audit report with their corrective 
action plan. 
 
16.1.2 Response Review 
 
Since therapeutic efficacy is a stated primary objective, all sites participants‟ responses are 
subject to review by MSK‟s Therapeutic Response Review Committee (TRRC). Radiology, 
and additional lab reports  will need to be obtained from the participating sites for MSK TRRC 
review and confirmation of response assessment. These materials must be sent to MSK 
promptly upon request. 
 
 
16.2 
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 


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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. 
 
 
16.2.1 Department of Defense Monitoring 
 
A. Per Department of Defense Instruction (DoDI) 3216.02, a Research Monitor is required for 
the current protocol.  Dr. Chau Dang has been appointed as the independent research 
monitor with expertise consonant with the nature of risk(s) identified within the research 
protocol. 
Research monitor functions include: 
 
* 
observing recruitment and enrollment procedures and the consent process for individuals, 
groups or units, 
* 
overseeing study interventions and interactions, 
* 
reviewing monitoring plans and UPIRTSO reports; 
* 
overseeing data matching, data collection, and analysis 
However, at a minimum, the research monitor: 
* 
may discuss the research protocol with the investigators, interview human subjects, and 
consult with others outside of the study about the research; 
* 
shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor's report; 
* 
shall have the responsibility to promptly report their observations and findings to the IRB 
or other designated official and the HRPO. 
 
 
 
16.3 
Regulatory Documentation 
Site Activation 
Prior to implementing this protocol at MSK, the protocol, informed consent, HIPAA authorization and 
any other information pertaining to participants must be approved by the MSK Institutional Review 
Board /Privacy Board (IRB/PB). There will be one protocol document and each participating site will 
utilize that document. 


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The following documents must be provided to MSK before participating site can be initiated and 
begin enrolling participants: 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
• 
Participating Site IRB‟s Federal Wide Assurance number and OHRP Registration number 
• 
Participating Site 1572 
• 
Conflict of Interest forms for participating site Investigators on the 1572 
• 
Curriculum vitae and medical licenses for each investigator and consenting professional 
• 
Documentation of Human Subject Research Certification training for investigators, 
consenting professionals and key study personnel at the participating site 
• 
Documentation of Good Clinical Practice training for the participating site PI and co-PI 
• 
Participating site laboratory certifications and normals 
 
 
Upon receipt of the required documents, MSK will formally contact the participating site and grant 
permission to proceed with enrollment. 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSK and approved 
first by the MSK IRB/PB. Protocol amendments that affect MSK only (e.g. change in MSK Co- 
Investigator, MSK translation, etc.) do not require IRB review at the participating site(s). All other 
protocol amendments will be immediately distributed to each participating site upon receipt of MSK 
IRB/PB approval. 
 
Each participating site must obtain IRB approval for all amendments within 45 calendar days of MSK 
IRB/PB approval. If the amendment is the result of a safety issue or makes eligibility criteria more 
restrictive, participating sites will not be permitted to continue enrolling new participants until the site 
IRB approval of the revised protocol documents is granted and submitted to MSK. 
16.3.2 Additional IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from each participating site‟s IRB and the most current 
approved version of the informed consent form must be submitted to MSK within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of new 
participant enrollment. 
Deviations 
A protocol deviation on this study is defined as any incident involving non-adherence to an IRB 
approved protocol. Deviations typically do not have a significant effect on the rights, safety, or 
welfare of research participants or on the integrity of the resultant data. Deviations that represent 
unanticipated problems involving risks to participants or others, or serious adverse events should be 
reported according to sections 17.2 and 17.4 in this protocol. 
 
Deviations that do not adversely affect the rights and/or welfare of the participant or the scientific 
validity of the study and are related to protocol scheduling changes outside of the allowed window 
due to a holiday (e.g., New Year‟s, Thanksgiving, etc.) and/or inclement weather or other natural 


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event do not require reporting to the MSK IRB/PB.  However, they must be clearly documented in 
the patient‟s medical record. 
 
Prospective Deviations 
 
Deviations to the research protocol that involve an informed consent procedure change and/or 
treatment/pharmacy alterations that are not allowed by the protocol require prospective approval 
from the MSK IRB/PB prior to the change being carried out. Participating sites should contact the 
MSK PI who will in turn seek approval from the MSK IRB/PB. Deviations to the research protocol 
that involve patient eligibility will not be permitted. 
 
Retrospective Deviations 
 
Deviations that include a change or departure from the research protocol without prior approval from 
the MSK IRB/PB are considered retrospective deviations. Retrospective deviations should be 
reported to the MSK PI as soon as possible, who will in turn report the deviation to the MSK IRB/PB 
as per MSK guidelines. 
 
Participating Site IRB Reporting 
Participating sites should report all deviations to their institution‟s IRB per local guidelines. 
Approvals/acknowledgments from the participating site IRB for protocol deviations should be 
submitted to MSK upon receipt. 
 
Other correspondence 
Participating sites should submit all other correspondences to their institution‟s IRB according to 
local guidelines, and submit copies of official site IRB correspondence, including approvals and 
acknowledgements, to MSK. 
 
 
16.3.3 Document maintenance 
 
The MSK PI and participating site PI will maintain adequate and accurate records to fully document 
protocol implementation and allow data to be subsequently verified. 
The participating sites will ensure that all regulatory documents and participating site IRB 
correspondence are maintained in an on-site regulatory binder and sent to MSK as outlined within 
this protocol. The on-site regulatory binder will be reviewed by the designated study monitor at 
monitoring visits. A regulatory binder for each participating site will also be maintained at MSK within 
the institution‟s Protocol Information Management System (PIMS). 
 
After study closure, the participating sites must maintain all source documents, study related 
documents and eCRFs for 7 years. 
16.4 
Noncompliance 
 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments may be withheld until the outstanding issues have been 
resolved. 
17.1 
PROTECTION OF HUMAN SUBJECTS 


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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; afatinib 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 cost of pharmacokinetic studies 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. Afatinib will be provided to the patient 
without charge. Correlative tests will be performed without charge to the patient. 
 
No incentives will be offered to patients/subjects to participate in this study 
 
 
Inclusion of women and minorities 
MSKCC has filed forms HHS 441 (civil rights), HHS 641 (handicapped individual), HHS 639-A (sex 
discrimination) and HHS 680 (age discrimination); we also take due notice of the NIH/ADAMHA 
policy concerning inclusion of women and minorities in clinical research populations. Patients of all 
races, both males and female, will be enrolled into the protocol. In the New York metropolitan area, 
there is a high proportion of minority patients (e.g., African-American, Hispanic). In general, about 
15% of patients at MSKCC are members of minority ethnic groups. We will actively try to recruit 
minority patients to this protocol. 
 
 
Exclusion of children and lactating or pregnant women 
Children are excluded from this protocol because there is insufficient data to determine the safety of 
afatinib in children. In addition, the incidence of esophagogastric cancer in children is limited and 
because the majority are already accessed by a nationwide pediatric cancer research network. This 
statement is based on exclusion 4b of the NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects. Similarly, lactating and pregnant women are 
excluded because of the potential teratogenicity and embryotoxicity of afatinib. 
 
 
 
Future Unspecified Use of Correlatives: 
 
The protocol includes an informed consent document and research authorization that meets 
statutory guidelines. They 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 MSKCC will save some of the biospecimens to use for future research. 
 
Type of futur e 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 MSKCC 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 


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samples could be lost or ruined because of mechanical failure, and that MSKCC 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), then 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. 
 
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. 
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. 
 
Risks of research participation 
The greatest risk is release of information from health or research records in a way that violates 
privacy rights. MSKCC 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 
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 MSKCC 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 also indicates that samples and genetic information collected may be shared with other 
qualified researchers. Such information will not include identifying information such as name. It is 


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also stated in the consent and Research Authorization that research data (e.g. genomic sequence) 
may be placed into databases monitored by the National Institutes of Health, and may be made 
accessible to investigators approved by the U.S. government. The requirements for submission of 
genotype/phenotype data into the NIH GWAS Repository (or any other public database) will be 
outlined in the biospecimen analysis application, i.e. IRB Biospecimen Protocol. 
 
17.2 
Privacy 
MSKCC‟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 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of Serious 
Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
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: 


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• 
Subject‟s initials 
• 
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 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
 
 
The PI‟s signature and the date it was signed are required on the completed report. 
 
The CRDB SAE report should be completed as per the above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
17.3.1 Adverse event and serious adverse event reporting 
SAE reporting to Boehringer Ingelheim (BI). 
 
MSK shall report all SAEs and non-serious AEs that are relevant to a reported SAE by fax 
using BI IIS SAE form to BI Unique Entry Point as detailed below in accordance with the following 
timelines: 
• Within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least 
one fatal or immediately life-threatening event 
• Within ten (10) calendar days upon receipt of any other initial and follow-up SAEs. 
 
 
Boehringer Ingelheim Pharmaceuticals, Inc 
900 Ridgebury Road 
Ridgefield, CT 06877 
Fax: 1-203-837-4329 


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For each adverse event, the investigator will provide the onset date, end date, intensity, treatment 
required, outcome, seriousness, and action taken with the investigational drug. The investigator will 
determine the relationship and expectedness with the investigational drug to all AEs as defined in 
the listed adverse event section of Boehringer Ingelheim„s (BI‟s) Investigator Brochure for the 
Product. 
The investigator does not need to actively monitor patients for adverse events once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the clinical trial (including any protocol-specified 
follow-up period), it should be reported to BI if the investigator considers it relevant to the BI 
study drug. 
 
 
 
 
17.3.2 SAE Reporting for Participating Sites 
 
Responsibilities of Participating Sites 
• 
Participating sites are responsible for reporting all SAEs to their site IRB per local 
guidelines. Site IRB SAE approvals/acknowledgements must be sent to MSK upon 
receipt. 
• 
Participating sites are responsible for submitting the SAE Report Form to MSK within 
3 calendar days of learning of the event. 
• 
When a life-threatening event or death is unforeseen and indicates participants or 
others are at increased risk of harm, participating sites should notify the MSK PI as 
soon as possible but within 24 hours of the time the site becomes aware of the event. 
 
SAE contact information: 
 
Email: MSK Multicenter Study Coordinators 
AND 
Email: janjigiy@ mskcc.org 
 
 
Responsibilities of MSK 
• 
MSK is responsible for submitting all SAEs to the MSK IRB/PB and funding entities (if 
applicable) as described in the protocol. 
• 
MSK is responsible for informing all participating sites about all unexpected SAEs that 
are either possibly, probably, or definitely related to the study intervention within 15 
days of receiving the stamped SAE report from the MSK IRB/PB. 
• 
MSK is responsible for informing all participating sites within 24 hours or on the next 
business day about a life-threatening event or death that is unforeseen and indicates 
participants or others are at increased risk of harm. 
 
17.4 
Safety Reports 
 
MSK must submit outside safety reports to the MSK IRB/PB according to institutional 
guidelines. All outside safety reports will be made available to the participating sites. Outside 
safety reports that are reportable to the MSK IRB/PB will be distributed to the participating 
sites immediately upon receiving a stamped copy from the MSK IRB/PB. Participating sites 
will receive a special alert for any outside safety reports that warrant a significant change to 


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the conduct of the study. Outside safety reports that are not reportable to the MSK IRB/PB, 
will be sent to the participating sites monthly. 
 
Participating sites are responsible for submitting safety reports to their site IRB per their local 
guidelines. All site IRB approvals/acknowledgments of safety reports must be sent to MSK 
upon receipt. 
17.5 
Unanticipated Problems 
 
Unanticipated problems involving risks to participants or others (UPs) are defined as any 
incident, experience or outcome that meets all of the following criteria: 
• 
Unanticipated (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied; and 
• 
Related or possibly related to participating in the research (possibly related means there is a 
reasonable probability that the incident, experience or outcome may have been caused by 
procedures involved in the research); and 
• 
Suggests that the research place participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
Participating sites are responsible for reporting all UPs to MSK as soon as possible but within 
3 calendar days of learning of the event. UPs that are SAEs should be reported to MSK via 
SAE Report form as per section 17.2. All other UPs should be reported to MSK in a memo 
signed by the site PI. 
 
MSK is responsible for submitting UPs to the MSK IRB/PB according to institutional 
guidelines. In addition, MSK is responsible for notifying participating sites of all non-SAE UPs 
that may affect the sites. 
 
 
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. 
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. 


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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 
 
 
18.1 
Informed Consent Procedures for Participating Sites 
 
The investigators listed on the Consenting Professionals Lists at each participating site may 
obtain informed consent and care for the participants according to Good Clinical Practice and 
protocol guidelines. 
 
A note will be place in the participant‟s medical record documenting that informed consent 
was obtained for this study, and that the participant acknowledges the risk of participation. 
 
 
 
19.0 
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20.0 
APPENDICES 
 
APPENDIX A: Afatinib patient diary 
APPENDIX B: Afatinib Fact Card