Clinical trial NCT03783936
Conditions: Gastric Adenocarcinoma Esophageal Adenocarcinoma Metastasis HER-2 Gene Amplification
Sponsor: Ashwin Somasundaram
Start date: 2019-01-24; Completion date: 2022-08-30
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The initial intent of the study was to be a multi-center single-arm open-label Simon's two-stage Phase II clinical trial of first-line mFOLFOX6 + trastuzumab + avelumab in metastatic HER2-amplified gastric and esophageal adenocarcinomas.

Accrual will halt after completion of Stage I (enrollment of 18 patients). This decision is not due to safety issues. Subjects currently on treatment will continue until criteria as defined in the protocol is met.

Detailed description:

Arms: arm 1: Cycles 1-9; Induction; Cycle = 14 days

mFOLFOX6

* oxaliplatin 85 mg/m2 IV Day 1 and
* leucovorin 400 mg/m2 IV Day 1 and
* 5 fluorouracil 400 mg/m2 IV bolus and 2400 mg/m2 IV over 46 hours Day 1 and

Trastuzumab 6 mg/kg IV loading dose C1D1 then Trastuzumab 4 mg/kg IV Day 1 and

Avelumab 800 mg IV Day 1

Cycles 10 and subsequent; Maintenance; Cycle = 14 days

Trastuzumab 4 mg/kg Day 1 and Avelumab 800 mg Day 1
Interventions: intervention 1: Oxaliplatin intervention 2: Leucovorin intervention 3: 5 fluorouracil intervention 4: Trastuzumab intervention 5: Avelumab
Intervention descriptions: intervention 1: Oxaliplatin 85 mg/m2 intervention 2: Leucovorin 400 mg/m2 intervention 3: 5 fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion intervention 4: Trastuzumab 6 mg/kg loading dose C1D1 then 4 mg/kg Day 1 intervention 5: Avelumab 800 mg

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN GI17-319 
 
A single arm, multi-center Phase 2 trial of mFOLFOX6 + trastuzumab + avelumab in first-line, 
metastatic, HER2-amplified gastric and esophageal adenocarcinomas 
 
 
Sponsor Investigator 
Autumn McRee, MD 
The University of North Carolina at Chapel Hill 
 
 
Statistician 
Dominic T. Moore 
University of North Carolina at Chapel Hill 
dominic_t_moore@unc.edu 
Phone: 919-966-8647 
Fax: 919-966-4244 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 Interactive Way Suite 120 
Indianapolis, IN 46278 
 
 
Trial Funding & Avelumab Supply Provided by  
EMD Serono MS100070 
 
 
Investigational New Drug (IND) #: 141388 
 
 
 
 
Initial Protocol Version Date: 05NOV2018 
Protocol Amendment Version Date:  
07JAN2020 
29SEP2020 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A single arm, multi-center Phase 2 trial of mFOLFOX6 + trastuzumab + avelumab in first-line, 
metastatic, HER2-amplified gastric and esophageal adenocarcinomas 
 
VERSION DATE: 29SEP2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s) 
 
 
 
 
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SYNOPSIS 
TITLE 
A single arm, multi-center Phase 2 trial of mFOLFOX6 + trastuzumab + 
avelumab in first-line, metastatic, HER2-amplified gastric and 
esophageal adenocarcinomas 
SHORT TITLE 
Phase 2 trial of mFOLFOX6 + trastuzumab + avelumab in metastatic, 
HER2+ gastroesophageal adenocarcinomas 
PHASE  
II 
OBJECTIVES 
Primary Objective 
Determine the best objective response rate (CR or PR, bORR) 
within 24 weeks by RECIST v1.1 in first-line treatment of 
metastatic HER2-amplified gastroesophageal adenocarcinoma 
patients with the addition of avelumab to mFOLFOX6 + 
trastuzumab 
 
Secondary Objectives   
• Determine progression free survival (PFS) by both 
RECIST v1.1 and iRECIST criteria in first-line treatment 
of metastatic HER2-amplified gastroesophageal 
adenocarcinoma patients with the addition of avelumab to 
mFOLFOX6 + trastuzumab. 
• Determine overall survival (OS) in first-line treatment of 
metastatic HER2-amplified gastroesophageal 
adenocarcinoma patients with the addition of avelumab to 
mFOLFOX6 + trastuzumab. 
• Determine overall response rate (ORR) at 24 weeks by 
iRECIST and clinical benefit by the disease control rate 
(CR or PR or SD) at 24 weeks by both RECIST v1.1 and 
iRECIST criteria in first-line treatment of metastatic 
HER2-amplified gastroesophageal adenocarcinoma 
patients with the addition of avelumab to mFOLFOX6 + 
trastuzumab. 
• Determine the safety and tolerability of avelumab when 
combined with mFOLFOX6 + trastuzumab. 
 
Exploratory Objectives 
Exploratory and correlative studies of tumor genomics and immunology 
and peripheral lymphocytes.
STUDY DESIGN 
Multi-center, single-arm, open-label, Simon’s two-stage Phase II clinical 
trial. Accrual will stop after enrollment of Stage 1 is complete. Total 
accrual will be 18 subjects.
 
 


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KEY ELIGIBILITY 
CRITERIA (See 
Section 3 for 
complete eligibility 
criteria) 
Inclusion Criteria 
1. Histologically confirmed esophageal, gastroesophageal junction, 
or gastric adenocarcinoma that is unresectable or metastatic 
2. Age ≥ 18 years at the time of consent. 
3. ECOG Performance Status of 0 or 1. 
4. HER2 amplification confirmed by prior standard of care testing of 
tumor specimen (3+ by immunohistochemistry, or 2+ on IHC with 
ISH with HER2/CEP17 ratio ≥2). 
5. Radiographically measurable disease per RECIST 1.1. 
6. Adequate organ function within 14 days prior to registration. 
• 
ANC ≥ 1.5 x 109/L 
• 
Hemoglobin ≥ 9 g/dL (may be transfused) 
• 
Platelets ≥ 100 x 109/L 
• 
Creatinine clearance ≥ 30 mL/min OR serum creatinine ≤ 
1.5 × ULN 
• 
Bilirubin ≤ 1.5 × ULN 
• 
AST ≤ 2.5 × ULN  
• 
ALT ≤ 2.5 × ULN 
7. Left ventricular ejection fraction (LVEF) ≥ 50% or above the 
lower limit of the institutional normal range, whichever is lower. 
 
Exclusion Criteria 
1. Previous systemic therapy for stage IV disease. NOTE: may have 
received up to one cycle of mFOLFOX6 while HER2 status was 
pending prior to start of study treatment within the 4 weeks prior 
to registration. 
2. Active infection requiring intravenous systemic therapy. 
3. Pregnant or breastfeeding. 
4. Prior immune checkpoint inhibitor therapy, or HER2-directed 
therapy 
5. Evidence of interstitial lung disease or active, non-infectious 
pneumonitis 
6. Untreated brain metastasis or brain metastasis treated within 4 
weeks prior to enrollment. 
7. Known additional malignancy that is active and/or progressive 
requiring treatment 
8. Serious cardiovascular event within 6 months prior to study entry. 
9. History of organ allograft, allogeneic stem cell transplantation, 
immunodeficiency, or is receiving systemic steroid therapy or 
other immunosuppressive therapy within 7 days before first dose 
of investigational treatment. 
10. Known HIV, HBV, or HCV infection.  
11. Active autoimmune disease requiring systemic therapy in the past 
3 months. 
12. Persisting toxicity related to prior therapy (NCI CTCAE v5 Grade 
> 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other 
Grade ≤ 2 not constituting a safety risk based on investigator’s 
judgment are acceptable.
 
 


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STATISTICAL 
CONSIDERATIONS 
 
This study will be a prospective, open-label, single arm, multi-
center phase 2 clinical trial of mFOLFOX6 + trastuzumab + 
avelumab in first-line, metastatic, HER2-amplified gastric and 
esophageal adenocarcinomas. The primary objective of this study 
is to estimate the best objective response rate (CR or PR, ORR) in 
these patients within 24 weeks by RECIST 1.1 criteria.  Secondary 
objectives include; estimating PFS by both RECIST 1.1 and 
iRECIST criteria, estimating OS, estimating the disease control 
rate (DCR) at 24 weeks by RECIST 1.1 and iRECIST, and 
characterizing the safety issues associated with this regimen. 
Exploratory objectives involve investigating various biomarkers 
and peripheral blood and tumor assays.
TOTAL  
NUMBER OF 
SUBJECTS 
N = 18 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 22 months 
ESTIMATED 
STUDY DURATION  
Estimated 36 months until primary analysis 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 7 
1. 
Background and Rationale ..................................................................................... 9 
2. 
Study Objectives and Endpoints........................................................................... 11 
3. 
Eligibility Criteria .................................................................................................. 13 
4. 
Subject Registration............................................................................................... 16 
5. 
Treatment Plan....................................................................................................... 16 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 21 
7. 
Study Calendar & Evaluations ............................................................................. 33 
8. 
Biospecimen Studies and Procedures ................................................................... 36 
9. 
Criteria for Disease Evaluation ............................................................................ 37 
10 
Drug Information ................................................................................................... 40 
11 
Adverse Events ....................................................................................................... 46 
12 
Statistical Methods ................................................................................................. 50 
13 
Trial Management ................................................................................................. 52 
14 
Data Handling and Record Keeping .................................................................... 53 
15 
Ethics ....................................................................................................................... 54 
16 
References ............................................................................................................... 59 
17 
Appendices .............................................................................................................. 55 
 
 
 
 
 


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SCHEMA 
 
Accrual will halt after completion of enrollment of Stage 1 (18 subjects) 
 
 
 
 
 
 
 
 
 


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Informed Consent 
Histologically confirmed advanced unresectable gastroesophageal 
adenocarcinoma 
Subjects may have received one cycle of mFOLFOX6 +/- 
trastuzumab for first-line therapy immediately prior to registration 
28 days prior to registration: 
ECOG 0-1 
Radiological assessment 
HER2 amplification confirmed with prior testing 
Clinical and laboratory testing 
Induction Treatment (Cycles 1-9): 
Avelumab 
Trastuzumab 
mFOLFOX6 
Disease evaluation every 12 weeks 
Disease Progression 
Sustained CR, PR or SD 
Discontinuation of 
study treatment; 
follow up for 
survival for 3 years 
 
Continue Maintenance 
Avelumab 
Trastuzumab 
 
Cycle 10 + 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
Gastroesophageal cancer is the fourth most common type of cancer worldwide, and despite 
advances in the diagnosis and treatment, it remains the world's second highest cause of cancer-
related deaths [1]. Locally advanced unresectable and metastatic gastroesophageal cancers are 
not curable conditions, and the goals of therapy include palliation of symptoms, including 
malignant dysphagia; improvement of quality of life, and prolongation of survival. Prognosis is 
generally poor, with a median survival time of 3–5 months with best supportive care and 7–9 
months with systemic chemotherapy [2, 3]. Systemic chemotherapy is the mainstay of treatment 
for these patients. Several cytotoxic agents are active against gastroesophageal cancer, including 
fluoropyrimidines, platinum agents (cisplatin and oxaliplatin), taxanes (paclitaxel, docetaxel), 
and irinotecan. Additionally, as it is known that the human epidermal growth factor receptor 
(EGFR) type 2 (HER2) gene is commonly amplified [4-6] and overexpressed in 
adenocarcinomas of the stomach, gastroesophageal junction (GEJ), and esophagus and is a 
potential target for therapeutic intervention. Although the role of HER2 as a prognostic marker in 
gastric cancer remains an issue of debate, HER2 amplification/overexpression is an important 
therapeutic target for trastuzumab and is associated with significant improvements in 
progression-free (PFS) and overall survival [7]. Routine diagnostic testing is now recommended 
in gastric and GEJ adenocarcinomas based on these findings that led to approval of the drug by 
the FDA [8] and European Medicines Agency (EMA). 
 
1.2 
Current Standard of Care 
Patients with newly diagnosed metastatic or unresectable gastric, GEJ, and esophageal 
adenocarcinomas are typically treated with first-line cytotoxic chemotherapy including 
fluoropyrimidine and platinum agents. The standard of care also calls for testing these patients’ 
tumors for HER2 amplification and adding the anti-HER2 antibody trastuzumab to 
fluoropyrimidine and platinum chemotherapy in patients with HER2-amplified advanced 
esophagogastric adenocarcinoma.  
 
HER2 amplification is found in 32% of esophageal adenocarcinomas[9] and 13% of gastric 
adenocarcinomas[10]. The phase III ToGA trial established that addition of trastuzumab to 
fluoropyrimidine/platinum combination chemotherapy significantly improved overall survival 
(OS) from 11.1 months to 13.8 months and response rate from 35% to 47%[7], establishing 
trastuzumab-based chemoimmunotherapy as the first-line standard of care in these patients. 
However, patients do invariably develop disease progression, with median progression-free 
survival of 6.7 months in the ToGA trial, and so therapies that extend the duration of benefit or 
provide chance at durable response are needed.  
 
1.3 
Investigational Treatment 
Recent clinical trials have demonstrated the efficacy of immune checkpoint inhibitors in 
metastatic gastroesophageal cancers, but the optimal biomarkers for patient selection and 
strategies to optimize efficacy of therapy remain unclear. Notably, in biomarker-unselected 
refractory gastroesophageal cancer patients, response rates have been roughly 11-12% with 
nivolumab in the ATTRACTION-2 and CHECKMATE-032 trials of nivolumab[25-27] and the 
KEYNOTE-059 trial of pembrolizumab[28]. However, studies have varied regarding 


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improvement in overall survival, with nivolumab improving median overall survival (OS) 
compared to placebo in an Asian population [26] but avelumab reportedly failing to improve 
median OS compared to investigator’s choice chemotherapy in a global population.  Thus, the 
majority of patients do not derive substantial benefit from immune checkpoint inhibitor 
monotherapy in this refractory setting. Positive immunohistochemistry for PD-L1 within tumor 
cells, lymphocytes, or macrophages using the Dako 22C3 antibody, found in 55% of patients, 
enriched for patients who responded to pembrolizumab in the KEYNOTE-059, improving 
response rate among microsatellite stable or unknown subjects to 13.3%, and accelerated 
approval was granted for pembrolizumab in refractory gastric or GE junction PD-L1+ 
adenocarcinomas. Nevertheless, further improvement in biomarkers and strategies to potentiate 
the immune response and efficacy of immune checkpoint therapy in more subjects for a longer 
duration are needed. 
 
There is significant rationale for combining immune checkpoint antibodies with HER2-directed 
therapy like trastuzumab. Preclinical studies demonstrated that anti-HER2 antibody therapy 
requires an intact immune system, including IFN-γ secreting CD8+ T-cells, for efficacy, and in 
mouse models of HER2-amplified breast cancer, co-treatment with anti-HER2 and anti-PD1 
antibodies caused significant tumor regression[11]. The immune response to trastuzumab was 
significantly associated with improved responses in HER2-positive breast cancers, providing 
further evidence that a major mechanism of trastuzumab’s efficacy is harnessing the adaptive 
immune response [12]. Importantly, in HER2-amplified gastroesophageal cancer models, 
cytotoxic T lymphocytes directed against HER2 also depend on intact tumoral cellular antigen-
processing machinery [13]. Chemotherapy can also facilitate tumor antigen presentation and 
immune response, including reports of humoral immune responses after 5-fluorouracil[14] or 
oxaliplatin-based chemotherapy regimens [15, 16]. Moreover, HER2-amplified gastroesophageal 
cancers have significantly greater expression of PD-L1 [17, 18]. Many ongoing clinical trials of 
immune checkpoint inhibitors in gastroesophageal cancers, including all the key ongoing first-
line trials with chemotherapy (i.e. KEYNOTE-062, JAVELIN Gastric 100), exclude HER2-
amplified patients. Thus, HER2-amplified patients represent an understudied cohort within the 
increasingly crowded gastroesophageal cancer space. 
 
To potentiate benefit with anti-HER2 therapy, it would be ideal to administer immune 
checkpoint antibodies with first-line therapy, as there is no clear role for continuation of HER2-
directed therapy after progression.  Several post-progression studies have been negative, 
including the second-line TYTAN trial of lapatinib [19] and the GATSBY trial of second-line T-
DM1 vs. taxane [20]. Though mechanisms of resistance remain unclear, data from a single 
institution indicates that 35% of patients with a repeat biopsy post-progression indeed had lost 
HER2 positivity [21]. This would not be surprising given that there is marked intratumoral 
heterogeneity of HER2 staining even at diagnosis [22], and so outgrowth of HER2-
nonexpressing subclones under the selective pressure of anti-HER2 antibody is not unexpected. 
However, there is emerging data that targeted therapies increase tumor antigen presentation and 
can potentiate the antitumor adaptive immune response, motivating combinations of targeted 
therapies with immune checkpoint inhibitors. Indeed, combining BRAF and MEK inhibitors 
with anti-PD1 therapy is effective in a mouse model of BRAF mutant melanoma[23] and is 
being studied in several early phase clinical trials[24]. Indeed, this work is now being extended 
into GI cancers, with ongoing promising trials combining atezolizumab and cobimetinib in 


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microsatellite stable colorectal cancer, suggesting that paired MAPK inhibition with immune 
checkpoint inhibitor antibodies is a promising strategy. Thus, in patients with HER2-amplified 
gastroesophageal cancers, unleashing an amplified antitumor adaptive immune response through 
administration of immune checkpoint inhibitors with first-line trastuzumab and chemotherapy 
may provide a more durable response and may have greater likelihood of success than combining 
immune checkpoint inhibitors with HER2-directed therapy in the second-line setting. 
 
The combination of chemotherapy with FOLFOX and immune checkpoint inhibitors is 
undergoing testing in a variety of indications but has generally been well tolerated. Notably, 
combinations of capecitabine, cisplatin, trastuzumab, and pembrolizumab are also starting 
clinical evaluation (NCT02954536, NCT02901301), reflecting the promise of this strategy. 
Notably, a combination of 5-fluorouracil and oxaliplatin (i.e. FOLFOX) is the preferred systemic 
chemotherapy for patients with metastatic gastroesophageal cancer, and though in practice 
clinicians often extrapolate results from trials of cisplatin/capecitabine, there may well be 
confounding due to the alternative chemotherapy backbone and differential toxicities and 
supportive care measures (like corticosteroids) that likely need to be employed with the highly 
emetogenic cisplatin, as opposed to the less emetogenic oxaliplatin. Several trials have reported 
on the safety and feasibility of combinations of FOLFOX with PD-1 or PD-L1 antibody therapy, 
including atezolizumab and pembrolizumab, and multiple studies combining 
chemoimmunotherapy with PD-1 or PD-L1 antibodies are ongoing, including an ongoing clinical 
trial of FOLFOX + cetuximab + avelumab in colorectal cancer (NCT03174405). Moreover, 
combination therapy of trastuzumab with PD-1 antibodies was well tolerated in the PANACEA 
study, with most common immune-related adverse events of hyper- or hypothyroidism at 6/7% 
(grade 1-2) and 3.4% pneumonitis (grade 3-4)[29]. 
 
1.4 
Rationale 
Initially we proposed a multi-center single-arm open-label Simon’s two-stage Phase II clinical 
trial of first-line mFOLFOX6 + trastuzumab + avelumab in metastatic HER2-amplified gastric 
and esophageal adenocarcinomas, following an initial safety run-in of six patients. Archival 
tissue and longitudinal peripheral blood samples were collected from all patients to facilitate 
study using UNC’s robust immunogenomics translational program and facilities to perform 
extensive correlative studies to help identify potential biomarkers. Accrual will halt after 
completion of Stage I (enrollment of 18 patients). Subjects currently on treatment will continue 
until criteria as defined in Section 6.7 is met. 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Determine the best objective response rate (CR or PR, bORR) within 24 weeks by RECIST v1.1 
in first-line treatment of metastatic HER2-amplified gastroesophageal adenocarcinoma patients 
with the addition of avelumab to mFOLFOX6 + trastuzumab 
 
 
 


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2.1.2 Secondary Objectives 
 
2.1.2.1 Determine progression free survival (PFS) by both RECIST v1.1 and iRECIST criteria 
in first-line treatment of metastatic HER2-amplified gastroesophageal adenocarcinoma 
patients with the addition of avelumab to mFOLFOX6 + trastuzumab. 
  
2.1.2.2 Determine overall survival (OS) in first-line treatment of metastatic HER2-amplified 
gastroesophageal adenocarcinoma patients with the addition of avelumab to 
mFOLFOX6 + trastuzumab. 
 
2.1.2.3 Determine overall response rate at 24 weeks by iRECIST and clinical benefit by the 
disease control rate (CR or PR or SD) at 24 weeks by both RECIST v1.1 and iRECIST 
criteria in first-line treatment of metastatic HER2-amplified gastroesophageal 
adenocarcinoma patients with the addition of avelumab to mFOLFOX6 + trastuzumab. 
 
2.1.2.4 Determine the safety and tolerability of avelumab when combined with mFOLFOX6 + 
trastuzumab. 
 
2.1.3 Correlative/Exploratory Objectives 
Perform studies of tumor genomics including DNA and/or RNA sequencing to elucidate tumor 
associated and stromal/immunologic biomarkers of activity and analyze peripheral blood for 
circulating lymphocyte characteristics and circulating tumor DNA analyses. 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
Best Objective Response Rate (bORR): The best objective response rate will be defined as the 
total number of patients whose best response by 24 weeks are either a CR or PR divided by the 
number of response evaluable patients 
 
2.2.2 Secondary Endpoints 
 
2.2.2.1 Progression Free Survival (PFS) by RECIST 1.1 will be defined as the time from the 
start date of treatment to the date of documented progression as determined by RECIST 
1.1 or death from any cause. Any patient who has received study treatment but has 
neither progressed nor died will be censored on the date the patient was known to be 
alive and progression free. 
 
2.2.2.2 Progression Free Survival by iRECIST (iPFS) will be defined as the time from the start 
date of treatment to the date of documented progression as determined by iRECIST 
criteria or death from any cause. Any patient who has received study treatment but has 
neither progressed nor died will be censored on the date the patient was known to be 
alive and progression free. 
 
 


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2.2.2.3 Overall Survival (OS) will be defined as the time from start of treatment to the date of 
death. If the patient has not died, survival will be censored on last date the patient was 
known to be alive.  
 
2.2.2.4 Disease Control Rate (DCR) used to help determine clinical benefit will be defined as 
the total number of patients whose best responses are either a CR, PR, or SD divided by 
the number of response evaluable patients. Patients with best response of SD will need 
to maintain SD by 24 weeks to be considered to have received clinical benefit from the 
treatment regimen 
 
2.2.2.5 Safety and tolerability will be assessed by adverse events using CTCAE version 5. 
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of 0 or 1. 
 
4. Histologically confirmed esophageal, gastroesophageal junction, or gastric 
adenocarcinoma, with unresectable or metastatic disease documented on diagnostic 
imaging studies. 
 
5. HER2 amplification confirmed by prior standard of care testing of tumor specimen (3+ 
by immunohistochemistry, or 2+ on IHC with ISH with HER2/CEP17 ratio ≥2). 
 
6. Radiographically measurable disease according to RECIST 1.1 within 28 days prior to 
registration.  
 
7. Adequate organ function as defined in the table below. All screening labs to be obtained 
within 28 days prior to registration. 
 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC)
≥ 1.5 x 109/L 
Hemoglobin (Hgb) 
≥ 9 g/dL (may have been transfused) 
Platelets  
≥ 100 x 109/L OR ≥ 75 x 109/L for patients who 
received Cycle 1 of mFOLFOX6 +/- trastuzumab 
prior to registration
Renal 
Calculated creatinine clearance1
≥ 30 mL/min  
OR creatinine  
≤1.5 × upper limit of normal (ULN) 


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Hepatic 
Bilirubin 
≤ 1.5 × upper limit of normal (ULN) (Subjects with 
Gilbert's syndrome may be enrolled despite a total 
bilirubin level >1.5 mg/dL, if their conjugated 
bilirubin is < 1.5× ULN) 
Aspartate aminotransferase (AST) 
≤ 2.5 × ULN OR ≤ 5x ULN in patients with known 
liver metastases 
Alanine aminotransferase (ALT) 
≤ 2.5 × ULN OR ≤ 5x ULN in patients with known 
liver metastases 
1 Cockcroft-Gault formula will be used to calculate creatinine clearance (See Appendix B). Only needs to 
meet one criterion for renal inclusion criterion. 
 
10. Left ventricular ejection fraction (LVEF) ≥ 50% or above the lower limit of the 
institutional normal range, whichever is lower. 
 
11. Females of childbearing potential must have a negative serum pregnancy test at 
screening. NOTE: Females are considered of child bearing potential unless they are 
surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. 
 
12. Females of childbearing potential and males must be willing to abstain from heterosexual 
activity or to use 2 forms of effective methods of contraception from the time of informed 
consent until 7 months (210 days) after treatment discontinuation. The two contraception 
methods can be comprised of two barrier methods, or a barrier method plus a hormonal 
method. 
 
13. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Previous systemic therapy for stage IV disease – EXCEPT that patient may have received 
one cycle of mFOLFOX6 +/- trastuzumab within the 4 weeks prior to registration.  
 
2. Active infection requiring intravenous systemic therapy. 
 
3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
 
4. Treatment with any investigational drug within 28 days prior to registration.  
 
5. Prior immune checkpoint inhibitor therapy (i.e. anti-CTLA-4, anti-PD-L1, anti-PD-1), or 
HER2-directed therapy (including trastuzumab) 
 
6. Evidence of interstitial lung disease or active, non-infectious pneumonitis 
 


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7. Untreated brain metastasis or brain metastasis treated within 4weeks prior to enrollment. 
 
8. Known additional malignancy that is active and/or progressive requiring treatment; 
exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder 
cancer, or other cancer for which the subject has been disease-free for at least five years. 
 
9. Serious cardiovascular event within 6 months prior to study entry, including myocardial 
infarction, malignant hypertension, severe/unstable angina, symptomatic congestive heart 
failure (≥ New York Heart Association Classification Class II), cerebral vascular 
accident, transient ischemic attack, or serious cardiac arrhythmia requiring medication. 
 
10. History of organ allograft or allogeneic stem cell transplantation  
 
11. Active autoimmune disease requiring systemic treatment in the past 3 months (for 
example with disease modifying agents, corticosteroids, or immunosuppressive drugs).  
Exceptions Include:  
• Subjects with endocrine diseases stable on replacement therapy (e.g., thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) or hormone suppression.  
• Subjects that require intermittent use of bronchodilators, local steroid injections, 
or inhaled or topical steroids 
• Subjects with vitiligo, psoriasis, Sjogren’s syndrome, or resolved childhood 
asthma/atopy  
 
12. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, 
inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. 
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). 
 
13. Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome. 
 
14. Known history of Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects 
with laboratory evidence of cleared HBV and HCV infection will be permitted. 
 
15. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited 
except for administration of inactivated vaccines. 
  
16. Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v5 Grade ≥ 3). 
 
17. Persisting toxicity related to prior therapy (NCI CTCAE v5 Grade > 1); however, 
alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk 
based on investigator’s judgment are acceptable. 


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18. Other severe acute or chronic medical conditions including immune colitis, inflammatory 
bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions 
including recent (within the past year) or active suicidal ideation or behavior; or 
laboratory abnormalities that may increase the risk associated with study participation or 
study treatment administration or may interfere with informed consent, the interpretation 
of study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. Subjects 
must be registered prior to starting protocol therapy. Subjects must begin therapy within 28 days 
of registration. 
 
5. 
TREATMENT PLAN 
The initial intent of the study was to be a multi-center single-arm open-label Simon’s two-stage 
Phase II clinical trial of first-line mFOLFOX6 + trastuzumab + avelumab in metastatic HER2-
amplified gastric and esophageal adenocarcinomas.   
 
Accrual will halt after completion of Stage I (enrollment of 18 patients). This decision is not due 
to safety issues. Subjects currently on treatment will continue until criteria as defined in Section 
6.7 is met. 
 
5.1 
Treatment Administration for Induction  
The order of administration for study treatment during induction is avelumab, trastuzumab then 
mFOLFOX6. Subjects should receive 9 cycles of induction therapy with avelumab, trastuzumab, 
and mFOLFOX6, regardless of whether they received a cycle of mFOLFOX6 +/- trastuzumab 
immediately prior to registration. If a cycle of mFOLFOX6 +/- trastuzumab is given prior to 
registration, loading dose of trastuzumab will not be repeated.  
 
An infusion window of ± 10 minutes may be applied to the avelumab. Institutional standards for 
infusion and infusion window may be applied to trastuzumab and mFOLFOX6. Body surface 
area (BSA) should be recalculated for change in weight based on institutional standards. A 
window of ± 3 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration should be 
clearly documented in subject’s chart and electronic case report forms (eCRFs). 
 
Drug 
Dose 
Route 
Schedule 
Cycle 
Length 
INDUCTION (Cycles 1-9) 
Avelumab 
800 mg  
Intravenously (IV)  
over 60 minutes
Day 1 of 
Cycles 1-9 
14 days 
Trastuzumab 
6 mg/kg loading 
dose 
IV (e.g. over 90 min) 
Day 1 of 
Cycle 1 
Trastuzumab 
4 mg/kg  
IV (e.g. over 30 min) 
Day 1 of 
Cycles 2-9 
Oxaliplatin  
85 mg/m2 
IV (e.g over 2 hours) 
Day 1 of 
Cycles 1-9 


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Leucovorin 
400 mg/m2  
IV per (e.g. over 2 hours) 
Day 1 of 
Cycles 1-9 
5-fluorouracil 
400 mg/m2 bolus 
and 2400 mg/m2  
IV bolus and IV infusion  
(e.g. continuous 46 hour infusion) 
Day 1 of 
Cycles 1-9 
 
5.2 
Treatment Administration for Maintenance 
The order of administration for study treatment during induction is avelumab then trastuzumab. 
An infusion window of ± 10 minutes may be applied to the avelumab. Institutional standards for 
infusion and infusion window may be applied to trastuzumab. Dose recalculation for change in 
weight is based on institutional standards. A window of ± 3 days may be applied to all study 
visits to accommodate observed holidays, inclement weather, scheduling conflicts etc. Date and 
time of each drug administration should be clearly documented in subject’s chart and electronic 
case report forms (eCRFs). 
 
Drug 
Dose 
Route 
Schedule 
Cycle 
Length 
MAINTENANCE (Cycles 10-n) 
Trastuzumab 
4 mg/kg  
IV (e.g. over 30 min) 
Day 1 of 
Cycles 10-n 
14 days 
Avelumab 
800 mg 
IV over 60 minutes 
Day 1 of 
Cycles 10-n 
 
5.3 
Safety Lead-In 
The study will be designed with a 6-subject safety run-in. If 2 or more subjects have significant 
toxicities as defined below during the DLT period, study accrual will pause, and the treatment 
plan will be reassessed and amended as appropriate. Toxicities will be assessed per NCI CTCAE 
v5. After the sixth subject is enrolled, there will be a pause in further enrollment until the first six 
subjects have completed two cycles to assess toxicities per NCI CTCAE v5.  
 
5.3.1 Definition of Dose Limiting Toxicity 
DLTs are defined as at least as possibly related to study treatment with avelumab, trastuzumab, 
or mFOLFOX6. If an apparent DLT is clearly due to underlying gastroesophageal 
adenocarcinoma or is otherwise clearly unrelated to the study treatment, then the investigator 
will specify that the event is not a DLT. The DLT period consists of the first 2 cycles of 
treatment. 
 
An event will be considered a DLT per NCI CTCAE criteria v5, if it occurs within the DLT 
reporting period (i.e., within two cycles of therapy) as specified below: 
• Any grade 5 AE 
• Grade 4 diarrhea or colitis 
• Grade 3 diarrhea or colitis that is refractory to corticosteroids (worsens or persists for 
more than 5 days despite corticosteroid treatment as described in Section 6.2) 
• Grade 4 rash 
• Grade 3 rash that recurs despite prior course of corticosteroids 
• Grade 3-4 pneumonitis 


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• Grade 3-4 blood bilirubin increased (total bilirubin >3x ULN) 
• AST or ALT increased to >5x ULN if baseline AST and ALT were within normal limits; 
or AST or ALT increased to >10x ULN if baseline AST and ALT were >1 to 5x ULN 
• Immune-mediated myocarditis 
• Grade 3-4 infusion related reaction or anaphylaxis 
• Grade 4 creatinine increased (>6x ULN) 
• Any other immune-related non-endocrine AEs that are Grade 4 or are Grade 3 that recur 
despite prior course of corticosteroids (excluding alopecia, isolated electrolyte 
disturbances that responds to correction within 72 hours of onset, isolated amylase or 
lipase abnormalities that are not associated with symptoms or clinical signs of 
pancreatitis and decrease to < Grade 4 within 1 week of onset) 
 
5.4 
Pre-medication and Hydration for Study Treatment 
 
5.4.1 Avelumab 
Premedication: In order to mitigate infusion related reactions, a premedication with an 
antihistamine and with paracetamol (acetaminophen) 30 to 60 minutes prior to the first 4 
infusions of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg 
paracetamol IV or oral). Premedication should be administered for subsequent avelumab 
infusions based upon clinical judgment and presence/severity of prior infusion reactions. This 
may be modified based on local treatment standards and guidelines, as appropriate.  
 
Avelumab should be administered in a setting that allows for immediate access to an intensive 
care unit or equivalent environment and administration of therapy for anaphylaxis, such as the 
ability to implement immediate resuscitation measures. Steroids (dexamethasone 10 mg), 
epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or 
equivalents, and oxygen should be available for immediate access. Following avelumab 
infusions, patients must be observed for 30 minutes post infusion for potential infusion related 
reactions. 
 
5.4.2 Trastuzumab  
Premedication, hydration and administration will be provided as per institutional standards per 
routine care for patients who receive trastuzumab. Please see Section 5.7.2 for information 
regarding management of infusion reactions. The biosimilar for trastuzumab may be used. 
 
5.4.3 mFOLFOX6 
Premedication, hydration and administration will be provided as per institutional standards per 
routine care for patients who receive mFOLFOX6. For prophylaxis of emesis, premedication 
with a 5HT3 antagonist is typically administered. Premedication with corticosteroids on Day 1 
only may be considered per institutional standard practice. 
 
5.5 
Concomitant Medications 
 
5.5.1 Allowed Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 


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medical care. Hematopoietic growth factors should not be routinely administered. All 
concomitant medication and concurrent therapies will be documented at Baseline/Screening and 
throughout the study as summarized in the Time and Events Table in Section 0. Dose, route, unit 
frequency of administration, and indication for administration and dates of medication will be 
captured. 
 
5.5.2 Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician. The following medications are 
prohibited while receiving protocol therapy: 
• Systemic anticancer or biological therapy. 
• Immunotherapy not specified in this protocol. 
• Chemotherapy not specified in this protocol. 
• Systemic glucocorticoids for any purpose other than to manage symptoms of suspected 
immune-related adverse events of interest (irAEIs) or emergent management of serious 
infusion/allergic reactions. (NOTE: Use of inhaled steroids, local injection of steroids, 
topical steroids, and steroid eye drops are allowed). If medically deemed necessary (eg, 
acute asthma or chronic obstructive pulmonary disease exacerbation), Investigators are 
allowed to use their judgment to treat patients with systemic steroids. In such cases, 
systemic steroids should be stopped at least 24 hours prior to the next dose of avelumab. 
• Live vaccines within 4 weeks prior to the first dose of study treatment. Seasonal flu 
vaccines that do not contain live viruses are allowed. Examples of live vaccines include, 
but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, 
rabies, bacille Calmette-Guerin, and typhoid (oral) vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed. Intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed. 
 
5.6 
Supportive Care 
 
5.6.1 Chemotherapy Induced Nausea/Vomiting 
This chemotherapy regimen has moderate emetogenicity, and all subjects on study should 
receive an appropriate prophylactic antiemetic regimen per local standard of care such as a 5HT3 
receptor antagonist +/- NK1 receptor antagonist. Corticosteroids may be administered per routine 
institutional practice on Day 1. Additional corticosteroids on subsequent days are not allowed 
and alternative antiemetics should be used. 
 
5.6.2 Chemotherapy Associated Diarrhea 
Diarrhea that occurs during treatment should be aggressively managed given that diarrhea may 
be secondary to cytotoxic chemotherapy or may arise as a consequence of autoimmune colitis. 
Patients should start an anti-diarrheal such as loperamide at the earliest evidence of diarrhea, and 
should be instructed to take 4 mg loperamide by mouth immediately, followed by 2 mg every 2-4 
hours after each unformed stool. Patients should also be instructed to increase intake of clear 
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to monitor stool output closely and monitor for fever, abdominal pain, lightheadedness, and other 
symptoms concerning for complicated diarrhea. 
 
5.6.3 Reproductive Information 
Females of childbearing potential and males must be willing to abstain from heterosexual 
activity or to use 2 forms of highly effective methods of contraception from the time of informed 
consent until 7 months (210 days) after treatment discontinuation. The two contraception 
methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: Oral route, intravaginal route, transdermal route 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, 
injectable, implantable 
• Other: Intrauterine device, intrauterine hormone-releasing system, bilateral tubal 
occlusion, vasectomized partner, sexual abstinence (if the preferred and usual lifestyle) 
 
5.7 
Hypersensitivity/Infusion Reactions 
 
5.7.1 Avelumab 
 
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 h. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening. 
Grade 3 or Grade 4 – severe or 
life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop avelumab infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
study avelumab and must not receive any further 
avelumab treatment. 
If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it 
must remain decreased for the next scheduled infusion.  If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based on 
investigator’s medical judgment. If hypersensitivity reaction occurs, the subject must be treated 
according to the best available medical practice. 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs = nonsteroidal anti-inflammatory drugs. 
 


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5.7.2 Trastuzumab 
Infusion reactions to trastuzumab should be treated per institutional standards. The following 
measures are suggested for trastuzumab related infusion reaction: 
 
Grade 1-2 infusion related reaction without dyspnea or transient hypotension: Decrease infusion 
rate to half the rate given at the time of event onset. If symptoms persist, consider temporarily 
interrupting drug infusion and administering acetaminophen and/or diphenhydramine. After 
symptoms resolve, may resume infusion at original rate after 30 minutes. For subsequent 
infusions, may consider adding acetaminophen and diphenhydramine premedication and slowing 
infusion rate at treating physician’s discretion. 
 
Grade 2 infusion related reaction with dyspnea or transient hypotension: Temporarily interrupt 
drug infusion and administer acetaminophen and/or diphenhydramine. After symptoms resolve, 
may resume infusion. For subsequent infusions, add acetaminophen, diphenhydramine, and H2 
histamine receptor antagonist premedication, and slow infusion rate at treating physician’s 
discretion. 
 
Grade 3-4 infusion related reaction or Grade 3-4 anaphylaxis: Discontinue drug infusion and 
immediately start supportive management of anaphylaxis and resuscitation. Supportive 
medications may include antihistamines, epinephrine, bronchodilators, oxygen, and 
corticosteroids.  
 
5.7.3 Chemotherapy 
Infusion reactions to chemotherapy should be treated per institutional standards. 
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study as specified 
in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or discontinuation as 
specified in Study Calendar & Evaluations.   
 
6.1 
Dose Delays/Dose Modifications 
Unless otherwise noted in the dose modification tables below, treatment may be delayed ≤ 2 
weeks from the expected day of the next treatment for any reason. If treatment is delayed > 2 
weeks, subjects will proceed with the next cycle of treatment at the dose level recommended 
according to the tables below. 
 
 
 


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6.2 
Dose Levels for Dose Reductions 
 
Dose level 
5FU 
Bolus 
5FU 
Infusion 
Leucovorin 
Oxaliplatin 
Trastuzumab 
(after loading 
dose) 
Avelumab 
Starting 
Dose 
400 
mg/m2 
2400 mg/m2 
400 mg/m2 
85 mg/m2 
4 mg/kg 
800 mg 
Dose level 
(-1) 
320 
mg/m2 
1920 mg/m2 
400 mg/m2 
65 mg/m2 
4 mg/kg 
800 mg 
Dose level 
(-2) 
270 
mg/m2 
1600 mg/m2 
400 mg/m2 
50 mg/m2 
4 mg/kg 
800 mg 
Dose level 
(-3) 
230 
mg/m2 
1360 mg/m2 
400 mg/m2 
40 mg/m2 
4 mg/kg 
800 mg 
 
If a dose reduction beyond level -3 is required for oxaliplatin, oxaliplatin will be discontinued 
and 5FU/leucovorin+trastuzumab+avelumab will be continued. 
 
If a dose reduction beyond level -3 is required for 5FU, then mFOLFOX6 will be discontinued 
and trastuzumab+avelumab will be continued 
 
6.3 
Dose Modifications for Study Treatment 
 
 
Supportive 
Management 
Avelumab Dose 
Modification 
Trastuzumab Dose 
Modification 
mFOLFOX6 Dose 
Modification  
(during cycles 1-9) 
Diarrhea/Colitis 
 
 
Grade 1 
Increase of <4 
stools per day over 
baseline; mild 
increase in ostomy 
output compared to 
baseline 
Symptomatic 
treatment (e.g. 
loperamide) 
Continue avelumab 
 
If worsens: 
Treat as Grade 2, 3 
or 4. 
Continue 
Continue 
Grade 2 
Increase of 4-6 
stools per day over 
baseline; moderate 
increase in ostomy 
output compared to 
baseline; limiting 
instrumental ADL 
Symptomatic 
treatment (e.g. 
loperamide) 
Delay starting next 
cycle until grade ≤1, 
then resume without 
any dose reduction. 
 
If persists > 5-7 
days or recurs: Treat 
as Grade 3 or 4
Delay starting next 
cycle until grade ≤1, 
then resume without 
any dose reduction. 
Delay starting next 
cycle until grade ≤1, 
then resume without 
any dose reduction. 
Grade 3 to 4 
Increase of >=7 
stools per day over 
baseline; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting 
self care ADL 
 
1.0 to 2.0 
mg/kg/day 
prednisone IV or 
equivalent. 
Add prophylactic 
antibiotics for 
opportunistic 
infections  
Consider lower 
endoscopy 
 
Withhold avelumab 
until steroids are 
tapered off. 
If event was initially 
grade 3, may 
resume avelumab 
without dose 
reduction. 
If event was 
recurrent grade 3 or 
grade 4 or diarrhea 
Delay starting next 
cycle until grade ≤1, 
then resume without 
any dose reduction. 
Delay starting next 
cycle until grade ≤1, 
then resume with 
5FU and oxaliplatin 
reduced by one dose 
level 
 


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Grade 4: Life-
threatening, 
perforation 
IF IMPROVED 
Continue steroids 
until Grade ≤ 1, 
then taper over at 
least 1 month;  
 
IF WORSENED, 
PERSISTS >3-5 
DAYS, OR 
RECURS AFTER 
IMPROVEMENT:  
Add infliximab 
5mg/kg (if no 
contraindication). 
Note: infliximab 
should not be used 
in cases of 
perforation or 
sepsis. 
/colitis is refractory 
to corticosteroids, 
permanently 
discontinue 
avelumab 
Rash 
 
 
Grade 1-2 
Covering ≤ 30% body 
surface area 
Symptomatic therapy 
(for example, 
antihistamines, topical 
steroids) 
Continue avelumab 
for first instance. 
 
However, if persists 
>1-2 weeks or recurs, 
withhold avelumab. 
Consider skin biopsy. 
Consider 0.5-1 
mg/kg/day prednisone 
or equivalent, and 
once improving taper 
steroids over at least 1 
month. May resume 
avelumab after steroid 
taper completed. 
 
If worsens, treat as 
grade 3-4 
Continue 
Continue 
Grade 3-4 
Grade 3: Covering > 
30% body surface 
area;  
Grade 4: Life 
threatening 
consequences 
 
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone or 
equivalent 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
 
If improves to Grade ≤ 
1:  
 
Taper steroids over at 
least 1 month 
Withhold avelumab 
for Grade 3. May 
resume avelumab 
therapy following 
steroid taper 
 
Permanently 
discontinue avelumab 
for Grade 4 or 
recurrent Grade 3 
May continue if grade 
3 
 
Delay if grade 4 
May continue if grade 
3 
 
Delay if grade 4 
 
 


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Supportive 
Management 
Avelumab Dose 
Modification 
Trastuzumab Dose 
Modification 
mFOLFOX6 Dose 
Modification  
(during cycles 1-9) 
Pneumonitis 
 
 
Grade 1: 
Asymptomatic, 
radiographic changes 
only 
Monitor for symptoms 
every 2 to 3 days  
Consider Pulmonary and 
Infectious Disease 
consults 
 
If worsens, treat as grade 
2 or grade 3-4 
Consider 
withholding 
avelumab therapy 
Continue 
Continue 
Grade 2: 
Symptomatic (mild to 
moderate), medical 
intervention indicated 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
If improves:  
When symptoms return 
to Grade ≤ 1, taper 
steroids over at least 1 
month 
 
If not improving after 2 
weeks or worsening:  
Treat as Grade 3 to 4.
Withhold avelumab 
therapy. 
May resume 
avelumab 
following steroid 
taper 
Withhold trastuzumab 
therapy. 
May consider 
resuming trastuzumab 
when improved to 
≤Grade 1 after 
discussion with 
medical monitor. 
May continue 
5FU/leucovorin or 
delay until improved 
to ≤Grade 1. 
 
Withhold oxaliplatin 
until improved to 
≤Grade 1. 
Grade 3-4 
Grade 3: Severe 
symptoms; 
New/worsening 
hypoxia 
 
Grade 4:  Life-
threatening 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent  
Add prophylactic 
antibiotics for 
opportunistic infections  
Consider bronchoscopy, 
lung biopsy 
 
If improves to Grade ≤ 1:  
Taper steroids over at 
least 1 month  
If not improving after 48 
hours or worsening:  
Add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil)
Permanently 
discontinue 
avelumab 
Discontinue 
trastuzumab 
Delay until ≤Grade 1. 
Discontinue on-
protocol therapy. 
Subsequent therapy at 
discretion of 
investigator 
 
 


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Supportive 
Management 
Avelumab Dose 
Modification 
Trastuzumab Dose 
Modification 
mFOLFOX6 Dose 
Modification  
(during cycles 1-9) 
Hepatic  
 
 
CATEGORY 1 
AST or ALT > ULN 
to 3.0 x ULN (if 
baseline AST and 
ALT were normal)  
OR  
AST or ALT >3 to 5 
x ULN (if baseline 
AST and ALT were 1 
to 3 x ULN)  
OR 
AST or ALT > 5 to 8 
x ULN (if baseline 
AST and ALT were 
>3 to 5 x ULN)  
OR 
Total bilirubin > 
ULN to 1.5 x ULN 
If worsens, treat as Grade 
2 or Grade 3-4 
Continue avelumab 
Continue 
trastuzumab 
Continue 
CATEGORY 2 
AST or ALT >3 to 5 
x ULN (if baseline 
AST and ALT were 
normal)  
OR  
AST or ALT >5 to 10 
x ULN (if baseline 
AST and ALT were 
>1 to 3 x ULN)  
OR 
AST or ALT > 8 to 
10 x ULN (if baseline 
AST and ALT were 
>3 to 5 x ULN)  
OR 
Total bilirubin > 1.5 
to ≤ 3 x ULN 
Increase frequency of 
monitoring to every 3 
days. 
 
If elevation persists >5-7 
days or worsens, treat as 
Category 3 
Withhold avelumab 
 
If improved to 
Category 1, resume 
avelumab and 
routine monitoring 
May continue 
trastuzumab or delay 
until Category 1 
May continue or 
delay until Category 
1 
CATEGORY 3 
AST or ALT > 5 x 
ULN (if baseline 
AST and ALT were 
normal)  
OR  
AST or ALT > 10 x 
ULN (if baseline 
AST and ALT were 
>1 to 5 x ULN)  
OR 
Total bilirubin > 3 x 
ULN 
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections  
Consult 
gastroenterologist/ 
hepatologist 
Consider obtaining 
MRI/CT scan of liver 
and liver biopsy if 
clinically warranted
Permanently 
discontinue 
avelumab 
Delay until Category 
1 
Delay until Category 
1 
 
 


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Supportive 
Management 
Avelumab Dose 
Modification 
Trastuzumab Dose 
Modification 
mFOLFOX6 Dose 
Modification  
(during cycles 1-9) 
Cardiac  
 
 
 
 
If LVEF decreases 
≥16% from baseline or 
decreases below the 
lower limit of normal 
and is ≥10% below 
baseline, and 
ASYMPTOMATIC 
Check EKG, cardiac 
enzymes including 
troponin I or T, CK, and 
CK-MB. If any 
abnormality, treat as 
Suspected myocarditis.  
 
If initial workup shows 
no other abnormalities,  
repeat echocardiogram or 
MUGA every 4 weeks.  
 
Strongly consider referral 
to cardiology and 
initiation of medical 
therapy for 
cardiomyopathy, such as 
beta blockers and 
angiotensin converting 
enzyme (ACE) 
inhibitors. 
Withhold avelumab 
when trastuzumab is 
held. May resume 
avelumab if/when 
trastuzumab is 
resumed. 
Withhold 
trastuzumab for at 
least 2 cycles. 
 
If LVEF returns to 
normal limits within 
4-8 weeks and 
remains at ≤15% 
decrease from 
baseline value, may 
resume trastuzumab 
 
Discontinue 
trastuzumab 
permanently if LVEF 
remains persistently 
decreased for >8 
weeks or if treatment 
must be interrupted 
for cardiomyopathy 
for more than 3 
episodes.
May delay or 
continue per 
investigator 
judgment 
Suspected myocarditis - 
New onset of cardiac 
signs or symptoms and / 
or new laboratory 
cardiac biomarker 
elevations (e.g. 
troponin, CK-MB, 
BNP) or cardiac 
imaging abnormalities 
suggestive of 
myocarditis. 
Hospitalize. 
In the presence of life 
threatening cardiac 
decompensation, 
consider transfer to a 
facility experienced in 
advanced heart failure 
and arrhythmia 
management. 
Cardiology consult to 
establish etiology and 
rule-out immune-
mediated myocarditis.  
Guideline based 
supportive treatment as 
per cardiology consult.* 
 
Consider myocardial 
biopsy if recommended 
per cardiology consult. 
Withhold avelumab. 
 
If symptoms 
improve and immune 
mediated etiology is 
ruled out, and there 
is no decline in 
LVEF, resume 
avelumab therapy. 
 
If symptoms 
improve and immune 
mediated etiology is 
ruled out, but there is 
persistent decline in 
LVEF, treat as 
asymptomatic LVEF 
decline above. 
 
If symptoms do not 
improve/worsen, 
viral myocarditis is 
excluded, and 
immune-mediated 
etiology is suspected 
or confirmed 
following cardiology 
consult, manage as 
immune-mediated 
myocarditis.
Withhold until 
myocarditis 
exonerated 
 
If symptoms improve 
and serious etiology 
is ruled out, and there 
is no decline in 
LVEF, resume 
trastuzumab therapy. 
 
If symptoms improve 
and immune 
mediated etiology is 
ruled out, but there is 
persistent decline in 
LVEF, treat as 
asymptomatic LVEF 
decline above. 
 
Withhold until 
myocarditis and 
5FU-related 
cardiotoxicity are 
exonerated 


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Immune-mediated 
myocarditis 
Guideline based 
supportive treatment as 
appropriate as per 
cardiology consult.* 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic 
antibiotics for 
opportunistic infections. 
 
Once improving, taper 
steroids over at least 1 
month. 
 
If no improvement or 
worsening, consider 
additional 
immunosuppressants 
(e.g. azathioprine, 
cyclosporine A). 
Permanently 
discontinue 
avelumab 
Discontinue on-
protocol therapy 
Discontinue on-
protocol therapy 
*Local guidelines, or eg. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
 
6.4 
mFOLFOX6 Modification 
 
6.4.1 Hematologic Toxicity 
For grade 2 neutrophil count decreased on Day 1, delay starting next cycle until grade ≤ 1, then 
resume without any dose reduction. If delay is two or more weeks or recurrent events occur 
requiring at least two delays, then subsequently decrease 5FU and oxaliplatin by one dose level. 
 
For grade 3 neutrophil count decreased on Day 1 or grade 2 platelet count decreased, delay 
starting next cycle until grade ≤1, then resume oxaliplatin with one dose level decreased and 
resume 5FU without any dose reduction. If delay is two or more weeks or recurrent events occur 
requiring at least two delays, then decrease 5FU and oxaliplatin by one dose level. 
 
For grade 4 neutrophil count decreased on Day 1 or febrile neutropenia or grade 3-4 platelet 
count decreased, delay starting next cycle until grade ≤1, then decrease 5FU and oxaliplatin by 
one dose level.  
 
6.4.2 Nausea/Vomiting 
For grade 3-4 nausea/vomiting, delay starting next cycle until grade ≤ 1, then decrease 5FU and 
oxaliplatin by one dose level. 
 
6.4.3 Sensory or Motor Neuropathy 
For grade 2 symptoms persisting for an entire cycle (14 days) or transient grade 3 symptoms that 
last for < 7 days, continue mFOLFOX6 with one dose level reduction of oxaliplatin for all 
subsequent cycles. 
 
For grade 3 symptoms persisting for an entire cycle (14 days) or grade 4 symptoms, discontinue 
oxaliplatin. 


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For prolonged duration of pharyngolaryngeal dysesthesia, increase duration of oxaliplatin 
infusion to 6 hours for all subsequent cycles. 
 
6.5 
Select Immune Related Adverse Events Requiring Avelumab Dose Delay 
 
Renal irAEs 
Grade of Creatinine Increased 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue avelumab therapy 
 
Continue renal function monitoring
If worsens: 
Treat as Grade 2 to 3 or 4.
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy
If returns to  Grade ≤1: 
Taper steroids over at least 1 
month, and resume avelumab 
therapy following steroids taper. 
If worsens:  
Treat as Grade 4. 
 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue avelumab 
therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month. 
 
 
 
 
 
 
 
 
 


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Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy. 
Endocrinology consult if needed 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy. Consider 
hospitalization. Endocrinology consult 
 
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.   
 
Rule-out secondary endocrinopathies 
(i.e. hypopituitarism / hypophysitis) 
Resume avelumab once 
symptoms and/or laboratory tests 
improve to Grade ≤ 1 (with or 
without hormone 
replacement/suppression). 
 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e. 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH): 
• 
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women)  
• 
Hormone 
replacement/suppressive therapy 
as appropriate  
• 
Perform pituitary MRI and visual 
field examination as indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month 
• 
Withhold avelumab if moderate, 
severe or life-threatening 
Resume avelumab once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone replacement). 
 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the 
pituitary gland on MRI/CT scan 
is documented.  
 
Continue hormone 
replacement/suppression therapy 
as appropriate. 


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symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed by corticosteroids taper 
during at least 1 month. 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
Other irAEs (not described above) 
Grade of other irAEs 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive of 
a potential irAE 
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy 
If irAE is confirmed, treat as 
Grade 2 or 3 irAE. 
Grade 2 irAE or first 
occurrence of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month and resume avelumab 
therapy following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 
Grade 4  
 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult.
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue avelumab 
therapy 
Specialty consult 
 


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6.6 
Toxicities Requiring Avelumab Discontinuation 
Any toxicities that occur as described below that are deemed related to study therapy with 
avelumab will mandate discontinuation of protocol therapy. Subjects may subsequently continue 
on standard of care therapies including mFOLFOX6 +/- trastuzumab per the judgment of the 
treating investigator and should continue to be followed radiographically until disease 
progression.  
• Grade 4 diarrhea or colitis 
• Grade 3 diarrhea or colitis that is refractory to corticosteroids 
• Grade 4 rash 
• Grade 3 rash that recurs despite prior course of corticosteroids 
• Grade 3-4 pneumonitis 
• Grade 3-4 blood bilirubin increased (Total bilirubin >3x ULN) 
• AST or ALT increased to >5x ULN if baseline AST and ALT were within normal limits; 
or AST or ALT increased to >10x ULN if baseline AST and ALT were >1 to 5x ULN 
• Immune-mediated myocarditis 
• Grade 3-4 infusion related reaction or anaphylaxis 
• Grade 4 creatinine increased (>6x ULN) 
• Any other immune-related non-endocrine AEs that are Grade 4 or are Grade 3 that recur 
despite prior course of corticosteroids (excluding alopecia, isolated electrolyte 
disturbances that responds to correction within 72 hours of onset, isolated amylase or 
lipase abnormalities that are not associated with symptoms or clinical signs of 
pancreatitis and decrease to < Grade 4 within 1 week of onset) 
 
6.7 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below.  The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF)   
• Documented disease progression by RECIST 1.1 with lack of clinical benefit 
o NOTE that subjects who are clinically benefiting from therapy may continue on 
protocol therapy at the discretion of the treating investigator if it is felt to be in the 
subject’s best interest. Subsequent restaging scans must occur within 4-8 weeks to 
either confirm or refute progression by iRECIST. Subjects who subsequently have 
further progression confirmed by iRECIST must discontinue protocol therapy.  
• 
Site investigator determines a change of therapy would be in the best interest of the 
subject 
• 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), 
the subject should be asked if he or she may still be contacted for further scheduled 
study assessments. The outcome of that discussion should be documented in both the 
medical records and in the eCRF. 
• 
Female subject becomes pregnant  
• 
Protocol therapy is interrupted for ≥28 days.  
 


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6.8 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 


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7. 
STUDY CALENDAR & EVALUATIONS 
Study Evaluation  
Cycle = 14 days 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 
4-9 
Cycles 
10-n 
30/90 day safety 
follow up12 
Long-term 
Follow up13 
-28 days 
Day 111 
± 3 days 
Day 1 
± 3 days 
Day 1 
± 3 days 
Day 1 
± 3 days 
Day 1 
± 3 days 
30/90 days 
(+ 7 days) 
Every 3 months 
(±14 days) 
REQUIRED ASSESSMENTS 
 
Informed Consent 
X
 
Medical History1 
X
 
HER2, PD-L1 and MSI/MMR results2 
X
 
Physical Exam14 
X
X
X
X
X 
X14 
D30
Vital signs and ECOG Performance Status3 
X
X
X
X
X 
X
Echocardiogram or MUGA scan4 
X
X4 
X4 
AE and concomitant medication review  
X
X
X
X
X 
X
X
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count with diff (CBC)
X
X
X
X
X 
X
D30
Comprehensive Metabolic Profile (CMP) 
X
X
X
X
X 
X
D30
Magnesium, Phosphate  
X
X
X
X
X 
X
Thyroid Function Testing5 
X
X5 
X5 
D30
Pregnancy test (serum or urine) (WOCBP)5
X
X
X5 
X5 
DISEASE ASSESSMENT 
CT of chest6 
X
X6 
X6 
X6 
CT or MRI of abdomen and pelvis6 
X
X6 
X6 
X6 
MRI Brain (only if clinically indicated) 6 
X
 
TREATMENT EXPOSURE 
Avelumab IV 
X
X
X
X 
X
Trastuzumab IV 
X
X
X
X 
X
mFOLFOX6 IV 
X
X
X
X 
SPECIMEN COLLECTION  
Archival Tumor Tissue7 
X
 
Standard of Care Biopsy Tissue7 
X7 
X7 
X7 
X7 
X7 
X7 
Correlative Blood Samples8 
X8 
X8 
D30 
Stool for microbiome analysis9 
X9 
 
BANKING SAMPLES  
 
Whole Blood10 
X
X10 
Unstained Slides9 (if available)10 
X
 
Serum and Plasma10 
X
X10 
D30
FOLLOW-UP 
Survival Status, Subsequent Therapy 
 
 
 
 
 
 
 
X 


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CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase 
 
Key to Footnotes  
1. Medical History to include: diagnosis and staging per AJCC staging manual Ed 8 (pathology report, radiology imaging, staging 
documentation), a smoking history questionnaire and trial awareness question. Prior anti-cancer treatment should be documented including 
medications (chemotherapy, checkpoint inhibitors, etc), radiation therapy, or surgery.  
 
2. HER2 amplification confirmed by prior standard of care testing of tumor specimen (3+ by immunohistochemistry, or 2+ on IHC with ISH 
with HER2/CEP17 ratio ≥2) is required for eligibility. Consensus guidelines from NCCN recommend testing for PD-L1 expression using the 
Combined Positive Score (CPS) and testing for microsatellite instability/deficient mismatch repair status for metastatic gastric or 
gastroesophageal cancer. This testing, if not already done, should be requested and performed per standard of care and results reported when 
available. Results do not need to be available and reported in any specific timeframe, and if testing is requested but is not successfully 
performed, this would not comprise a deviation. 
 
3. Vital signs to include blood pressure, heart rate, resting oxygen saturation, weight, and height (screening only) and ECOG performance status.    
 
4. Echocardiogram or MUGA scan should be performed at screening, then every 6 cycles (Cycle 6, Cycle 12 and on). The same modality should 
be used over the duration of the study. 
 
5. Thyroid Function testing should be performed at screening, then every 3 cycles (Cycle 4, Cycle 7, Cycle 10 and on) and at safety visit (if not 
performed in the previous 8 weeks). TSH will be obtained. T4 and T3 including free versus total testing is at the discretion of the site 
investigator. Serum β-HCG must be performed at screening for women of child-bearing potential. The test result must be confirmed as 
negative prior to dosing with study medication. A serum or urine pregnancy test must be repeated every 4 weeks while receiving study 
medication. 
 
6. Radiological assessments should be done within 4 weeks prior to Cycle 1 Day 1 of treatment. Tumor imaging should remain consistent 
throughout study, and should include those thought by investigator to best capture status of disease. Disease assessments should include 
contrasted computed tomography (CT) of the chest and either contrasted CT of abdomen and pelvis or MRI of abdomen and pelvis. Repeat 
tumor imaging every 12 weeks (± 1 week). During long term follow up, radiology imaging should be performed per institutional standards. 
NOTE: Subjects who have progression per RECIST 1.1 but are clinically well may continue on therapy per investigator discretion per Section 
6.4 but should have repeat scans 4-8 weeks later. If subject does not have iCPD, then scans should resume every 12 weeks (± 1 week). MRI of 
the brain should only be done if clinically indicated.  
 
 
 


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7. Archival tissue will be requested during screening and is required if available. If archival tissue is not available, a new biopsy is not required 
and the subject may still be eligible. If a biopsy is done for standard of care purposes at any point after registration, tissue for correlative 
analysis will be requested and subject consent will be obtained. Every effort should be made to document the objective progression even after 
discontinuation of treatment. In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the complete response status. See Correlative Laboratory Manual (CLM) for details regarding this sample 
collection. 
 
8. Blood samples for correlative analysis will be collected prior to treatment on Cycle 1 Day 1 (C1D1), at first disease evaluation (roughly after 
Cycle 6) and at progression/D30 safety visit. Samples collected for correlative analysis will include: samples for ctDNA analysis and PBMCs 
for flow cytometry. See CLM for details regarding this collection. 
 
9. Stool will be collected for microbiome analysis within the 28 days prior to the start of treatment on C1D1 after the subject has been registered 
to the study. See CLM for details regarding this collection. 
 
10. Whole blood for banking is to be collected at Pre-Treatment C1D1 and at first disease evaluation (roughly after Cycle 6). Submission of 
unstained slides for banking from an archived FFPE tumor block (if available). Serum and plasma for banking are to be collected at Pre-
Treatment C1D1, at first disease evaluation (roughly after Cycle 6) and at progression/30-Day Safety Follow up visit. See CLM for collection, 
labeling, processing, and shipping instructions. 
 
11. C1D1 labs obtained within 7 days prior to study drug administration do not need to be repeated. 
 
12. The safety visit should only occur when subjects permanently stop study treatment, around 30 days (+7 days) after last dose of study drug. The 
Day 90 safety follow up may be accomplished via email, phone call or communication with local physician.  
 
13. Subsequent long term follow-up will occur in all subjects until documented disease progression. Subjects who discontinue treatment for any 
reason without documented disease progression will be followed after their D90 safety visit for disease progression every 3 months for 3 
years.  Once disease progression is documented, subjects will enter a survival follow up period every 3 months for 3 years from the time of 
documented progression (±14 days). Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. Long term 
survival follow up will be limited to history of any subsequent cancer treatments, an assessment of any SAEs (including checking for 
pregnancy) considered to be possibly or probably related to study treatment until resolution, and survival status.   
 
14. During the maintenance period, a physical exam may be performed every other cycle beginning with Cycle 10. All other assessments will be 
performed as outlined in the calendar prior to each cycle and a member of the research staff will assess AEs/conmeds of the subject. A 
physical exam may be performed at site investigator discretion.  


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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, 
labeling, and shipping instructions for the samples described below. 
 
8.1 
Tissue 
 
8.1.1 Archival Tissue 
Archival tumor tissue is required if available and will be identified at screening for correlative 
studies to evaluate and explore potential biomarkers in gastroesophageal adenocarcinoma, 
including DNA and RNA somatic mutation sequencing. Germline mutations will not be studied. 
If archival tissue is not available, the subject may still be eligible for the study provided they 
meet all other eligibility criteria. 
 
8.1.2 Samples obtained during standard of care biopsy 
Tissue samples remaining after routine standard of care procedures will be requested for 
correlative studies. Subject consent will be obtained.  
 
8.2 
Peripheral Blood Samples 
Samples will be collected at Cycle 1 Day 1 visit, at the time of first restaging (prior to Cycle 6) 
and at the safety visit. Correlative analysis will include: ctDNA analysis and PBMCs for flow 
cytometry.. 
 
8.3 
Stool Collection for Microbiome Analysis 
Stool for microbiome analysis will be collected after registration to the study and prior to the 
start of treatment on C1D1.  
 
8.4 
Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional samples for future unspecified cancer 
related research. Hoosier Cancer Research Network will manage the banked samples. Samples 
will be retained for 15 years.  
 
This includes: 
• Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
• Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment 
on Cycle 1 Day 1, at the time of first restaging (prior to Cycle 6) and at the 30-day Safety 
Follow-up visit.  
• Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment on 
Cycle 1 Day 1 at the time of first restaging (prior to Cycle 6) and at the 30-day Safety 
Follow-up visit. 
• Unstained slides: Unstained slides will be obtained from the subject’s archived formalin 
fixed paraffin embedded tumor sample.  
 
8.5 
Storage of Biospecimens 
Any specimens remaining (leftover) once protocol described biospecimen-based studies are 
complete will be stored for future unspecified cancer related research for 15 years. Permission to 
retain the specimens will be obtained from subjects through informed consent.  


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8.6 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s sequence ID assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s study number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
For the purposes of this study, patients should be re-evaluated for response per the study 
calendar. Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee 
(version 1.1) (see Eisenhauer EA et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Can, 2009.45:p.228-247) and the iRECIST 
criteria. See Seymour, L. et al. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3): e143-3152. 
 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
9.1.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.2 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 


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largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
9.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1 (Eur J Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm.
Partial Response 
(PR) 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note:  the 
appearance of one or more new lesions is also considered 
progressions).
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
 
 
 


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9.6 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (<10 mm short axis) 
 
NOTE:  If tumor markers are initially above the 
upper normal limit, they must normalize for a subject 
to be considered in complete clinical response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of 
overall disease status change, not a single lesion 
increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR 
CR
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
CR 
Not evaluated
No
PR 
PR 
Non-PD/ or not all 
evaluated
No 
PR 
SD 
Non-PD or not all evaluated
No
SD 
Not all evaluated 
Non-PD
No
Non-evaluable
PD 
Any
Yes or No
PD 
Any 
PD*
Yes or No
PD 
Any 
Any
Yes
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 


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9.7 
Definitions for Response Evaluation – RECIST 1.1 
 
9.7.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.7.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
9.7.3 iRECIST 
See Appendix C for details regarding iRECIST. 
 
10. 
DRUG INFORMATION 
 
10.1 
mFOLFOX6 
mFOLFOX6 is a chemotherapy regimen that includes leucovorin calcium (calcium folinate), 5-
fluorouracil, and oxaliplatin. These drugs are commercially available and will be dispensed as 
such for this study. For more information on these agents, refer to the FDA approved package 
inserts. 
 
10.1.1 Oxaliplatin 
Oxaliplatin is a platinum alkylating agent, which contains platinum complexed to oxalate and 
diaminocyclohexane (DACH) complex. Platinum complexes are formed intracellularly and 
inhibit DNA synthesis through covalent binding of DNA molecules to form intrastrand and 
interstrand DNA cross-links. Oxaliplatin differs molecularly, from other platinums (cisplatin and 
carboplatin), by its bulky DACH carrier ligand that most likely accounts for both its efficacy and 
lack of cross-resistance with other platinum compounds. Cytotoxicity is cell-cycle nonspecific. 
Oxaliplatin is a radiationsensitizing agent.  
 
*Oxaliplatin is incompatible with 0.9% NaCl. *Oxaliplatin is incompatible in solution with 
alkaline medications or media and must not be mixed with these.  *Storage and handling 
materials containing aluminum parts that may come in contact with oxaliplatin should not be 
used for preparation or mixing of the drug, as aluminum can degrade platinum compounds. 
 
1) The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for 
the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer 
the reconstituted solution without further dilution.   
 
2) After reconstitution in the original vial, the solution may be stored up to 24 hours under 
refrigeration [2º to 8°C (36º to 46° F)]. Do not freeze the concentrated solution. 
 
3) The solution must be further diluted in an infusion solution of 250-500 mL of D5W.  A final 
dilution must never be performed with a sodium chloride solution or other chloride-containing 
solutions.  Concentration must be between 0.2 to 0.7 mg/mL. 
 


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4) After final dilution with D5W, the shelf life is 6 hours at room temperature [20º to 25°C (68º 
to 77°F)] or up to 24 hours under refrigeration [2º to 8°C (36º to 46°F)].  
 
5) Store under normal lighting conditions at 20°-25°C (68°-77°F); excursions permitted to 15-
30°C (59- 86°F)]. Do not freeze. 
 
10.1.2 Leucovorin 
Leucovorin calcium (folinic acid) is a reduced form of folic acid. It is usually used 24 hours after 
methotrexate to selectively “rescue” normal cells from the adverse effects of methotrexate 
caused by inhibition of production of reduced folates. It is not used simultaneously with 
methotrexate, as it might then nullify the therapeutic effect of the methotrexate. Leucovorin has 
also been used to enhance the activity of fluorouracil by binding to the enzyme thymidylate 
synthetase and decreasing intracellular levels of thymidylate. Leucovorin is available in D and L 
stereoisomers; the L stereoisomer is the active moiety. 
 
* Each 50, 100, and 200 mg vial of Leucovorin when reconstituted with 5, 10, and 20 mL, 
respectively, of sterile diluent yields a leucovorin concentration of 10 mg per mL. Each 350 mg 
vial of Leucovorin when reconstituted with 17.5 mL of sterile diluent yields a leucovorin 
concentration of 20 mg per mL. *Leucovorin should not be mixed in the same infusion as 
fluorouracil as a precipitate may form. 
 
1) Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP 
(benzyl alcohol preserved), or Sterile Water for Injection, USP.  When reconstituted with 
Bacteriostatic Water for Injection, the resulting solution must be used within 7 days. If the 
product is reconstituted with Sterile Water for Injection, use immediately and discard any unused 
portion. Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, when 
doses greater than 10 mg/m2 are administered, Leucovorin should be reconstituted with Sterile 
Water for Injection, and used immediately. 
 
2) Dilute leucovorin in 50-1000 mL D5W or NS for infusion. Lecovorin may be mixed in 50mL 
NS or D5W minibag (doses up to 500mg) or 100mL minibag (doses >500mg) or in 100mL fluid 
in graduated administration set (D5W, NS or 2/3-1/3).  Parenteral admixture is stable for 24 
hours stored at room temperature (25°C) and for 4 days when stored under refrigeration (4°C).  
 
3) Lyophilized powder vials should be stored at 20° to 25°C (68° to 77° F). Solution for injection 
should be stored in refrigerator 2° to 8°C (36° to 46°F).  Protect from light. Retain in carton until 
time of use.   
 
10.1.3 5 Fluorouracil 
Fluorouracil was developed based on the observation that tumor cells utilized the base pair uracil 
for DNA synthesis more efficiently than did normal cells of the intestinal mucosa. It is a 
fluorinated pyrimidine antimetabolite that is metabolized intracellularly to its active form, 
fluorouridine monophosphate (FdUMP). The active form inhibits DNA synthesis by inhibiting 
thymidylate synthetase and the normal production of thymidine. Effects on RNA (incorporation 
into RNA and RNA inhibition) occur especially with bolus administration. Fluorouracil is cell 
cycle phase-specific (S-phase). 


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*1 vial of Fluorouracil Injection contains: 500 mg fluorouracil in 10 ml solution (50 mg/ml); 
1000 mg fluorouracil in 20 ml solution (50 mg/ml); 2500 mg fluorouracil in 50 ml solution (50 
mg/ml); 5000 mg fluorouracil in 100 ml solution (50 mg/ml) 
 
1) Fluorouracil may be mixed in a 50 mL minibag of NS or D5W, yielding a clear, colorless to 
light yellow solution.  Solutions of fluorouracil are expected to be stable in solution 7 days at 37 
°C, several weeks at 25 °C, and at least 4 months at 0-4 °C.  
 
2)  Store 5-fluorouracil in airtight containers protected from light. 
 
10.1.4 Adverse Events 
• Neuropathy  
• Nausea 
• Vomiting 
• Increased liver function testing 
• Diarrhea  
• Fatigue 
• Mucositis 
• Abdominal pain 
• Myelosuppression 
• Infection 
• bleeding  
• Rash, hand-foot syndrome 
• Pharyngolaryngeal dysesthesia 
 
10.2 
Trastuzumab 
Trastuzumab is commercially available and will be dispensed as such for this study. Please refer 
to the latest version of the prescribing information for additional information. The biosimilar for 
trastuzumab may be used. Biosimilar means that the biological product is approved based on 
data demonstrating that it is highly similar to an FDA-approved biological product, known as a 
reference product, and that there are no clinically meaningful differences between the biosimilar 
product and the reference product. Please refer to the latest version of the prescribing 
information for additional details for the biosimilar if used. 
 
Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high 
affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, 
HER2. Trastuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese 
Hamster Ovary) culture containing the antibiotic gentamicin. Gentamicin is not detectable in the 
final product. The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein 
of 185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab 
has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human 
tumor cells that overexpress HER2. 
 


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10.2.1 Supplier/How Supplied 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for Injection, 
for intravenous administration. 
 
420 mg Multiple-dose vial 
Trastuzumab for Injection 420 mg/vial is supplied in a multiple-dose vial as a lyophilized sterile 
powder, under vacuum. Each carton contains one multiple-dose vial of trastuzumab and one vial 
(20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a 
preservative.  
 
150 mg Single-dose vial 
Trastuzumab for Injection 150 mg/vial is supplied in a single-dose vial as a lyophilized sterile 
powder, under vacuum. Each carton contains one single-dose vial of trastuzumab.  
 
10.2.2 Preparation for administration 
420 mg Multiple-dose vial 
Reconstitution 
Reconstitute each 420 mg vial of trastuzumab with 20 mL of Bacteriostatic Water for Injection 
(BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution 
containing 21 mg/mL trastuzumab that delivers 20 mL (420 mg trastuzumab). In patients with 
known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection 
(SWFI) without preservative to yield a single use solution. 
Use appropriate aseptic technique when performing the following reconstitution steps: 
• Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the 
lyophilized cake of trastuzumab. The stream of diluent should be directed into the 
lyophilized cake. The reconstituted vial yields a solution for multiple-dose use, containing 
21 mg/mL trastuzumab. 
• Swirl the vial gently to aid reconstitution. DO NOT SHAKE. 
• Slight foaming of the product may be present upon reconstitution. Allow the vial to 
stand undisturbed for approximately 5 minutes. 
• Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Inspect 
visually for particulates and discoloration. The solution should be free of visible 
particulates, clear to slightly opalescent and colorless to pale yellow. 
• Store reconstituted trastuzumab in the refrigerator at 2○C to 8○C (36°F to 46°F); discard 
unused Trastuzumab after 28 days. If Trastuzumab is reconstituted with SWFI without 
preservative, use immediately and discard any unused portion. Do not freeze. 
Dilution 
• Determine the dose (mg) of Trastuzumab [see Dosage and Administration (2.2)]. 
Calculate the volume of the 21 mg/mL reconstituted Trastuzumab solution needed, 
withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 
0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) 
SOLUTION. 
• Gently invert the bag to mix the solution. 


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• The solution of Trastuzumab for infusion diluted in polyvinylchloride or polyethylene 
bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C 
(36°F to 46°F) for no more than 24 hours prior to use. Do not freeze. 
 
150 mg Single-dose vial 
Reconstitution 
Reconstitute each 150 mg vial of Trastuzumab with 7.4 mL of Sterile Water for Injection 
(SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that 
delivers 7.15 mL (150 mg trastuzumab). 
Use appropriate aseptic technique when performing the following reconstitution steps: 
• Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial 
containing the lyophilized 150 mg Trastuzumab, directing the diluent stream into the 
lyophilized cake. The reconstituted vial yields a solution for single-dose use, containing 
21 mg/mL trastuzumab. 
• Swirl the vial gently to aid reconstitution. DO NOT SHAKE. 
• Slight foaming of the product may be present upon reconstitution. Allow the vial to 
stand undisturbed for approximately 5 minutes. 
• Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Inspect 
visually for particulates and discoloration. The solution should be free of visible 
particulates, clear to slightly opalescent and colorless to pale yellow. 
• Use the Trastuzumab solution immediately following reconstitution with SWFI, as it 
contains no preservative and is intended for single-dose only. If not used immediately, 
store the reconstituted Trastuzumab solution for up to 24 hours at 2○C to 8○C (36○F to 
46○F); discard any unused Trastuzumab after 24 hours. Do not freeze. 
Dilution 
• Determine the dose (mg) of Trastuzumab [see Dosage and Administration (2.1)]. 
• Calculate the volume of the 21 mg/mL reconstituted Trastuzumab solution needed. 
• Withdraw this amount from the vial and add it to an infusion bag containing 250 mL 
of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) 
SOLUTION. 
• Gently invert the bag to mix the solution. 
• The solution of Trastuzumab for infusion diluted in polyvinylchloride or polyethylene 
bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C 
(36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This 
storage time is additional to the time allowed for the reconstituted vials. Do not 
freeze. 
 
10.2.3 Storage  
Store Trastuzumab vials in the refrigerator at 2°C to 8°C (36°F to 46°F) until time of 
reconstitution. 
 
10.2.4 Adverse Events 
Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, 
weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, 


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nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in 
discontinuation of treatment on the Trastuzumab containing arm in the absence of disease 
progression were infection, diarrhea, and febrile neutropenia. Less common adverse events that 
can be serious include embryo-fetal toxicity, pulmonary toxicity, cardiac toxicity, infusion 
reaction and exacerbation of chemotherapy-induced neutropenia. Please see prescribing 
information for full details regarding adverse events. 
 
10.3 
Avelumab 
EMD Serono will supply avelumab for this study. Please refer to the current version of the 
Investigator’s Brochure (IB) for additional information regarding this drug. 
 
The active pharmaceutical ingredient in avelumab drug product is a fully human antibody of the 
IgG1 isotype that specifically binds to the PD-L1 cell-surface molecule and blocks the 
interaction between PD-L1 and its receptors, programmed death 1 (PD-1) and B7-1. 
 
10.3.1 Supplier/How Supplied 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution presented at 
concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United States 
Pharmacopeia (USP) type I glass vials closed with a rubber stopper and sealed with an aluminum 
Flip Off® crimp seal closure. 
 
Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered 
solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween20). For avelumab drug 
product, only excipients that conform to the current Ph. Eur. and/or the current USP are used. 
 
10.3.2 Preparation  
For administration in clinical trials, avelumab drug product must be diluted with 0.9% saline 
solution (sodium chloride injection) supplied in an infusion bag; alternatively a 0.45% saline 
solution can be used if needed. The chemical and physical in-use stability for the infusion 
solution of avelumab in 0.45% or 0.9% saline solution has been demonstrated for a total of 24 
hours at room temperature. However, from a microbiological point of view, the diluted solution 
should be used immediately. If not used immediately, it can be considered that the diluted 
product is sufficiently stable from a microbiological perspective for up to 8 hours when stored at 
ambient room temperature or up to 24 hours at 2°C to 8°C. The in-use storage times and 
conditions prior to administration are the responsibility of the user. 
 
10.3.3 Storage and Stability 
Avelumab drug product must be stored at 2°C to 8°C until use. The storage condition is based on 
data from ongoing long term stability studies with avelumab. Avelumab drug product stored at 
room (23°C to 27°C) or higher temperatures for extended periods of time might be subject to 
degradation. Avelumab drug product must not be frozen. Rough shaking of the solution must be 
avoided. 
 


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10.3.4 Handling and Disposal 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
10.3.5 Dispensing 
Avelumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Avelumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.3.6 Adverse Events 
Please see the Investigator’s Brochure for complete details regarding adverse events. Common 
side effects include: 
• Fatigue 
• Peripheral edema 
• Musculoskeletal pain (back pain, neck pain, pain in extremities) 
• Diarrhea 
• Nausea 
• Infusion-related reactions (chills, fever, back pain, hypersensitivity reactions and low 
blood pressure, 
• Rash and skin redness 
• Decreased appetite 
 
Immune mediated adverse events include: colitis, skin reaction, pulmonitis, liver dysfunction, 
renal failure, myocarditis, endocrine abnormalities and infusion reaction. 
 
11. 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v5.0 will be utilized for AE 
assessment. A copy of the CTCAE v5.0 can be downloaded from the CTEP website at 
http://ctep.cancer.gov.  
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 
• An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests Hospitalization for elective 
surgery or routine clinical procedures that are not the result of an AE (e.g., surgical insertion of 


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central line) should not be recorded as an AE. Disease progression should not be recorded as an 
AE, unless it is attributable to the study regimen by the site investigator. 
 
11.1.2 Serious Adverse Event (SAE) 
 
A SAE is an adverse event that: 
• Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Other Reportable Events 
These events are considered important medical events and should be reported as SAEs 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 
• Occupational exposure (even if not associated with an adverse event) 
• Potential drug-induced liver injury (Hy’s Law cases) 
 
11.1.4 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
 
 


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11.1.5 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.2 
Reporting 
 
11.2.1 Adverse Events  
• AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) and/or until a new anti-cancer treatment starts, 
whichever occurs first.  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
• Asymptomatic laboratory abnormalities that do not require treatment will not be collected 
as adverse events. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
• SAEs will be reported from time of signed informed consent until 90 days after 
discontinuation of study drug(s) and/or until a new anti-cancer treatment starts, 
whichever occurs first.  
• SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
• SAEs include events related and unrelated to the study drug(s).  
• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 


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Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-
up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
11.2.2.2 
HCRN Requirements for Reporting SAEs to EMD Serono 
HCRN will report all SAEs to EMD Serono as stipulated by company within 1 business day of 
receipt of the SAE Submission Form from a site. Follow-up information will be provided to 
EMD Serono as it is received from site.  
 
Contact information for submission of reportable events to EMD Serono: Fax: +49 6151 72 6914 
OR E-mail: icsr_CT_GPS@merckgroup.com Specify: PROTOCOL Number, SUBJECT Number, 
SITE Number/PI Name, and SAE/ONSET DATE. 
 
11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.4 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
EMD Serono’s parent IND at the time of submission. Additionally, HCRN will submit a copy of 
these documents to EMD Serono at the time of submission to FDA. 
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report. Additionally, HCRN will submit a copy of these reports to 
EMD Serono at the time of submission to FDA. 
 
11.5 
 IND Safety Reports Unrelated to this Trial 
IND Safety Reports unrelated to this trial will not be provided to HCRN.  If there is an urgent 
safety issue related to Avelumab the sponsor-investigators will be informed immediately.  
HCRN will forward any urgent safety updates to participating sites within 1 business day of 
receiving the sponsor-investigator’s review.  Based on the sponsor-investigator’s review, 
applicable changes will be made to the protocol and informed consent document (if required).  
Any urgent safety update will also be made available to sites via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
urgent safety updates to their respective IRBs, as per their IRB policies. 
 
 
 


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12 
STATISTICAL METHODS 
 
12.1 
Study Design 
The initial intent of this study was to be a prospective, open-label, single arm, multi-center phase 
2 clinical trial of avelumab + trastuzumab + mFOLFOX6 in first-line, metastatic, HER2-
amplified gastric and esophageal adenocarcinomas. Accrual will halt after enrollment of 18 
subjects (completion of Stage I). This decision is not due to safety issues. Subjects currently on 
treatment will continue until criteria as defined in Section 6.7 is met. 
 
The primary objective of this study is to estimate the best objective response rate (CR or PR, 
ORR) in these patients within 24 weeks by RECIST 1.1 criteria.  Secondary objectives include; 
estimating PFS by both RECIST 1.1 and iRECIST criteria, estimating OS, estimating the disease 
control rate (DCR) at 24 weeks by RECIST 1.1 and iRECIST, and characterizing the safety 
issues associated with this regimen. Exploratory objectives involve investigating various 
biomarkers and peripheral blood and tumor assays. 
 
12.2 
Sample Size and Accrual 
The objective response rate of treatment with mFOLFOX6 + trastuzumab alone (per ToGA) is 
approximately 47%. The objective response rate of the treatment regimen which contains the 
addition of avelumab to mFOLFOX6 + trastuzumab is expected to be 65%. A Simon two-stage 
optimal design will be used, with alpha = 0.05 and 80% power, and with the null and alternative 
hypothesis response rates of 47% and 65%, respectively.  
 
In the first stage, 18 evaluable patients will be enrolled and treated. If only 9 (or less) of these 18 
patients are responders during this first stage, the trial will be suspended for futility. Enrollment 
will halt after this first stage. 
 
The intent was that if 10 (or more) responses are observed, then another 39 patients would be 
enrolled and treated in the second stage, for a total of 57 evaluable patients. If only 32 patients 
(or less) of the final total of 57 evaluable patients responded to this treatment regimen, then the 
regimen would not be considered of clinical interest. If 33 or more responses were observed 
among the 57 evaluable patients, then the treatment regimen would be considered of clinical 
interest and would therefore justify further development. Assuming a possible 10% consent and 
not treat or loss to follow-up rate, a total of 63 patients were planned for accrual. Accrual was 
expected to take approximately 22 months.  
 
12.3 
Toxicity Monitoring 
Toxicity will be assessed using NCI CTCAE version 5. Patients will be monitored for excessive 
toxicity over the duration of the study. A toxicity rate due to the study regimen greater than 35% 
would be considered unacceptable (with a desired probability of early stopping of 0.05). Toxicity 
events that will be monitored are defined as those that call for permanent discontinuation of 
avelumab, as defined in Section 6.3 or any grade 3-4 treatment-related adverse events that 
require holding all treatments for more than 14 days. 
 
Pocock-type boundaries will be utilized as described in Ivanova, A., et al. Biometrics. 2005; 
61(2):540-5.  If a toxicity boundary is reached, accrual for the study will be suspended and the 


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Data Safety Monitoring Board (DSMB) will be alerted. The DSMB (in consultation with the 
sponsor-investigator) will evaluate the toxicity events to help determine whether or not to 
terminate the study. 
 
Accrual to the trial is to be suspended if the number of protocol defined toxic events as defined 
above is equal to or larger than boundary in the table below. 
 
Number of Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary 
- - - - 5 6 6 7 7 8 9 9 10 10 11 11 12 12 12 13 
Number of Patients 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary 
13 14 14 15 15 16 16 17 17 18 18 18 19 19 20 20 21 21 22 22 
Number of Patients 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 
Boundary 
22 23 23 24 24 25 25 25 26 26 27 27 28 28 28 29 29 30 30 31 
 
12.4 
Assessment of Safety 
All subjects who have received at least one dose of study treatment will be evaluable for 
assessment of safety. CTCAE v5 will be used for assessment of safety. 
 
12.5 
Assessment of Efficacy 
All subjects who have received at least one cycle of study treatment and have had at least one 
post baseline disease assessment or die of any cause before the first post baseline disease 
assessment will be evaluable for assessment of efficacy. Only subjects who have a CR or PR by 
RECIST 1.1 will be considered responders. Consequently, for all subjects who discontinue study 
treatment before documentation of progression, every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
12.6 
Definitions 
• Best Objective Response Rate (bORR): The best objective response rate will be defined 
as the total number of patients whose best response by 24 weeks are either a CR or PR 
divided by the number of response evaluable patients  
• Progression Free Survival (PFS): A patient’s progression-free survival (PFS) will be 
defined as the time from the start date of treatment to the date of documented progression 
or death. Any patient who has received study treatment but has neither progressed nor 
died will be censored on the date the patient was known to be alive and progression free. 
• Overall Survival (OS): A patient’s survival time will be defined as the time from start of 
treatment to the date of his or her death. If the patient has not died, survival will be 
censored on last date the patient was known to be alive.  
• Disease Control Rate (DCR): The disease control rate used to help determine clinical 
benefit will be defined as the total number of patients whose responses are either a CR, 
PR, or SD divided by the number of response evaluable patients. Patients will need to be 
at least a SD for at 24 weeks to be considered to have received clinical benefit from the 
treatment regimen 
 
 


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12.7 
Data Analyses Plans 
bORR and DCR will be calculated and reported with their corresponding 95% confidence 
intervals. PFS and OS estimates will be calculated using the Kaplan-Meier method. The primary 
analysis will apply to the total number of efficacy-evaluable patients. Toxicity and safety 
information will be reported in a descriptive manner in the form of frequency tables. Adverse 
events will be classified and graded according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE, version 5.0). 
 
Hypothesis generating exploratory analyses will be performed when appropriate sample size 
considerations allow. Baseline tumor studies may include PD-L1 expression, degree of HER2 
amplification, sequencing of low-diversity B and T cell receptors, and RNASeq to include 
deconvolution of immune cell infiltrates. Changes in circulating markers of immune activation 
and circulating tumor DNA levels will be evaluated using peripheral blood samples collected at 
baseline, at first restaging, and at the end of treatment. 
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB). The DSMB is chaired by an 
independent medical oncologist external to this trial. The DSMB will meet quarterly during the 
active treatment and safety follow-up portion of the trial to review information. The DSMB will 
provide a recommendation to the sponsor-investigator after all information is reviewed.  
The DSMB review will include but is not limited to: 
• Adverse event summary report 
• Audit results if applicable 
• Data related to stopping/decision rules described in study design 
• Study accrual patterns  
• Protocol deviations 
 
13.2 
Data Quality Oversight Activities by HCRN 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.  
 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause audits may be performed as necessary. Selected source 
documents will be reviewed for verification of agreement with data entered into the EDC system.  
It is important for the site investigator and their relevant personnel to be available for a sufficient 
amount of time during the monitoring visits or audit, if applicable. The site investigator and 
institution guarantee access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by EMD Serono or its designee as well 
as inspection by appropriate regulatory agencies. 


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13.3 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform (EDC system), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations. HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and entered 
into the EDC system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  


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Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, EMD Serono, IRB, or government agencies, like the 
FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. If the results of the study are published, the subject’s 
identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 
 


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16 
APPENDICES 
APPENDIX A:  ECOG Performance Status Scale 
 
Score 
Definition 
Karnofsky Equivalent 
0 
Asymptomatic 
100 
1 
Symptomatic, fully ambulatory 
80 – 90 
2 
Symptomatic, in bed less than 50% of day 
60 – 70 
3 
Symptomatic, in bed more than 50% of day,  
but not bedridden 
40 – 50 
4 
Bedridden 
20 – 30 
 
 
 
APPENDIX B:  Cockcroft-Gault Formula 
 
 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        
x 0.85 
72 x serum creatinine (mg/dL) 


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APPENDIX C:  Immune-RECIST Criteria 
Table 1: Comparison of RECIST 1.1 and iRECIST 
 
RECIST 1.1 
iRECIST 
Definitions of measurable 
and non-measurable disease; 
numbers and site of target 
disease 
Measurable lesions are ≥10 
mm in diameter (≥15 mm for 
nodal lesions); maximum of 
five lesions (two per organ); 
all other disease is considered 
non-target  
(must be ≥10 mm in short 
axis for nodal disease)
No change from RECIST 1.1; 
however, new lesions are 
assessed as per RECIST 1.1 
but are recorded separately on 
the case report form (but not 
included in the sum of lesions 
for target lesions identified at 
baseline)
Complete response, partial 
response, or stable disease 
Cannot have met criteria for 
progression before complete 
response, partial response, or 
stable disease
Can have had iUPD (one or 
more instances), but not 
iCPD, before iCR, iPR, or 
iSD
Confirmation of complete 
response or partial response 
Only required for non-
randomized trials
As per RECIST 1.1 
Confirmation of stable 
disease 
Not required 
As per RECIST 1.1 
New lesions 
Result in progression; 
recorded but not measured 
Results in iUPD but iCPD is 
only assigned on the basis of 
this category if at next 
assessment additional new 
lesions appear or an increase 
in size of new lesions is seen 
(≥5 mm for sum of new 
lesion target or any increase 
in new lesion non-target); the 
appearance of new lesions 
when none have previously 
been recorded, can also 
confirm iCPD
Independent blinded review 
and central collection of 
scans 
Recommended in some 
circumstances—eg, in some 
trials with progression-based 
endpoints planned for 
marketing approval
Collection of scans (but not 
independent review) 
recommended for all trials 
Confirmation of progression 
Not required (unless 
equivocal)
Required 
Consideration of clinical 
status 
Not included in assessment 
Clinical stability is 
considered when deciding 
whether treatment is 
continued after iUPD 
“i” indicates immune responses assigned using iRECIST. RECIST=Response Evaluation 
Criteria in Solid Tumors. iUPD=unconfirmed progression. iCPD=confirmed progression. 
iCR=complete response. iPR=partial response. iSD=stable disease.
 
 
 


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Table 2: Assignment of timepoint response using iRECIST 
 
Timepoint response with no 
previous iUPD in any category 
Timepoint response with 
previous iUPD in any 
category* 
Target lesions: iCR; non-target 
lesions: iCR; new lesions: no 
iCR 
iCR 
Target lesions: iCR; non-target 
lesions:  
non-iCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target 
lesions:  
non-iCR/non-iUPD; new 
lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target 
lesions:  
non-iCR/non-iUPD; new 
lesions: no 
iSD 
iSD 
Target lesions: iUPD with no 
change, or with a decrease from 
last timepoint; non-target 
lesions: iUPD with no change, 
or decrease from last timepoint; 
new lesions: yes 
Not applicable 
New lesions confirm iCPD if 
new lesions were previously 
identified and they have 
increased in size (≥5 mm in sum 
of measures for new lesion 
target or any increase for new 
lesion non-target) or number; if 
no change is seen in new lesions 
(size or number) from last 
timepoint, assignment remains 
iUPD
Target lesions: iSD, iPR, iCR; 
non-target lesions: iUPD; new 
lesions: no 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a 
further increase in the size of 
non-target disease (does not 
need to meet RECIST 1.1 
criteria for unequivocal 
progression) 
Target lesions: iUPD; non-target 
lesions: non-iCR/non-iUPD, or 
iCR; new lesions: no 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a 
further increase in sum of 
measures ≥5 mm; otherwise, 
assignment remains iUPD
 
 
 
 


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Timepoint response with no 
previous iUPD in any category 
Timepoint response with 
previous iUPD in any 
category* 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: no 
iUPD 
Remains iUPD unless iCPD is 
confirmed based on a further 
increase in previously identified 
target lesion iUPD in sum of 
measures ≥5 mm or non-target 
lesion iUPD (previous 
assessment need not have shown 
unequivocal progression)
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of a 
further increase in previously 
identified target lesion iUPD 
sum of measures ≥5 mm, 
previously identified non-target 
lesion iUPD (does not need to 
be unequivocal), or an increase 
in the size or number of new 
lesions previously identified
Target lesions: non-iUPD or 
progression; non-target lesions: 
non-iUPD or progression; new 
lesions: yes 
iUPD 
Remains iUPD unless iCPD is 
confirmed on the basis of an 
increase in the size or number of 
new lesions previously 
identified 
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 principles; if no 
pseudoprogression occurs, RECIST 1.1 and iRECIST categories for complete response, partial 
response, and stable disease would be the same. *Previously identified in assessment immediately 
before this timepoint. “i” indicates immune responses assigned using iRECIST. iCR=complete 
response. iPR=partial response. iSD=stable disease. iUPD=unconfirmed progression. non-iCR/non-
iUPD=criteria for neither CR nor PD have been met. iCPD=confirmed progression. 
RECIST=Response Evaluation Criteria in Solid Tumors.
Reference: Seymour, L. et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. 
Lancet Oncol. 2017;18(3): e143-3152. 
 
 
 


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