A Randomized, Open Labeled Phase II Pilot Study of Total Neoadjuvant Chemotherapy With FLOT ( FLOT-TNT) VS Standard Perioperative FLOT ( FLOTPOP) in Patients With Gastric or GEJ Cancer, and Assessment of CTDNA as Correlative Biological Response
Phase: PHASE2
Conditions: Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma
Sponsor: Baylor College of Medicine

Cover Page 
Study Protocol and Statistical Analysis Plan 
Official Title: A RANDOMIZED, OPEN LABELED PHASE II PILOT STUDY OF TOTAL 
NEOADJUVANT CHEMOTHERAPY WITH FLOT (FLOT-TNT) VS STANDARD PERIOPERATIVE 
FLOT (FLOTPOP) IN PATIENTS WITH GASTRIC OR GEJ CANCER, AND ASSESSMENT OF 
ASSOCIATION OF MOLECULAR CORRELATES AND RESPONSE (TOGAR) 
NCT#: 05567835 
Document Date: Protocol Version 1.5 (dated 10-23-2024) 
 

 
1 
H-50068 (Version 1.5 Dated 10/23/2024) 
A RANDOMIZED, OPEN LABELED PHASE II PILOT STUDY OF TOTAL NEOADJUVANT 
CHEMOTHERAPY WITH FLOT (FLOT-TNT)  VS STANDARD PERIOPERATIVE FLOT (FLOT-
POP) IN PATIENTS WITH GASTRIC OR GEJ CANCER, AND ASSESSMENT OF ASSOCIATION 
OF MOLECULAR CORRELATES AND RESPONSE (TOGAR) 
Protocol H- 50068 
Version 1.5 10-23-2024 
NCT05567835 
 
Coordinating Center:  
Dan L. Duncan Comprehensive Cancer Center  
  
                                                    Baylor College of Medicine Medical Center McNair Campus 
  
    7200 Cambridge Street. BCM 905  
  
Houston, TX 77030  
 
Principal Investigator: 
Tannaz Armaghany, MD  
                                                           Phone: 713-798-3750 
                                                           Email: Tannaz.Armaghany@bcm.edu 
 
 
Sub-Investigators:                            Benjamin Musher, MD 
Cary Hsu, MD 
Eric Silberfein, MD 
George Van Buren, MD 
Ramsey Camp, MD  
Karen Riggins, MD 
Shalini Makawita, MD 
Shilpa Jain, MD 
Celia Marginean MD 
Robert Sealock, MD 
Sarah Bich-Phuong To 
Mohamed Othman, MD 
Wasif Abidi, MD 
Jason Mills, MD 
Tara Keihanian, MD 
Fares Ayoub, MD 
Deepika Satish, MD 
 
                                                            
Statisticians:    
Susan Hilsenbeck, PhD 
                                                           Eunji Jo 
 
Clinical Sites: 
 
 
Baylor College of Medicine Medical Center McNair Campus 
Baylor St. Luke’s Medical Center (BSLMC) 
Harris Health System – Smith Clinic 
HCHD: Harris County Hospital District Ben Taub 
 
 
 
 
TMH: The Methodist Hospital 
 
 

 
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H-50068 (Version 1.5 Dated 10/23/2024) 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Title Page, footer  
The co-investigator list was updated, 
protocol version and version date were 
updated 
Version control/version tracking 
Study Schema 
Removed duplicate study schema 
The duplicate study schema eas 
removed 
Section 2.0 
Study Synopsis 
The negative diagnostic laparoscopic 
(DL) assisted cytology of peritoneal 
fluid cytology was updated from not 
more than 28 days before registration 
to not more than 42 days before 
registration. 
A DL at 42 days is an acceptable 
timeframe in standard of care 
approach. 
Section 12.1 
Inclusion Criteria 
The negative diagnostic laparoscopic 
(DL) assisted cytology of peritoneal 
fluid cytology was updated from not 
more than 28 days before registration 
to not more than 42 days before 
registration. 
A DL at 42 days is an acceptable 
timeframe in standard of care 
approach. 
 
 

 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................................................................... 3 
STATEMENT OF COMPLIANCE ................................................................................................................................................ 5 
LIST OF ABBREVIATIONS AND DEFINITIONS ........................................................................................................................... 6 
1.0 
STUDY SCHEMA ........................................................................................................................................................... 7 
2.0 
SYNOPSIS ..................................................................................................................................................................... 8 
3.0 
BACKGROUND ........................................................................................................................................................... 12 
4.0 
GENERAL STANDARD TREATMENT APPROACH ........................................................................................................ 14 
5.0 
DRUG INFORMATION ................................................................................................................................................ 17 
6.0 
STUDY RATIONALE .................................................................................................................................................... 17 
7.0 
HYPOTHESIS .............................................................................................................................................................. 17 
8.0 
OBJECTIVES ............................................................................................................................................................... 17 
8.1 
Primary Objective ............................................................................................................................................. 18 
8.2 
Secondary Objectives ..................................................................................................................................... 18 
8.3 
Exploratory Objectives ................................................................................................................................... 18 
9.0 
STUDY DESIGN ........................................................................................................................................................... 18 
10.0 
STUDY CALENDAR ..................................................................................................................................................... 21 
10.1 
Arm A: FLOT-TNT (Investigational Arm) .................................................................................................... 21 
10.2 
Arm B: FLOT-POP (Standard Arm) .............................................................................................................. 22 
11.0 
STAGING CRITERIA .................................................................................................................................................... 24 
12.0 
SUBJECT CRITERIA ..................................................................................................................................................... 24 
13.0 
TREATMENT PLAN ..................................................................................................................................................... 25 
13.2 
Treatment of subjects ..................................................................................................................................... 26 
13.3 
Growth factors .................................................................................................................................................. 26 
14.0 
FOLLOW-UP PERIOD.................................................................................................................................................. 27 
15.0 
CRITERIA AT DISEASE PROGRESSION: ....................................................................................................................... 27 
16.0 
CRITERIA FOR REMOVAL FROM STUDY TREATMENT ............................................................................................... 28 
17.0 
CRITERIA FOR REMOVAL FROM STUDY PROTOCOL .................................................................................................. 28 
18.0 
DOSE MODIFICATIONS .............................................................................................................................................. 28 
18.1 
General Considerations: ............................................................................................................................................ 28 
19.0 
 PERFORMANCE STATUS ........................................................................................................................................... 34 
20.0 
 CRITERIA FOR DISEASE EVALUATION DURING STUDY: ............................................................................................ 35 

 
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21.0 
 ADVERSE EVENT REPORTING ................................................................................................................................... 36 
22.0 
 STATISTICAL CONSIDERATIONS: ............................................................................................................................... 38 
23.0 
 DATA AND SAFETY MONITORING AND QUALITY ASSURANCE: ............................................................................... 40 
APPENDIX I: ANATOMICAL BOUNDARIES OF GECS ............................................................................................................... 41 
24.0 
 REFERENCES ............................................................................................................................................................. 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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STATEMENT OF COMPLIANCE 
 
This trial will be conducted in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), and the applicable United States (US) Code of Federal Regulations (CFR).  All 
personnel involved in the conduct of this study have completed Human Subjects Protection and Good Clinical 
Practice trainings. The protocol, informed consent form, recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval prior to implementation. Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. All changes to 
the consent form will be IRB approved; a determination will be made whether participants will need to be re-
consented.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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H-50068 (Version 1.5 Dated 10/23/2024) 
 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation 
Definition 
5FU 
5-fluorouracil  
AC  
Adenocarcinoma  
ACRT 
Adjuvant Chemoradiation  
AE 
Adverse Event 
BSA 
Body Surface Area 
CAP 
College of American Pathologists 
CI 
Continuous infusion  
CRC 
Colorectal Cancer  
CT   
Computed Tomography  
DFS 
Disease Free Survival 
DL 
Diagnostic laparoscopy 
ECOG  
Eastern Cooperative Oncology Group  
EGD 
Endoscopic Gastroduodenoscopy  
EUS 
Endoscopic Ultrasound 
FDG 
Fluorodeoxyglucose 
FLOT 
5fu+ LV + Oxaliplatin + Docetaxel 
GC 
Gastric Cancer  
GCSF 
Granulocyte Colony-Stimulating Factor 
GEA 
Gastroesophageal Adenocarcinoma  
GEC(s) 
Gastroesophageal Cancer(S) 
GEJ 
Gastroesophageal Junction Cancer 
HTAP 
Human Tissue Acquisition and Pathology 
LNRR  
Lymph Node Negativity Rate 
LV 
Leucovorin  
MRD  
Molecular Residual Disease 
PCR 
Pathologic Complete Response 
POP 
Perioperative Therapy  
PRBC 
Packed Red Blood Cell  
SCC  
Squamous Cell Carcinoma 
SOX 
S-1 And Oxaliplatin 
TNT 
Total Neoadjuvant Therapy 
TRG 
Tumor Regression Grade 
XELOX  
Xeloda And Oxaliplatin  
 
 
 
 
 
 
 
 

 
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Schema  
1.0 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2.0 
SYNOPSIS 
 
Title  
A Randomized Open Labeled Phase II Pilot Study Of Total Neoadjuvant 
Chemotherapy With FLOT (FLOT-TNT) vs Standard Perioperative FLOT (FLOT-
POP) in Patients with Gastric or GEJ Cancer, and Assessment of Association of 
Molecular Correlates and Response (TOGAR ) 
 
Phase 
II Pilot 
Number of 
Subjects  
25 evaluable subjects on each arm for a total of 50 evaluable subjects. 
Study Design  
Total Neoadjuvant Chemotherapy with FLOT (FLOT-TNT) vs Standard 
Perioperative Chemotherapy with FLOT. 
 
Participants will be randomized 1:1 to either Total Neoadjuvant chemotherapy with 
FLOT-TNT (all 4 cycles of chemotherapy before surgery) or standard of care 
FLOT-POP (2 cycles of chemotherapy before surgery and 2 cycles of 
chemotherapy after surgery).  Each cycle of chemo is 28 days long with chemo 
administered on Days 1 and Day 15 of the cycle.  
 
Arm A 
(Investigational) 
FLOT-TNT: Total Neoadjuvant chemotherapy with FLOT 
 
Arm B 
(Standard) 
FLOT-POP: Perioperative chemotherapy with FLOT 
 
Hypothesis 
Roughly 40-50% of subjects with GC/GEJ cancer on peri-operative chemotherapy 
do not complete their planned chemotherapy after surgery. Elimination of 
micrometastasis and increase in pathological nodal response correlates with 
survival.  Chemotherapy in the post-operative setting is more challenging for the 
subjects and is frequently incomplete.  In this study, we aim to evaluate the feasibility 
of giving all cycles of chemotherapy in the neoadjuvant setting (FLOT-TNT) to 
maximize pathological response that is known to impact overall survival. 
Currently, there are no known predictive or prognostic biomarkers to predict 
response or survival rates for treatment of locally advanced GC. There is a clear 
deficiency of knowledge regarding the pathogenesis of gastric and GEJ  cancer. We 
aim to study molecular markers through an integrative multi-“omic” approach in our 
exploratory analysis to better understand the biological behavior of these cancers. 
Further elucidation of the molecular proteogenomics of locally advanced GC and 
GEJ cancer will potentially lead to improvements in patient survival 
Primary 
Objective 
The primary objective is to determine the proportion of participants who complete 
all allocated cycles of chemotherapy by comparing Arms A and B. The completion 
rate in Arm A: FLOT-TNT is expected to be higher than in Arm B: FLOT-POP. 
 
Secondary 
Objectives 
To estimate the nodal pathological response rate by comparing the two study arms 
on surgical nodal status. The frequency of positive nodes is expected to be lower 
in Arm A: FLOT-TNT compared to Arm B: FLOT-POP.  
 
Primary 
Endpoint 
The proportion of participants who complete their allocated cycles of 
chemotherapy in both Arms A and B.  
 
Secondary 
Endpoints 
In both Arm A and Arm B: 
• 
Pathologic response and nodal status based on TRG 
 

 
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Exploratory 
Objectives 
In both arms A and B 
 
1) Elucidate the molecular signature (integrated genomic, transcriptomic, 
and proteomic changes) associated with pathological complete response 
rates (as determined by TRG) 
2) Assess for molecular (integrated genomic, transcriptomic, and proteomic) 
changes associated with arm A and arm B  
3) Determine the feasibility of establishing gastric and gastroesophageal 
cancer  organoids pre- and post- neoadjuvant FLOT chemotherapy as a 
mechanism to individualize treatment.   
4) Disease free survival  
 
Inclusion 
criteria 
 
 
a. Must provide written informed consent. 
b. Must be ≥18 years of age. 
c. Must have life expectancy of greater than 3 months. 
d. Must have pathologically proven Siewert type  II and III GEJ or gastric 
adenocarcinoma from the main tumor or local lymph nodes (pre-
neoadjuvant chemo).   
e. Stage cT2 or higher, any N and M0, are eligible for the study.  
f. 
M0 disease must be established by both negative distant metastatic 
disease on imaging AND negative cytology of peritoneal fluid collected 
from the diagnostic  laparoscopy not more than 42 days before registration.  
g. Must be a candidate for Neoadjuvant chemotherapy. 
h. Must be a candidate for curative surgical approach.  
i. 
Must have an ECOG performance status 0-2. 
j. 
Male or female subjects of childbearing potential must be willing to use    
contraceptive precautions throughout the trial and for 3 months after 
discontinuation of study treatment. Female subjects of childbearing 
potential must have a negative pregnancy test within 28 days of 
registration. Post-menopausal women must be amenorrhoeic for at least 12 
months to be considered of non-childbearing potential. 
k. Must have adequate kidney, liver, and bone marrow function, within 28 
days prior to registration, as follows: 
i. 
Hemoglobin ≥ 8.0 gm/dL (PRBC transfusion is allowed to meet this 
criteria)  
ii. 
Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 
iii. 
Platelet count ≥ 100,000 /mm3 
iv. 
Total bilirubin ≤ 1.5 times upper limit of normal (ULN) 
v. 
AST (SGOT) and ALT (SGPT) ≤ 3.0 times the ULN 
vi. 
Patient must have adequate renal function as evidenced by one of the 
following: Serum creatinine ≤ IULN OR calculated creatinine clearance 
≥ 60 mL/min. This serum creatinine result must be obtained within 28 
days prior to registration. 
 
Calculated creatinine clearance = (140 - age) x wt* (kg) x 0.85 (if female) 
                                                                  72 Creatinine** (mg/dl)  
*The kilogram weight is the subject’s actual body weight with an upper limit 
of 140% of the IBW. 
 
            ** Actual lab serum creatinine value with a minimum of 0.8 mg/dL 
 

 
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l. 
Subjects who have required a short course urgent single modality non 
curative radiation treatment or gastric artery embolization for the purpose of 
tumor bleeding control are eligible.  
 
Exclusion 
Criteria 
 
 
a. Positive cytology for metastatic disease on diagnostic laparoscopy 
peritoneal fluid. Reports such as: “cannot rule out malignancy” or 
“suspicious for malignancy, but not definitive” will exclude the subject from 
enrolling. 
b. Seiwert type I GEJ cancer 
c. Subjects with clinical evidence of metastatic disease. 
d. Biopsy proven metastatic disease (excluding regional lymph nodes)   
e. Prior chemotherapy for gastric or GEJ cancer. 
f. 
No other prior malignancy is allowed except for the following:  adequately 
treated basal cell or squamous cell skin cancer, current non-advanced 
prostate cancer per the discretion of the investigator, and any other 
cancers from which the patient has been disease free for two years. 
g. Female subjects who are pregnant, breast feeding, or of childbearing 
potential with a positive pregnancy test prior to baseline. Women of 
childbearing potential must have a negative serum pregnancy test as a part 
of eligibility within 28 days of registration.  A persistent positive or elevated 
urine or blood Beta HCG test may be contributed to the primary diagnosis 
of GC or GEJ cancer after ruling out ectopic and intrauterine pregnancy 
and germ cell tumors.  
h. Subjects unwilling or unable to comply with the protocol or provide written 
informed consent. 
i. 
Any medical condition that, in the opinion of the investigator, would exclude 
the subject from participating in this study and treatment plan. 
j. 
ECOG > 2 
 
Criteria For 
Evaluation 
Efficacy: Baseline scans and labs and CEA, RECIST criteria for response, surgical 
pathology evaluation post operation. 
Efficacy is analyzed by imaging, pathology review, and tumor marker. 
Investigational Biomarker: Integrated genomics, transcriptomics, and proteomics 
based on changes in pre and post treatment tissues. 
Statistical 
Methods 
Power Analysis of primary objective:  
Based on published data, we expect that 45% of subjects in the FLOT-POP arm will 
complete all allocated chemotherapy. We are expecting 90% of subjects in the 
FLOT-TNT arm will complete the first 2 cycles 22 and  about 90% of those will 
complete the second 2 cycles resulting in a completion rate of 80%. With 25 
evaluable subjects in each group, we will have 85% power (alpha=10%, one-tailed) 
to detect an absolute improvement of 35% (FLOT-TNT completion rate=80%) using 
a Fisher Exact test.  
 
Analysis Plan and Power of secondary objectives:  
 
Response rate:  
 
Based on published data, at time of surgery in the FLOT-POP group, we expect to 
see 49% N0, 16% N1, 13% N2, and 22% N3 (includes not operable). We expect 
that FLOT-TNT will increase the frequency of N0 and reduce the frequencies of the 
other categories, especially N2 and N3. The pathological N stage of ypN is an 
ordinal variable and in this setting, the effect size is measured by the probability that 

 
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a randomly selected subject in the FLOT-TNT population has a lower ypN value 
than a randomly selected subject from the FLOT-TNT group, expressed as 
Pr(ypN.FLOT-TNT < ypN.FLOT-POP). When the distribution of ypN is the same in 
both groups, the null hypothesis probability (p0) is 0.5, like flipping a coin. If, in the 
FLOT-TNT group, we observe a change to 75% N0, 16% N1, 3% N2 and 6% N3, 
the corresponding effect size would be p1=0.65. In this pilot study, relatively large 
effect sizes of this magnitude will be detectable with 80% power (alpha=10%, one-
tailed) using a Wilcoxon Rank Sum test. 
 
Analysis Plan of exploratory objective: 
 
Estimate the association between changes in the integrated genomic, 
transcriptomic, and proteomic changes , pathological response and DFS.  
 
Analysis Plan: Baseline molecular findings should be the same in both groups of this 
randomized trial, but changes in the molecular findings could portend different 
likelihood of N0 overall or within groups. Logistic regression with N0 status at 
surgery as the outcome of interest and treatment group,molecular genomic,  
transcriptomic, and proteomic findings with their interactions as explanatory 
variables will be used to look for associations and molecular signatures. We can use 
the same method to evaluate the predictive value of pre-surgical molecular 
signatures  and/or presurgical changes in molecular signatures.  We can also use 
repeated measures ANOVA or general linear mixed models to examine the pattern 
of changes in integrated genomic, transcriptomic, and proteomic changes over time, 
overall and as a function of treatment group.  
 
 
 
 

 
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3.0 
BACKGROUND 
 
Gastroesophageal cancers (GECs) are a major global health problem with wide geographic variation. 
The highest gastric cancer incidence rates occur in East Asia, south and Central America and Eastern 
Europe. It is the most commonly diagnosed cancer in men in Korea and Japan, and is the leading cause 
of cancer related mortality in China.1-3 
 
In the US, gastroesophageal cancers (GECs) together, represent the fourth most common GI cancer 
(after colorectal, pancreatic, and hepatobiliary cancers), with the third highest mortality. 4 An estimated 
276,600 people were diagnosed, and 11,010 people died of this cancer in 2020.5 
Five-year survival rates for locally advanced GC remains at 50% 6 despite improvements in surgery 
technique 7and chemotherapy 8 
 
The recent classification of GECs generally comprises three main gastroesophageal subtypes reflecting 
current understanding of anatomy, histology, etiology, and molecular biology. These include: (i) 
esophageal SCC; (ii)GEJ AC, which includes ACs in the distal esophagus AC (type I Siewert), at the GEJ 
AC (type II Siewert), and in the gastric cardia AC (type III Siewert); and (iii) distal gastric AC.9 
Siewert Type I: adenocarcinoma of the lower esophagus with the epicenter located within 1 cm to 5 cm 
above the anatomic EGJ. ◊ Siewert Type II: true carcinoma of the cardia with the tumor epicenter within 
1 cm above and 2 cm below the EGJ. ◊ Siewert Type III: subcardial carcinoma with the tumor epicenter 
between 2 cm and 5 cm below the EGJ, which infiltrates the EGJ and lower esophagus from below. 
 
Numerous histologic subtypes have been described pertinent to gastric AC but also for GEJ AC, including 
histologic differentiation (i.e., well, moderate, poor), Lauren classification (i.e., intestinal, diffuse, mixed 
type), presence of signet-ring cells or not, and a whole host of other subtypes in the WHO criteria.  Despite 
the noted differences between GEJ and gastric AC, these two subtypes are often grouped together as 
gastroesophageal adenocarcinoma (GEA) in both the locally advanced and metastatic settings when 
considering therapy (see Appendix I).  
 
Overall, 95% of gastric cancers are adenocarcinomas and divided to cardia (proximal) and non-cardia 
(distal) and the most common histological types are intestinal and diffuse types. The intestinal type is 
usually a well differentiated tumor seen more frequently in high-risk areas and accounts for most of the 
geographic variation. The diffuse type is defined by being undifferentiated and more prevalent in low-risk 
areas. The intestinal type is often related to H. pylori infection, smoking and high salt intake and alcohol 
is considered a risk factor for non-cardia gastric cancer. 3, 10-12 
Gastric and GEJ adenocarcinoma patients have a poor prognosis and compared with surgery alone, 
multimodality 
intervention 
including 
neoadjuvant 
chemotherapy, 
adjuvant 
chemotherapy 
or 
chemoradiation improves survival; however, the survival for locally advanced and node positive gastric 
cancer remains poor. At initial presentation, 50% of the cases are locally advanced and 80% are node 
positive by clinical staging and upfront surgery is not advised.  Surgical resection of adenocarcinoma of 
the stomach is curative in less than 40% of cases. Surgery alone provides a 5 year OS is 20-30% in 
locally node positive patients.  
The current best perioperative chemotherapy regimens result in pathologic complete response rates as 
determined by TRG of only 16 percent 13. In addition, no predictive or prognostic biomarkers exist to 
predict response or survival rates for treatment of locally advanced GC. There is a clear deficiency of 
knowledge regarding the pathogenesis of gastric cancer. Specifically, TCGA (The Cancer Genome Atlas 
program) characterization of GC and GEJ cancer  subtypes has not resulted in meaningful clinical 
improvements 14 Integrated proteogenomics studies are means to further our molecular understanding 
of cancer, and in particular in how tumors respond to treatment. 15 16, 17 18 Specific applications have been 
applied towards other GI cancers including colon cancer 19 and pancreatic cancer 20. Further elucidation 
into the molecular proteogenomic signatures of locally advanced GC and GEJ cancer will lead to 
improvements in patient survival.  

 
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3.1  
Treatment effect and Tumor Regression Grade  
Tumor regression grading (TRG) systems are used to categorize the amount of regressive 
changes after cytotoxic treatment in order to demonstrate potential prognostic information based 
on objectively determinable histopathologic findings. Multiple TRGs have been developed. The 
TRG systems according to Mandard, 21  Becker, Dworak, or Rödel are examples for commonly 
used TRGs, which represent different approaches for estimating the degree of tumor regression. 
In our study we will be utilizing College of American Pathologists 2020 Grading system for the 
evaluation of response to neoadjuvant chemotherapy.   
Most of TRG systems evaluate the amount of therapy‐induced fibrosis in relation to residual tumor 
only at the primary lesion after neoadjuvant therapy. Patients with complete response (pCR) or 
near complete regression of the tumor show significant survival benefit and reduced risk of 
recurrence. 21-23 The value of lymph node regression in gastric cancer was evaluated from a 
prospective database in patients who had neoadjuvant chemotherapy followed by surgery. 
Patients with complete response (pCR) or near complete regression of the tumor show significant 
survival benefit and reduced risk of recurrence. 24-25 Pathological response and histological tumor 
regression after neoadjuvant therapy have been shown to be predictive of survival in GC patients.  
The (MAGIC) trial established perioperative Epirubicin, Cisplatin, and Fluorouracil chemotherapy 
as a standard of care for patients with resectable esophagogastric cancer.  Investigators 
assessed the correlation between node status post treatment and overall survival of patients to 
identify high risk patients for relapse.  Two independent pathologists using the Mandard TRG 
assessed pathologic regression in resection specimens. Three hundred thirty resection 
specimens were analyzed. In chemotherapy-treated patients with a TRG of 1 or 2, median OS 
was not reached, whereas for patients with a TRG of 3, 4, or 5, median OS was 20.47 months.26 
In another study at Cancer Hospital of China Medical University, Liaoning Cancer Hospital, 264 
patients with locally advanced gastric carcinoma (including esophagogastric junction carcinoma) 
treated by perioperative chemotherapy (SOX or XELOX) from May 2012 to December 2017 were 
prospectively in this study. Tumor regression grade (TRG, Mandard system) and Response 
Evaluation Criteria in Solid Tumor (RECIST v1.1) was used to evaluate tumor response. The 
clinical characteristics and the effect on survival were analyzed. On multivariate analysis, the 
chemotherapy cycle, Lauren classification, vascular invasion or lymphatic invasion, ypN and 
postsurgical pathologic stage were independent factors for OS and DFS, while TRG were 
negatively correlated to survival.27 Lowy et al reported that response to neoadjuvant 
chemotherapy was the only independent predictor of OS in patients who undergo curative GC 
surgery.28   Recently CAP has provided a guideline for reporting treatment effect on gastric cancer. 
37        
 
3.2 
Diagnosis and Staging  
a. 
EGD/EUS:  
This procedure is used for evaluation of both depth of tumor invasion through the gastric 
tissue = (T staging) and nodal (N staging).  
b. 
Diagnostic Laparoscopy and peritoneal cytology: 

 
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This procedure is used for evaluation of the peritoneal cavity under direct visualization 
with laparoscopy and to collect peritoneal fluid for cytology evaluation to accurately stage 
the subject.  
c. 
Imaging:  
Radiographic staging is performed with either CT chest with contrast, CT abdomen and 
pelvis with and without contrast. or MRI of the abdomen and or pelvis with/without contrast 
and FDG. PET CT scan is performed in special circumstances to clarify radiographic 
staging.    
    
3.3 
Pathology Evaluation: 
Initial pathological diagnosis is achieved per EGD/EUS biopsy of the main mass. A full 
pathological evaluation will be done after surgery has been completed. 
Recently, the college of American Pathologist updated their specimen exanimation and reporting 
protocol on July 2021, and recommended the use of the 4-tier tumor regression score for 
reporting gastric cancer specimen pathological evaluation after neoadjuvant therapy. Although 
grading systems for tumor response have not been established in general, 4-category systems 
provide good inter observer reproducibility 37.  
 
 
4.0 
GENERAL STANDARD TREATMENT APPROACH  
 
A universal treatment of choice for patients with locally advanced GEC has been elusive due to lack of 
consensus in different parts of the world.   The outcomes of these patients are proven to improve with 
including chemotherapy, surgery and radiation. (Tri-modality).   
 
For any lesions ≥ T3 (tumor invading the muscularis propria [T3]) and/or N+ disease amenable to surgical 
resection, multimodal management with chemotherapy with or without radiation therapy (RT), before 
and/or after surgery has become the standard, given high-risk of micrometastastic dissemination.  
Neoadjuvant chemoradiation followed by surgery (tri-modality therapy) versus perioperative triplet 
chemotherapy are both standard options to treat locally advanced GEJ AC tumors to decrease risk of 
recurrence. The optimal approach between these two strategies is unresolved and head-to-head studies 
are ongoing that are evaluating this question. 
 
There is a great deal of controversy among different regions from Asia to Europe to North America. The 
different incidences of each of the subtypes of GEC (i.e., esophageal SCC, GEJ AC, and gastric AC) 
geographically has led to different makeup of these tumor types within various studies, making cross-trial 
comparisons challenging and potentially misleading. For instance, GEA studies from Asia are almost 
exclusively of distal gastric AC, without any patients with proximal GEJ AC enrolled, whereas in western 
countries, GEJ AC accounts for at least half of patients enrolled in GEA studies. Similarly, different 
makeup of esophageal SCC and AC within different esophageal studies also makes comparison across 
studies challenging because these subtypes have a different biology, natural history, and sensitivities to 
the perioperative therapies. As such, various combinations of variables (e.g., the tumor site inclusion, the 
modalities included, nuanced details of type of chemotherapy or RT, doses and the timing of treatment 
as related to surgery) were studied in large GEC trials across centers and countries in parallel, each 

 
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compared with surgery alone. This ultimately has led to a fragmented treatment approach, with each 
approach deemed to be more effective than surgery alone, but it remains unclear which, if any, is 
superior.  
 
4.1 
Chemoradiotherapy: 
 
Chemoradiotherapy 
after 
Surgery 
was 
compared 
with 
Surgery 
Alone 
for 
Gastroesophageal Junction Adenocarcinoma in McDonald Intergroup (INT) trial 0116, 
(SWOG 9008) study.29 In this trial postop chemo with 5FU+ LV with concurrent radiation 
followed by 2 months 5FU/LV was compared to surgery alone.  Overall survival was 36 vs 
27 months and superior in the chemoradiation arm.  Local failure was less seen in the 
chemoXRT arm, however, distant failure was similar. Neoadjuvant chemoradiation 
followed by surgery vs surgery alone was tested in CROSS trial 30. In this study, majority 
75% of patients had adenocarcinoma (esophageal and GEJ) and 23% had squamous cell 
carcinoma and their clinical stage consisted of T1N1M0 or T2-3N0-1M0. After a median 
follow-up for surviving adenocarcinoma patients of 84.1 months overall survival of 43.2 
months was seen in the neoadjuvant chemoradiotherapy plus surgery group and 27.1 
months in the surgery alone group. The outcomes were significantly better for esophageal 
and squamous cell GEJ patients (81.6 vs 21.1 months).30 Distant recurrence remains 
substantial despite incorporation of local therapies such as radiation and D2 
lymphadenectomy. Intergroup 0116 study showed no survival benefit with adjuvant 
chemoXRT after D2 lymphadenectomy. Similarly, CRTITICS trial showed no benefit with 
adding radiation to chemo if patients had received neoadjuvant chemotherapy and D2 
lymphadenectomy with gastrectomy. 31, 32 
 
4.2 
Perioperative chemotherapy: 
 
Perioperative chemotherapy has been studied in multiple trials. Survival benefit was 
reported by Perioperative chemotherapy seen in the MAGIC trial.33 In this trial, 503 
patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or 
lower esophagus were randomly assigned to either perioperative chemotherapy and 
surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three 
preoperative and three postoperative cycles of intravenous epirubicin and cisplatin and 
continuous intravenous infusion of fluorouracil for 21 days. As compared with surgery 
alone group, peri-operative chemotherapy showed a statistically significant five-year 
survival rate, 36% vs. 23% and an improved Progression free survival rate. In this trial, 
70% of patients had gastric, 12% had GEJ and 15% had lower esophageal 
adenocarcinoma. In the Magic trial, 43% of subjects did not receive post chemotherapy.  
 
In FNCLCC FFCD/ACCORD Multicenter Phase III Trial French 2011 (n 224) patients 
consisted of Lower esophagus adeno (15%), GC (20%) and GEJ (70%). Patients had 6 
months perioperative chemo (cis + 5FU) vs surgery alone. 5-year OS rate was 38% v 24% 
in favor of perioperative chemotherapy; however, only 50% got post op chemotherapy 
completed. Lymph node negativity was seen more commonly in the perioperative group. 
Patients who had perioperative chemotherapy had less distant metastatic disease (30% 
vs 38%).34 Al-Bartan et al studied 700 patients with GC/GEJC and randomized them to a 
trial evaluating Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, 
and docetaxel (FLOT) and compared that with fluorouracil or Capecitabine plus cisplatin 

 
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and Epirubicin (ECX or ECF) for locally advanced, resectable gastric or gastro-esophageal 
junction adenocarcinoma in a randomized, phase 2/3 trial. Four preoperative and four 
post-operative biweekly cycles of 50 mg/m 2 docetaxel, 85 mg/m 2 oxaliplatin, 200 mg/m 
2 leucovorin, and 2600 mg/m 2 fluorouracil as 24-h infusion on day 1 consisted of the 
FLOT regimen. The results showed the best mOS of 50 vs 35 months in favor of FLOT, 
where 65 % were GEJ, 44% were gastric adenocarcinoma and 50% of the patients had 
D2 lymphadenectomy. Three hundred and twenty six (91%) patients in the ECF/ECX 
group and 320 (90%) patients in the FLOT group completed all cycles of allocated 
preoperative chemotherapy; however, of all the patients randomized, only 132 (37%) 
patients in the ECF/ECX group and only 162 (46%) patients in the FLOT group completed 
all allocated cycles due to lower postoperative chemotherapy completion.8  
 
FLOT significantly improved other clinically relevant endpoints such as resectability and 
disease-free survival. Regarding surgical morbidity and mortality, similar results were 
observed in both arms in terms of 30-day postoperative death rates (2% in the FLOT group 
and 3% in the ECF/ECX group) and surgical complications (51% in the FLOT group and 
50% in the ECF/ECX group). Node negativity was seen more in FLOT group and it was 
associated with better OS in this group. This is the first trial to show significant 
improvement over the available standard of care ECF in the treatment of patients with 
locally advanced, potentially resectable gastric and gastro-esophageal junction 
adenocarcinoma. The study showed that perioperative FLOT significantly improved 
overall survival as compared with perioperative ECF or ECX (Epirubicin and cisplatin plus 
either fluorouracil or capecitabine. FLOT induced pathological complete regression of up 
to 17% in phase 2 and retrospective studies. 
 
 
 
4.3 Surgery and D2 Lymphadenectomy 
 
Surgery is the main stay of management of GECs; however, in node positive and bulky 
tumors this modality carries a very poor prognosis.   
Gastric cancer is treated with partial or total gastrectomy. Gastroesophageal cancer 
surgery is divided into three groups based on the Siewert subtype (see appendix I).  
Siewert Type I is treated with esophagectomy. Siewert Type II is treated with the 
combination of lower esophagectomy, and total gastrectomy and  Siewert Type III is 
treated with gastrectomy only. In this study only Siewert type II and III are included.  
Historically, survival has been poor for patients with GEC treated with surgery alone, with 
5-year survival rates ranging from 5% to 34% leading to several studies evaluating the 
benefit of perioperative therapies. Total or partial gastrectomy with D2 Lymphadenectomy 
is now adopted as standard of in North America.  A D2 lymphadenectomy is defined as 
the contiguous resection of the second tier of lymph nodes along the branches of the celiac 
trunk (e.g., common hepatic artery, left gastric artery, and splenic artery). After 15-year 
follow-up of a randomized Dutch trial that included 1,078 patients with distal gastric AC, 
D2 lymphadenectomy was associated with lower locoregional recurrence (12% v 22%) 
and gastric cancer-related death rates (37% v 48%) than D1 (fewer lymph nodes removed) 
surgery.35 Although D2 dissection was associated with higher operative morbidity, these 
data suggest D2 lymphadenectomy should be considered the surgical standard of care. 
Larger meta-analyses have confirmed this, particularly among patients who have 
undergone D2 resection who did not undergo resection of the spleen or distal pancreas 
and nodal stations around these (modified D2), as well as for patients with higher risk 
T3/T4 or node-positive cancers.36-37 

 
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5.0 
DRUG INFORMATION 
 
For this study, all drugs are commercially available; therefore, Investigator Brochures are not applicable 
to these drugs. Information about commercial drugs is publicly available in the prescribing information 
and other resources. 
6.0 
STUDY RATIONALE 
 
Locally advanced gastric and gastroesophageal adenocarcinoma carries a poor prognosis despite 
multimodality treatment including surgery, perioperative chemotherapy and chemoradiation. Currently 
perioperative chemotherapy and D2 lymphadenectomy is the standard of care for GC and GEJ cancers; 
however, a significant number of subjects are unable to complete all or part of the post op section of their 
chemotherapy due to surgical recovery. Total neoadjuvant therapy in rectal cancer has proven to achieve 
higher pathological response rate (PCR) and disease-free survival rates in rectal cancer subjects. 
Improved outcome in CRC subjects is partially associated with total  delivery of uninterrupted systemic 
therapy and eradication of micrometastasis.38 Furthermore, higher PCR has proven to be associated with 
better outcomes in CRC. Here we aim to approach gastric and GEJ subjects with the same approach to 
investigate whether total neoadjuvant therapy (TNT) improves subject outcomes or not. 
To date there are no predictive or prognostic biomarkers to predict treatment response or survival rates 
for locally advanced GC and GEJ cancer. Here we aim to evaluate the molecular signature (integrated 
genomic, transcriptomic, and proteomic changes) associated with pathological complete response rates 
for locally advanced GC and GEJ cancers. We will assess for molecular (integrated genomic, 
transcriptomic, and proteomic) changes associated with 2 vs 4 cycles of neoadjuvant FLOT 
chemotherapy and assess the association of DFS with the molecular finding changes. Each cycle 
consists of two treatments (D1 and D15). We will also determine the feasibility of establishing GC 
organoids pre- and post- neoadjuvant FLOT chemotherapy as a mechanism to individualize GC 
treatment.  
 
7.0 
HYPOTHESIS 
 
A large percent of subjects with GC/GEJ cancer on peri-operative chemotherapy do not complete their 
planned chemotherapy after surgery. About 63% of subjects in the MAGIC trial and 54% in FLOT4 trial 
did not complete the post-operative chemotherapy due to prolonged recovery and/or post-operative 
complications.20,22 Elimination of micrometastasis and increase in pathological nodal response correlates 
with survival.23-25 Chemotherapy in the post-op setting is more challenging for the subjects and is 
frequently incomplete. Here we aim to evaluate the feasibility of giving all 4 cycles of chemotherapy in 
the neoadjuvant setting (FLOT-TNT) and hypothesize that total neoadjuvant therapy (FLOT-TNT) 
provides an improved completion of intended chemotherapy, and improves nodal clearance that may 
ultimately translate into better OS in subsequent trials.  We also aim to evaluate the molecular (integrated 
genomic, transcriptomic, and proteomic ) findings and their changes associated with cancer response to 
2 or 4 cycles of FLOT neoadjuvant chemotherapy. 
 
8.0 
OBJECTIVES 
 

 
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8.1 
Primary Objective 
 
1. The primary objective is to determine the proportion of participants who complete all 
allocated cycles of chemotherapy by comparing Arms A and B. The completion rate 
in Arm A: FLOT-TNT is expected to be higher than in Arm B: FLOT-POP. 
8.2 
Secondary Objectives 
 
1. To estimate the nodal pathological response rate by comparing the two study arms 
on surgical nodal status. The frequency of positive nodes is expected to be lower in 
Arm A: FLOT-TNT compared to Arm B: FLOT-POP. 
8.3 
Exploratory Objectives 
 In both arms A and B 
1) Elucidate the molecular signature (integrated genomic, transcriptomic, and proteomic 
changes) associated with pathological complete response rates (as determined by 
TRG) 
2) Assess for molecular (integrated genomic, transcriptomic, and proteomic) changes 
associated with arm A and arm B. 
3)  Determine the feasibility of establishing gastric cancer and gastroesophageal junction 
cancer organoids pre- and post- neoadjuvant FLOT chemotherapy as a mechanism to 
individualize treatment.  
 
 
 
9.0 
STUDY DESIGN 
 
 
 
9.1 
Enrollment  
 
The cancer diagnosis will be established at the time of the initial EGD prior to study enrollment. 
Subjects must have staging scans and considered non metastatic based on scan reports before 
they are considered for this study. After enrollment all subjects will get a diagnostic laparoscopy 
(DL) and an EUS assisted staging of the cancer. Both DL and EUS staging is considered standard 
of care in the management of gastric and GEJ adenocarcinoma. Subjects with a positive DL tissue 
diagnosis for metastatic cancer will be excluded from the study as screen failures. Subjects with 
a negative DL on pathology review will proceed with registration and randomization.  
This study is a two-arm phase II pilot design, with eligible subjects randomized 1:1 to either Arm 
A (Investigational arm) or Arm B (Standard arm).  The chemotherapy dose modification will follow 
routine clinical care.  Both arms will receive chemotherapy and curative surgery.  
 

 
19 
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9.2 
Arm A: FLOT-TNT (Investigational Arm) 
 
Arm A is the investigational arm with all 4 cycles of FLOT given as total neoadjuvant 
chemotherapy prior to surgery. Each cycle is 28 days and consists of 2 chemotherapy sessions 
given every 14 days. The total number of chemotherapy sessions in Arm A is 8. Every effort 
will be made to have Surgery in week 20 (-1 to +2 weeks), 4 weeks post C4 on arm A.  
9.3 
Arm B: FLOT-POP (Standard Arm)  
Arm B is the standard perioperative arm with 2 cycles of pre-operative FLOT (4 treatment 
sessions) and 2 cycles (4 treatment sessions) of post-operative FLOT.  Post-surgery FLOT 
will start 4-6 weeks post-surgery.  Each cycle of chemotherapy consists of 28 days and 
consists of 2 chemotherapy sessions given every 14 days. The total number of chemotherapy 
sessions in arm B is 8. Every effort should be done to have surgery done in week 12 (-1 to +2 
weeks) post completion of cycle 2 on Arm B.  
9.4 
Curative Surgery 
 
Curative gastric and GEJ surgery with D2 lymphadenectomy should be performed per given 
time frame instruction in table 10.1 and table 10.2. In this study only Siewert type II and III are 
included. Seiwert type I is considered pure esophageal cancer and not considered in this study 
(See appendix I). 
 
 The subject would not be removed from the study if D2 lymphadenectomy was not carried out 
per the surgeon’s discretion in the operation room for technical or safety reasons.  The 
boundaries of GEJ and GC would be defined by the surgeon performing the surgery. GEJ vs 
GC should be documented. Siewert level documentation is optional and not required. (See 
Appendix I). 
9.5 
Exploratory analysis:  
 
Tissue acquisition (See schema below): 
 
Samples for the exploratory analysis will be collected two times:  
1) At the time of EUS staging and 2) After gastrectomy.  
 
Tissue from a total of first five accrued subjects from each arm (A and B) will be collected for 
molecular analysis. (total 10 subjects).  After the subject is enrolled in the study a standard 
EUS is performed for staging. During the EUS, six sample biopsy bites will be collected from 
the cancer tissue and another six sample biopsy bites will be collected from the adjacent 
normal tissue. Three sample bites from the cancer tissue and three sample bites from the 
adjacent normal tissue will be immediately flash frozen and stored as fresh frozen samples for 
molecular studies. The remaining three sample bites from the cancer tissue and the remaining 
three sample bites from the adjacent normal tissue will be stored in ice cold sterile PBS for 
subsequent organoid formation.  
After gastrectomy is performed, we will obtain a 2 x 2 cm tumor tissue sample and a 2 x 2 cm 
adjacent normal tissue sample immediately.  We will store half of the tumor sample and half 
of the adjacent normal tissue sample as fresh frozen samples. The other half of cancer 

 
20 
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sample and normal tissue sample will be put in ice cold sterile PBS for organoid formation.  
All frozen samples will be securely stored in a -80C freezer in the lab of Dr. Jason Mills at 
Baylor College of Medicine until sample processing for molecular studies. All fresh tissues in 
sterile PBS will be immediately processed for organoid generation.  Given the novelty of this 
approach applied to locally advanced gastric and GEJ cancer, it will initially be difficult to 
predict the exact number of patients needed. Based on previous studies 18 we believe that 
only a few samples will yield meaningful results. As a result, we plan to obtain tissue 
samples from 5 patients in each arm of the study for these exploratory analyses.  
 
Molecular studies:  
 
Fresh frozen specimens will be processed for DNA, RNA, and protein extraction using the 
Qiagen All Prep DNA/RNA/Protein Mini Kit. Extracted DNA and RNA will be sent for whole-
exome and RNA sequencing, respectively (Novogene), and extracted protein will be sent for 
proteomics and phosphoproteomics using the BCM Lester and Sue Smith Breast Center 
Proteomics Laboratory 18. Integrative bioinformatics will be used to extract altered and 
meaningful molecular pathways in collaboration with Dr. Bing Zhang at Baylor College of 
Medicine.  
For organoid formation studies, further tissue processing will include mechanical stripping of 
the underlying muscle layers, enzymatic epithelial tissue digestion, and final embedding in 
Matrigel with previously well-defined culture media conditions.39 Successful organoid 
formation is defined as the ability to passage, characterize, and expand each organoid line 
derived from tumor and normal-adjacent stomach.  
                     Molecular analysis schema: Q  
 
Q: A total of ten subjects will provide tissue for molecular analysis.  Five subjects from arm A and five subjects from arm B. For each 
subject, tissue will be collected twice. First at the time of EUS and second at the time of gastrectomy.   
 

 
                                                                                                      
 
                             
TOGAR  
Version 1.4 
Page 21 of 44 
 
10.0 
STUDY CALENDAR  
 
 
10.1 Arm A: FLOT-TNT (Investigational Arm) 
 
Required Studies  
Pre-
registration J 
 
EUS G 
Cycle 1 
Wks  1-4 
Cycle 2 
Wks 5-8 
Cycle 3 
Wks 9-12 
Cycle 4 
Wks 13-16  
 
Wk 20  
Surgery 
K  
 
Wk 24  
Post-surgery L  
 
Surveillance 
M 
D 
1 
D 
15 
D 
1 
D 
15 
D 
1 
D 
15 
D 
1 
D 
15 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam A 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Weight and Performance 
status  A  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Toxicity Assessment A  
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Surgical specimen evaluation 
 
 
 
 
 
 
 
 
 
 
 
x 
 
LABORATORY B 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC C 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
CMP D 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
CEA  E 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x  
Pregnancy test F 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Research tissue collection 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI/PET for disease 
Assessment I 
x 
 
 
 
 
 
x 
 
 
 
xI 
 
x 
RECIST Radiographic 
Response 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
FLOT-Chemo  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Surgery  
 
 
 
 
 
 
 
 
 
 
x 
 
 
Survival/Progression 
 
 
 
 
 
 
 
 
 
 
 
 
x 

 
22 
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10.2 Arm B: FLOT-POP (Standard Arm)  
 
 
Required Studies  
Pre-
registration 
J 
 
 
   EUS G 
Cycle 1 
Wks 1-
4 
Cycle 2 
Wks 5-8 
  
 
Surgery  
Wk 12 K 
Cycle 3 
Wks 16-
20  
Cycle 4 
Wks 21-24  
 
Week 28 
Post chemo L 
 
 
Surveillance 
M 
D 
1 
D 
15 
D 
1 
D 
15 
D 
1 
D 
15 
D 
1 
D 
15 
 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam 
A 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Weight and Performance 
status A  
x 
 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
Toxicity Assessment A  
 
 
 
x 
x 
x 
 
  x 
 
x 
x 
x 
x 
x 
Surgical specimen 
evaluation 
 
 
 
 
 
 
 
  x 
 
 
 
 
 
LABORATORY B 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC C 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
CMP D 
x 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
CEA  E 
x 
 
 
 
x 
 
 
x 
 
x 
 
 
x  
Pregnancy test F 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Research tissue collection 
H 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI/PET scan for 
disease assessment I 
x 
 
 
 
 
 
xI 
 
 
 
 
x 
x 
RECIST Radiographic 
Response 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
FLOT-Chemo  
 
 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
 
Surgery  
 
 
 
 
 
 
x 
 
 
 
 
 
 
Survival/progression 
 
 
 
 
 
 
 
 
 
 
 
 
x 

 
23 
H-50068 (Version 1.5 Dated 10/23/2024) 
 
 
Footnotes for Arm A and Arm B Calendars.           Note: one cycle = 28 days 
A. Assessment must be performed prior to treatment on Days 1 and 15 (+/- 4 days) of each cycle.  Assessment of Toxicity during 
surveillance includes monitoring of long-term side effects of interventions such as chemotherapy related peripheral neuropathy. 
B. Labs do not need to be repeated at Cycle 1 Day1 if they were drawn within 14 days of registration. Labs can be drawn at +/- 5 days 
within the required time frame.  
C. CBC: Hemoglobin, WBC, platelet count, and ANC. 
D. CMP: Sodium, potassium, bicarbonate, chloride, BUN, calcium, total protein, magnesium, total bilirubin, alkaline phosphatase, 
albumin, creatinine and GFR 
E. CEA must be performed every 3 months during surveillance only in subjects who had an elevated CEA level at baseline. 
F. 
Pregnancy test (urine or plasma) to be performed on all females of childbearing age who have a uterus. 
G. EUS will be performed on all subjects after informed consent has been signed for staging and research tissue acquisition 
H. Tissue will be collected at the time of EUS and surgery for exploratory analysis, See further instructions under “ Exploratory analysis.”  
I. 
CT/MRI/ PET scan for disease assessment with imaging to be performed as below: 
Arm A:  28 days prior to subject-registration, on Day 1 of cycle 3, prior to surgery at week 16 to 20 [+ 2 weeks], and every 3 months 
during surveillance (+/- 2 weeks for all time points except baseline) 
Arm B:  28 days prior to subject registration, before surgery at week 8 to 12 [+2 weeks], at week 28 [+2 weeks post chemo], and every 
3 months during surveillance (+/- 2 weeks for all time points except baseline) 
- 
Every effort should be made to use the same modality of imaging used at screening.  CT or MRI must include chest, abdomen, 
and pelvis. CT scans must be CT chest with contrast, CT abdomen and pelvis with and without contrast. If an MRI is used, it must 
be an MRI of the chest with contrast, MRI of the abdomen and pelvis with and without contrast and FDG. PET scan is not 
necessary for initial or subsequent imaging unless needed to clarify imaging status per the discretion of the treating physician.  
J. 
Informed consent should be signed on day -42 to -1 prior to registration. 
K. Arm A: surgery should be performed on week 20 (-1 /+2 weeks) 4 weeks post Cycle 4. 
Arm B: surgery should be performed on week 12 (-1 /+2 weeks) post cycle 2.   
L. 
Arm A: post-surgery visit should be done on week 24, 4 weeks after surgery (-1 /+ 2 weeks).  
Arm B: post-surgery visits should be done on week 28, 4 weeks after completion of post-op chemotherapy (-1/+2 weeks). 
M. Arm A: Subjects will be followed every 3 months (+/- 3 weeks) for a total of 12 months starting from their post-surgery visit.   
Arm B: Subjects will be followed every 3 months (+/- 3 weeks) for a total of 12 months starting from Cycle 4, Day 15.    

 
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11.0 
STAGING CRITERIA  
 
AJCC 8th edition will be used for staging before and after surgery and on each restaging scan.  
12.0 
SUBJECT CRITERIA  
 
12.1 Inclusion Criteria: 
 
a. 
Must provide written informed consent. 
b. 
Must be ≥18 years of age. 
c. 
Must have life expectancy of greater than 3 months. 
d. 
Must have pathologically proven Siewert type II or III GEJ or gastric 
adenocarcinoma from the main tumor or local lymph nodes (pre-
neoadjuvant chemo). 
e. 
Stage cT2 or higher, any N and M0, are eligible for the study.  
f. 
M0 disease must be established by both negative distant metastatic 
disease on imaging AND negative diagnostic laparoscopic assisted 
cytology of peritoneal fluid cytology not more than 42 days before 
registration.  
g. 
Must be a candidate for neoadjuvant chemotherapy. 
h. 
Must be a candidate for curative surgical approach.  
i. 
Must have an ECOG performance status 0-2. 
j. 
Male or female subjects of childbearing potential must be willing to use    
contraceptive precautions throughout the trial and for 3 months after 
discontinuation of study treatment. Female subjects of childbearing 
potential must have a negative pregnancy test within 28 days of 
registration. Post-menopausal women must be amenorrhoeic for at least 
12 months to be considered of non-childbearing potential. 
k. 
Must have adequate kidney, liver, and bone marrow function, within 28 
days prior to registration, as follows: 
i. 
Hemoglobin ≥ 8.0 gm/dL (PRBC transfusion is allowed to meet this 
criteria) 
ii. 
Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 
iii. 
Platelet count ≥ 100,000 /mm3 
iv. 
Total bilirubin ≤ 1.5 times upper limit of normal (ULN) 
v. 
AST (SGOT) and ALT (SGPT) ≤ 3.0 times the ULN 
vi. 
Patient must have adequate renal function as evidenced by one of the 
following: Serum creatinine ≤ IULN OR calculated creatinine clearance ≥ 
60 mL/min. This serum creatinine result must be obtained within 28 days 
prior to registration. 
 
Calculated creatinine clearance = (140 - age) x wt* (kg) x 0.85 (if female) 
                                                                   
72 Creatinine** (mg/dl)  

 
25 
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*The kilogram weight is the subject’s actual body weight with an upper 
limit of 140% of the IBW. 
 
** Actual lab serum creatinine value with a minimum of 0.8 mg/dL 
l. 
Subjects who have required a short course urgent single modality non 
curative radiation treatment or gastric artery embolization for the purpose 
of tumor bleeding control are eligible.  
 
12.2 Exclusion Criteria: 
 
a. 
Positive cytology or histology for metastatic disease on diagnostic 
laparoscopy peritoneal fluid. Reports such as: “cannot rule out 
malignancy” or “suspicious for malignancy, but not definitive” will exclude 
the subject from enrolling. 
b. 
Seiwert type I GEJ cancer  
c. 
Subjects with clinical evidence of metastatic disease. 
d. 
Biopsy proven metastatic disease (excluding regional lymph nodes)   
e. 
Prior chemotherapy for gastric cancer or GEJ cancer 
f. 
No other prior malignancy is allowed except for the following:  adequately 
treated basal cell or squamous cell skin cancer, current non-advanced 
prostate cancer per the discretion of the investigator, and any other 
cancers from which the patient has been disease free for two years. 
g. 
Female subjects who are pregnant, breast feeding, or of childbearing 
potential with a positive pregnancy test prior to baseline. Women of 
childbearing potential must have a negative serum pregnancy test as a 
part of eligibility within 28 days of registration.  A persistent positive or 
elevated urine or blood Beta HCG test may be contributed to the primary 
diagnosis of GC or GEJ cancer after ruling out ectopic and intrauterine 
pregnancy and germ cell tumors.  
h. 
Subjects unwilling or unable to comply with the protocol or provide written 
informed consent. 
i. 
Any medical condition that, in the opinion of the investigator, would 
exclude the subject from participating in this study and treatment plan. 
j. 
ECOG > 2 
 
 
13.0 
TREATMENT PLAN 
 
13.1 Pre-Medication and Supportive Care 

 
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Pre-medications and concomitant medicines should be administered to counter 
the expected common side effects of chemotherapy. These will be ordered by the 
treating physician per institutional standards and tailored to the subject’s 
condition. 
           The following is recommended prior to treatment: 
 
a. 
Supportive care, including but not limited to anti-emetic 
medications, may be administered at the discretion of the 
Investigator. Erythropoietin and G-CSF may be administered at the 
discretion of the investigator, consistent with ASCO guidelines.
 
 
b. 
In the unlikely event of a mild hypersensitivity reaction, 
premedication may be administered using the premedication 
regimen the institution typically uses for Oxaliplatin and Docetaxel. 
In the rare event of a severe hypersensitivity reaction, discontinue 
the suspected drug.  
 
13.2 Treatment of subjects 
 
Subjects assigned to Arm A and Arm B will both receive the following 
combination of 5-FU, Leucovorin, Docetaxel and Oxaliplatin also known as 
FLOT. The FLOT regimen is standard chemotherapy.  Arm A will receive FLOT-
TNT and Arm B will receive FLOT-POP. 
 
Subjects in both arms will undergo a D2 lymphadenectomy with gastrectomy. 
 
Treatment plan Arm A and B: 5-FU, Oxaliplatin, LV, Docetaxel 
 
13.3 Growth factors 
 
GCSF:  
13.3.1 Long acting GCSF (Neulasta of Fulphila- or Biosimilar) is 
recommended on day 2 and 16 of C1 of the protocol while getting 
chemotherapy.  
13.3.2 GSCF can be discontinued at the discretion of the physician 
during subsequent cycles if dose modifications to lower-level 
doses for non–neutropenic toxicities have occurred and in the 
Agent 
Dose 
Route 
Day  
5-FU 
2600 mg/m2 
IV over 26 hours (+/- 1 hour) CI with home 
pump 
1,15 
LV 
200 mg/m2 
IV over 2 hours 
1,15 
Oxaliplatin 
85 mg/m2 
IV over 2 hours  
1,15 
Docetaxel 
60 mg/m2 
IV over 60 minutes  
1,15 
GCSF© 
see below  
SC 
2,16  

 
27 
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investigator’s opinion GCSF is no longer necessary to keep the 
ANC above 1000. 
13.3.3 Subject’s insurance plan is to be considered for best selection 
GCSF agent.  
 
 
GCSF agents include:  
a. 
Neulasta® Onpro- 6 mg subcutaneous administer on day 2 and 
16 
 
b. 
Pegfilgrastim (Neulasta® or a pegfilgrastim biosimilar): 6 mg 
subcutaneous administer on day 2 and 16  
 
c. 
Filgrastim (Neupogen® or a filgrastim biosimilar): 5 mcg/kg/day 
(rounded to nearest syringe size of 300 mcg or 480 mcg) 
 
d. 
Per physician discretion during neutropenic fever episodes.  
 
 
 
14.0 
FOLLOW-UP PERIOD 
 
All subjects will be followed up until the end of 12 months of surveillance. After completion of the 
surveillance period, they will have completed the study. For subjects in Arm A, the surveillance 
period will start from their post-surgery visit.  For subjects in Arm B, the surveillance period will 
start from cycle 4, day 15 of chemo.  
 
15.0 
CRITERIA AT DISEASE PROGRESSION:  
 
15.1 Progression of primary disease confirmed by imaging or EGD and or 
metastatic disease confirmed by pathological confirmation.  
1. 
Progression is evaluated by evidence of disease progression on 
scans, preferably using the same scans performed at baseline per 
RECIST v1.1 criteria. 
2. 
A tissue biopsy is required from the suspected metastatic site 
including tissue biopsy of peritoneal metastasis deposit or 
peritoneal cytology if it can be carried out safely and the metastatic 
deposit is accessible.  Biopsy is not required if in the opinion of the 
investigator progression to metastatic status is unequivocal.  The 
rationale and reason for such conclusion should be clearly 
documented. 

 
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3. 
Increase of CEA without evidence of measurable disease 
progression on  scans is not considered progression of disease by 
itself unless accompanied by other evidence such as presence of 
ascites not explained by any other etiology and strongly believed 
to be related to progression of the disease in the peritoneum if 
cytology of the peritoneum is negative. 
 
15.2 Subjects who progress to distant metastatic disease between registration and 
infusion of chemotherapy on cycle 1, day 1 will enter the surveillance follow-
up period and complete the protocol-dictated 12 months of surveillance.  
15.3 Subjects who progress during study treatment will enter the surveillance 
follow-up period and complete the protocol-dictated 12 months of surveillance.  
15.4 Subjects who progress during surgery will enter the surveillance follow-up 
period and complete the protocol-dictated 12 months of surveillance.  
 
16.0 
CRITERIA FOR REMOVAL FROM STUDY TREATMENT 
 
16.1 Toxicity that requires all chemotherapy agents to be stopped. 
16.2 The subject request to stop chemotherapy at any time for any reason. 
16.3 Subjects who are removed from study treatment will enter the 12 month 
surveillance follow-up period.  
17.0 
CRITERIA FOR REMOVAL FROM STUDY PROTOCOL 
 
17.1 The subject requests to withdraw from the study at any time for any reason.  
17.2 If surgery is deemed not to be the best approach in the opinion of the treating 
surgeon or subject declines surgery. 
17.3 Chemotherapy delay for any reason more than 4 weeks other than the allowed 
timeframe between chemotherapy and planned gastrectomy per protocol.  
17.4 If a subject is a woman of child bearing potential and becomes pregnant during 
the study. 
Subjects who require a short course of urgent non-curative single modality radiation 
course to stop the bleeding of the tumor when chemotherapy or embolization of the 
gastric artery is not feasible or effective to stop the acute bleeding are allowed to 
continue on the protocol and enroll.  
 
18.0 
DOSE MODIFICATIONS 
18.1 General Considerations:  
 

 
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Dose modifications and treatment delays based on observed drug-related toxicity 
will be performed as described below: 
 
1. Any toxicity associated or possibly associated with 5FU, Oxaliplatin, LV, 
Docetaxel treatment should be managed according to standard medical 
practice. 
2. The maximum allowed dose delay of any of the chemotherapy agents for any 
reason is 4 weeks. If per the investigator’s opinion the subject cannot be started 
on the chemotherapy drug that was held in 4 weeks, that chemotherapy agent 
will be permanently discontinued form the rest of the treatment.   
3. No dose re-escalations are permitted. If the subject experiences toxicity 
requiring a dose reduction, the dose will remain lowered for subsequent cycles. 
4. Subjects on either arm may continue chemotherapy as long as not all drugs 
need to be discontinued for toxicities. 
5. Dose modifications of drug toxicities not specified in the protocol, e.g, abnormal 
liver function tests, creatinine insufficiency, etc., should follow standard of care 
approaches and need to be documented. 
 
18.2 Dose Level changes:  
 
18.2.1 
For both Arm A and Arm B 
Drug 
Initial Dose 
Dose reduction 
level -1 
Dose reduction  
level -2** 
5FU 
2600 mg/m2 
2000mg/m2 
1600 mg/m2  
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2 ** 
Docetaxel 
60 mg/m2 
45 mg/m2 
35 mg/m2** 
LV 
200mg/m2 
none 
none 
 
1. Any dose reduction other than instructions mentioned below should be 
discussed with the study investigator, justified and clearly explained and 
documented.  
2. Reduction of the doses starts with changing the doses of Docetaxel or 
Oxaliplatin. It is at the discretion of the investigator which drug dose to reduce 
first. If a subject experiences the first hematologic toxicity, the investigator can 
choose between Oxaliplatin or Docetaxel to dose reduce one of these 2 drugs 
to dose level -1. Dose modification occurs with only one drug at a time and 
one dose level at a time.   
3. If a subject experiences a second hematologic toxicity despite reduction of -1 
reduction of docetaxel or Oxaliplatin, -1 level dose reduction should be done 
on the drug that has not been reduced. (Oxaliplatin or Docetaxel)   
4. If a subject experiences a hematologic toxicity while Docetaxel is at a dose - 
2 level, Oxaliplatin will be dose reduced if it is not already at dose -2 level.  
5. If a subject experiences a hematologic toxicity while Oxaliplatin is at dose -2 
level, Docetaxel will be dose if it is not already at dose -2 level.  
6. If subject experiences a hematologic toxicity and Oxaliplatin and Docetaxel 
are both at dose level -2, 5FU will be reduced to dose level  -1. 

 
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7. If subject experiences a hematologic toxicity with Oxaliplatin and Docetaxel 
both at dose level -2 and 5FU at dose level to  -1,  the investigator is allowed 
to make a clinical decision to remove Oxaliplatin or Docetaxel in subsequent 
cycles to preserve the treatment with 5FU at minimum does level -1.   Every 
effort should be made to continue the treatment with 5FU in this scenario even 
if the toxicity requires it to remain on a single agent 5FU.  
8. If a subject experiences hematologic toxicities on single agent 5FU at dose 
level -1, 5FU should be reduced to dose level -2.  
9. If hematologic toxicity continues despite -2 dose level reduction of 5FU, 
chemotherapy should be stopped.  
10. If for a particular drug, a dose reduction is required below Dose Reduction 
Level 2, that drug must be discontinued. 
 
18.3 Hematological Toxicities: 
 
In the event dose modifications are required at the beginning of a cycle or 
within a cycle due to hematologic toxicities, doses of 5FU, Oxaliplatin, LV, 
Docetaxel may be adjusted as detailed below. 
 
18.3.1 Dose Modification For Day 1 And Day 15 Of Each Cycle For Hematologic 
Toxicity 
 
Day 1, 15 
Laboratory results 
Day 1, 15 
Gemcitabine 
Day 1, 15 
Docetaxel 
Day 1, 15 
5FU 
ANC > 1000 and 
Platelets ≥ 75,000 
No modification  
No modification 
No modification  
 
 
 
ANC <1000  or  
Platelets <75,000 
Hold until ANC ≥ 1000  
And Platelets > 
75,000. Delay 
treatments by 1 week 
intervals until recovery. 
Once recovered, treat 
based on dose 
reduction per table 
18.2.1 
 
Hold until ANC ≥ 1000  
And Platelets > 
75,000. Delay 
treatments by 1 week 
intervals until recovery. 
Once recovered, treat  
based on dose 
reduction per table 
18.2.1 
Hold until ANC ≥ 1000  
And Platelets > 
75,000. Delay 
treatments by 1 week 
intervals until 
recovery. Once 
recovered, treat based 
on dose reduction per 
table 18.2.1 
 
 
 
Febrile Neutropenia 
(Grade 3 or 4)* 
Hold until ANC 
> 1500 and 
fever-free for 
48 hours, then treat 
based on dose 
reduction per table 
18.2.1 
Hold until ANC 
> 1500 and 
fever-free for 
48 hours, then 
Treat based on dose 
reduction per table  
18.2.1 
Hold until ANC 
> 1500 and 
fever-free for 
48 hours, then 
Treat based on dose 
reduction per table  
18.2.1 

 
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18.3.2 
Neutropenic Fever considerations: * 
 
1. If a subject does not experience resolution of neutropenia within 4 
weeks despite uninterrupted daily G-CSF treatment, study treatment 
will be discontinued.  
 
2. Subjects with febrile neutropenia should have their chemotherapy 
treatment held.  Sepsis workup should follow standard approach.  
 
3. Subjects may also receive short acting daily G-CSF, in addition to 
antibiotic treatment, to hasten the resolution of their febrile 
neutropenia.  
 
4. In all cases, blood counts must have returned to non-neutropenic 
levels before resuming chemotherapy treatment.  
 
5. All Subjects are highly recommended to be on a long acting G-CSF 
agent administered on day 2 and 15 during chemotherapy per the 
protocol.  
 
6. The additional shot acting G-CSF preparation is optional per the 
discretion of the investigator with febrile neutropenia. The exact 
dosage amount and schedule for G-CSF support will be left to the 
treating physician’s discretion.   
 
7. ANC ≥ 1500 AND resolution of fever for at least 48 hours is required 
to resume chemotherapy with dose reduction per section 18.2.1 after 
febrile neutropenia has resolved. 
 
18.3.3 
Considerations on Anemia and PRBC transfusion:  
 
Hemoglobin should be maintained at ≥7 g/dl. If Hb is between 6 and 7, 
subject can receive chemotherapy but must receive PRBC in no longer 
than 48 hours after the end of the chemotherapy infusion.  If Hb is <6, 
chemotherapy should be withheld until PRBC transfusion has been given 
and Hb is ≥ 7 or the subject has recovered from serious symptoms. 
Serious anemia related symptoms include but not limited to chest pain, 
shortness of breath, confusion, etc. Mild to moderate fatigue without other 
serious symptoms is acceptable and chemotherapy can be continued if 
Hb is ≥ 7. Treatment can continue with PRBC support despite known GI 
bleeding if in the opinion of the investigator chemotherapy is believed to 
contribute to the control of the malignancy bleeding.   
 
18.3.4   
Non-hematologic toxicities: 
 
All treatment related non-hematological toxicities (with the exception of 
hair loss and nausea and vomiting that can be controlled with 

 
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antiemetics) should resolve to ≤ Grade 2 prior to starting next cycle of 
therapy. 
Dose modification or delay may occur in the setting of lower Grade 
toxicity if the treating physician believes that it is in the interest of a 
subject’s safety. 
Alopecia and nausea and/or vomiting that can be controlled by 
antiemetics do not require dose modification. No dose modification will 
be required for anemia as it can be satisfactorily managed by 
transfusions. 
 
 
 
18.3.5 Dose Modification For Day 1 And Day 15 Of Each Cycle For Non-
Hematologic Toxicity * 
CTCAE Grade 
Treatment Modification 
Grade 0-2 Toxicity 
Same as Day 1 previous cycle (except for Grade 2 
cutaneous toxicity where docetaxel needs to be reduced to a 
lower dose and Grade 2 diarrhea where 5-FU needs to be 
reduced to a lower dose) 
 
Grade 3 Toxicity a, c Hold all drugs until resolution to < Grade 1. Then 
resume treatment at the next lower dose level for all 
drugs 
Grade 4 Toxicity a, b Hold all drugs until resolution to < Grade 1. Then 
resume treatment at the next lower dose level for all 
drugs 
 
 
*      Except peripheral neuropathy CTCAE v5.0 table below for sensory 
neuropathy) 
 
a.     If the toxicity only affects neuropathy, then only Oxaliplatin or Docetaxel 
should   be reduced. If the specific toxicity is attributed to only one drug (i.e. 
Docetaxel skin rash, 5Fu mucositis), only the offending drug should be withheld, 
and resume treatment at the next lower dose level of only that specific drug when 
toxicity resolves to < grade 1. 
 
b. Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or 
asymptomatic, will be exempt from this requirement. 
 
c.  Excluding 
electrolyte 
abnormalities 
per 
judgment 
of 
the 
physician/investigator. 
 
 
 
Sensory Neuropathy 
Modify Oxaliplatin or Docetaxel treatment per below. 5FU administration can 
continue during this period.  
 

 
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Duration of Toxicity 
Persistent between 
cycles 
Toxicity 
Grade  
1-7 days 
> 7 days 
 
2 
No dose modification 
No dose modification 
Next lowest dose 
level for Oxaliplatin* 
3 
Next dose level for 
Oxaliplatin 
Next dose level for 
Docetaxel 
Discontinue 
4 
Discontinue 
Discontinue 
Discontinue 
 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 for Sensory 
neuropathy  
 ((http://ctep.cancer.gov). 
 
Peripheral sensory neuropathy 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Asymptomatic 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe symptoms; 
limiting self care 
ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
 
Modify Oxaliplatin and Docetaxel treatment for sensory neuropathy per below:  
 
a. 5FU administration can continue during this period.  
b. Subjects experiencing peripheral neuropathy that requires a delay in scheduled 
Oxaliplatin and Docetaxel dosing for > 4 weeks will discontinue study treatment. 
In those subjects who experience Grade 4 sensory neuropathy, Docetaxel and 
Oxaliplatin  should be stopped.  
c. Grade 3 If persistent between cycles: Decrease Oxaliplatin and Docetaxel at next 
lowest dose level.  
d. If peripheral sensory neuropathy stays at grade 2 after dose reduction, dosing can 
continue at the same dose level if toxicity remains grade 2 
 
e. Grade 3: hold Oxaliplatin and Docetaxel until grade <2 then restart Oxaliplatin and 
Docetaxel at next lowest dose level 
 
f. Grade 4: Discontinue Oxaliplatin and Docetaxel reduction 
 
 
Cutaneous Toxicity 
 
Subjects who develop Grade 2 or 3 cutaneous toxicity should have the dose 
reduced of the drug the local investigator deems most contributory to the next 
lower dose level. If the subject continues to experience these reactions, despite 
dose reduction, treatment should be discontinued. Subjects who develop Grade 
4 cutaneous toxicity should have treatment discontinued. 
 
Gastrointestinal Toxicity 

 
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Subjects who develop Grade 2 or 3 gastrointestinal toxicity (Except nausea and 
vomiting that can be satisfactorily treated and prevented with antinausea 
medications) should have their dose reduced to the next lower dose level.  If the 
subject continues to experience these reactions, despite dose reduction, 
treatment should be discontinued. Subjects who develop Grade 4 gastrointestinal 
toxicity should have treatment discontinued. e.g. Oral mucositis, diarrhea. 
 
Pulmonary Embolism 
 
 
Asymptomatic or clinically mild pulmonary embolism can be treated with  
 
 
Anticoagulant of the investigator’s choice per standard practice without 
interruption 
of therapy. Moderate to severe pulmonary embolism at the discretion of the local 
investigator will require permanent discontinuation of treatment. 
 
Sepsis 
 
If a subject becomes febrile while not being neutropenic initiate sepsis work 
up and treatment with broad spectrum antibiotics. Dose modification of any 
of the chemotherapy agents is required. For febrile neutropenia, withhold all 
chemotherapy agents until fever resolves for at least 48 hours and ANC ≥ 
1500, then resume treatment at reduced dose levels. 
 
Prophylaxis Against Sepsis 
 
Due to the incidences of non-neutropenic sepsis, at the first occurrence of 
fever ≥ 38.5°C (regardless of neutrophil count), institution of ciprofloxacin 
(500 mg orally, twice daily) or amoxicillin/clavulanate (500 mg orally, 2-3 
times daily) in subjects with allergy to fluoroquinolones should be initiated in 
the outpatient setting  if the subject is clinically stable. If the subject is not 
clinical stable (e.g. hypotension, tachycardia, altered mental status, etc.) per 
the discretion of the investigator, the subject should be referred to the 
emergency room for IV antibiotics and sepsis work up.  
 
                          Hypersensitivity 
 
 
Hypersensitivity reactions rarely occur. If they do occur, minor symptoms   such 
as flushing, skin reactions, dyspnea lower back pain, hypotension, or tachycardia 
may require temporary interruption of the infusion. However, severe reactions, 
such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema or generalized urticarial rash requiring immediate discontinuation of 
study drug administration and aggressive symptomatic therapy. Subjects who 
experience severe hypersensitivity reactions to any of the chemotherapy agents 
should not be re-challenged. 
 
19.0  
PERFORMANCE STATUS 
 
Subjects will be graded according to the ECOG Performance Status Scale 

 
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20.0  
CRITERIA FOR DISEASE EVALUATION DURING STUDY: 
 
 
20.1. Restaging scans should be compared to the baseline scans during pre-
operative chemotherapy per RECIST criteria v1.1 for evaluation of disease 
status to measure stable disease, partial response, complete response and 
progression of disease.  
20.2. CEA should be measured at specific timeframes per table 5.1 and 5.2 for the 
respected treatment arms if this marker has been elevated at baseline. 
20.3 Surgical pathology after surgery should be reviewed for neoadjuvant 
chemotherapy effect per standard guidelines and response should be 
documented per College of American Pathologists version 4.2.1.0 updated 
on July 2021.  
20.4    Investigational Biomarkers will be evaluated for integrated genomics,  
transcriptomics, and proteomics based on changes in pre and post treatment 
tissues. 
 
 
College of American Pathologists definition of Tumor Regression Grade37:  
 
 
 
 
 
Point 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of light and sedentary nature, e.g., light house work 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities. Up and about more than 50% of the waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
the waking hours 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed or 
chair. 

 
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21.0  
ADVERSE EVENT REPORTING 
21.1 
 Adverse Event:  
Any unfavorable medical occurrence in a human subject, including any abnormal sign, 
symptom, or disease, whether or not it is considered related to the subject’s participation 
in the research.  
 
21.2 
Descriptions and Grading:  
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting. A copy of 
the CTCAE version 5.0 can be downloaded from the CTEP website.  
 
21.3 
Attribution / Relatedness:  
Each event should be evaluated by the treating investigator for its relatedness to 
participation in the research: 
 
Definite: The AE is clearly related to the study treatment.  
Probable: The AE is likely related to the study treatment.  
Possible: The AE may be related to the study treatment.  
Unlikely: The AE is doubtfully related to the study treatment. 
Unrelated: The AE is clearly NOT related to the study treatment.  
 
21.4 
Seriousness:  
A Serious Adverse Event (SAE) is any adverse event that:  
• Results in death;  
• Is life-threatening;  
• Results in inpatient hospitalization or prolongation of existing hospitalization;  
• Results in a persistent or significant disability/incapacity;  
• Results in a congenital anomaly/birth defect; or  
• Based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes listed 
in this definition.  
 
21.5 
Expectedness:  Definition of expected and unexpected adverse event.    
21.5.1 Expected adverse events are those that have been previously 
identified as resulting from administration of the agent.  For 
purposes of this study, an adverse event is considered expected 
when it appears in the current adverse event list in the 
Investigator’s Brochure, the package insert, or is included in the 
informed consent document as a potential risk.  
 
  

 
37 
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21.5.2  An adverse event is considered unexpected when it varies in 
nature, intensity, or frequency from information provided in the 
current adverse event list in the Investigator’s Brochure, the 
package insert or when it is not included in the informed consent 
document as a potential risk.   
  
21.6 
Reporting:  
 
21.6.1 All adverse events that are Grade 3 or above, regardless of 
relatedness, will be reported and recorded on the appropriate 
CRFs.  
 
21.6.2 The AE description will include the nature of the experience, the 
date of onset, the resolution date, the severity of each sign or 
symptom reported using the NCI-CTCAE, the seriousness of the 
event, the relatedness to study treatment, the course of action 
taken (if any), and the outcome of the experience.     
 
21.6.3 Serious adverse events are to be reported to the BCM Institutional 
Review Board (IRB) according to the board’s reporting 
requirements and required time frame.  
 
 
21.6.4 Any adverse event that is unexpected, serious, and 
possible/probably/definitely related to the study should be reported 
to the review committee (DRC or DSMB) within 15 calendar days of 
knowledge of the event.  
 
21.6.5 Any event that is reportable to the BCM IRB must also be reported 
to the DLDCCC Data Review Committee (DRC) via the Patient 
Safety Officer at dldcc-pso@bcm.edu. 
 

 
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22.0  
STATISTICAL CONSIDERATIONS: 
 
22.1. 
Study Design/Description: 
This is a randomized pilot study to evaluate and to compare the completion rates of Total 
Neoadjuvant chemotherapy with FLOT (FLOT-TNT) and perioperative chemotherapy with FLOT 
(FLOT-POP).   
22.2. 
Sample Size Justification: 
The trial will require 50 evaluable subjects (25 per arm). A subject is evaluable if any chemo 
treatment has been received. We anticipate at most 10% of subjects will withdraw before 
beginning study treatment; therefore, we expect to consent accrue at most 56 subjects. 
We expect about 5% of evaluable subjects with disease progression. In routine care, they would 
go to surgery and should be approximately equal between groups. They will go off-treatment and 
be included for the primary and secondary objectives. 
 
We expect to see the completion rate in FLOT-TNT will be higher than FLOT-POP. Based on 
published data, we expect that 45% of subjects in the FLOT-POP will complete all allocated 
chemotherapy. Considering that we expect 90% of subjects complete the first 2 cycles (Lancet 
ref 24), and if about 90% of those complete the second 2 cycles in the FLOT-TNT arm, then the 
expected completion rate will be about 80%. With 25 evaluable subjects in each group, we will 
have 85% power (alpha=10%, one-tailed) to detect an absolute improvement of 35% (FLOT-
TNT completion rate=80%) using a Fisher Exact test. 
22.3. 
Randomization/Stratification/Treatment assignment Procedures: 
Subjects will be randomized in a 1:1 ratio to either FLOT-TNT group or control FLOT-POP group. 
Randomization will be open-label and performed by entering data into OnCore. No stratification 
factors will be used. 
22.4. 
Accrual and Feasibility:  
Roughly 10-15 subjects per year are estimated to be enrolled. The accrual period will be 60 
months.  
22.5. 
Stopping Rules:  
See section 17.0 
22.6. 
Analysis Populations: 
22.6.1 Efficacy Intent to Treat (ITT): 
The ITT population will consist of all eligible and randomized subjects in 
the   study. Primary objective will be analyzed. 
22.6.2. Efficacy Modified Intent to Treat (MITT) 
 
 
 
NA 

 
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22.6.2 Safety population: 
NA 
22.7 Statistical Analyses 
 
22.7.1 Primary objective, endpoints, analysis plan: 
The primary objective analysis will be based on the efficacy intent to treat (ITT) 
population. The primary endpoint is the number of subjects who have completed their all-
allocated cycles. The proportion of subjects that complete all allocated cycles will be 
calculated and summarized. Fisher Exact test will be used to compare the proportion 
between FLOT-TNT group and FLOT-POP group.  
 
22.7.2 Planned Interim Analysis:  
N/A 
22.7.3 Secondary objective, Exploratory objective, Endpoints, Analysis Plan: 
The secondary objectives endpoint analysis will be based on the efficacy intent to treat 
(ITT) population. The secondary endpoints include pathologic response and nodal status 
(N stage) based on TRG [CAP criteria (20.1.c)]  
 
The exploratory objective endpoints are organoid growth, and molecular signatures 
(integrated genomic, transcriptomic, and proteomic) and changes, and disease free 
survival (DFS) after surgery. 
22.8 Response rate:  
Based on published data, at time of surgery in the FLOT-POP group, we expect to see 49% N0, 
16% N1, 13% N2, and 22%N3 (includes not operable). We expect that FLOT-TNT will increase 
the frequency of N0 and reduce the frequencies of the other categories, especially N2 and N3. 
The pathological N stage of ypN is an ordinal variable and in this setting, the effect size is 
measured by the probability that a randomly selected subject in the FLOT-TNT population has a 
lower ypN value than a randomly selected subject from the FLOT-TNT group, expressed as 
Pr(ypN.FLOT-TNT< ypN.FLOT-POP). When the distribution of ypN is the same in both groups, 
the null hypothesis probability (p0) is 0.5, like flipping a coin. If, in the FLOT-TNT group, we 
observe a change to 75% N0, 16% N1, 3% N2 and 6% N3, the corresponding effect size would 
be p1=0.65. In this pilot study, relatively large effect sizes of this magnitude will be detectable 
with 80% power (alpha=10%, one-tailed) using a Wilcoxon Rank Sum test. 
The pathological response rate with frequency of positive nodes and nodal status (ypN) obtained 
from post gastrectomy surgical specimen will be compared between FLOT-TNT group and 
FLOT-POP group using Fisher’s exact test and Wilcoxon Rank Sum test.   
 
22.9 As a pilot exploration, tissues from a total of five subjects from each arm (A 
and B) will be collected for molecular analysis at two time points: 1) EUS 
staging and 2) gastrectomy. Tumor, if any and adjacent normal will be 
collected from the resection specimen after required pathology samples are 
taken. If possible, samples will be divided to yield fresh and frozen material. 
Fresh tissue specimens will be processed in the lab of Dr. Ramon Jin at Baylor 
College of Medicine for organoid formation and treatment studies. Frozen 

 
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specimens will be processed for DNA, RNA, and protein extraction. Extracted 
DNA and RNA will be sent for whole-exome and RNA sequencing, 
respectively (Novogene), and extracted protein will be sent for proteomics and 
phosphoproteomics using the BCM Lester and Sue Smith Breast Center 
Proteomics Laboratory. Integrative bioinformatics will be performed in 
collaboration with Dr. Bing Zhang at Baylor College of Medicine 
 
Disease free survival (DFS) is defined as the time between the first day of the chemo treatment 
and disease progression or death from any cause. A progression is defined by PI’s decision after 
surgery based on standard approaches. Time to first event of DFS will be estimate using the 
Kaplan-Meier survival method.  
 
23.0  
DATA AND SAFETY MONITORING AND QUALITY ASSURANCE: 
 
This study will be monitored regularly by the Data Review Committee (DRC) of the Dan L Duncan 
Comprehensive Cancer Center, at a frequency of at least once per year, in accordance with the 
DLDCCC Data and Safety Monitoring Plan.  The DRC will monitor the study for progress and 
enrollment, toxicities, adverse events, and soundness of data.   
 
This study will be monitored by the DLDCCC Quality Assurance program for study conduct and 
quality of data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX I: ANATOMICAL BOUNDARIES OF GECS  
 
 
 

 
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24.0  
REFERENCES 
 
1 
Torre LA, Siegel RL, Ward EM et al. Global Cancer Incidence and Mortality Rates and Trends--An 
Update. Cancer Epidemiol Biomarkers Prev 2016; 25 (1): 16-27. 
2 
Collaborators GSC. The global, regional, and national burden of stomach cancer in 195 
countries, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017. Lancet 
Gastroenterol Hepatol 2020; 5 (1): 42-54. 
3 
Zhao JK, Wu M, Kim CH et al. Jiangsu Four Cancers Study: a large case-control study of lung, 
liver, stomach, and esophageal cancers in Jiangsu Province, China. Eur J Cancer Prev 2017; 26 
(4): 357-364. 
4 
Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in the incidence of esophageal and gastric 
carcinoma in the United States. Cancer 1998; 83 (10): 2049-2053. 
5 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70 (1): 7-30. 
6 
Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk 
factors, screening and prevention. Nat Rev Clin Oncol 2023. 
7 
Bonenkamp JJ, Hermans J, Sasako M et al. Extended lymph-node dissection for gastric cancer. 
N Engl J Med 1999; 340 (12): 908-914. 
8 
Al-Batran SE, Homann N, Pauligk C et al. Perioperative chemotherapy with fluorouracil plus 
leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and 
epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction 
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