Clinical trial NCT03636893
Conditions: Gastric Cancer Chemotherapy Effect
Keywords: Neoadjuvant chemotherapy perioperative chemotherapy Systemic chemotherapy FLOT SOX Gastric cancer
Sponsor: Ruijin Hospital
Start date: 2018-08-24; Completion date: 2025-05-08
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Safety and efficacy study of neoadjuvant chemotherapy (FLOT versus SOX) for gastric cancer patients in high volume center of China

Detailed description:
DRAGON III research, Neoadjuvant Chemotherapy (FLOT versus SOX) for Gastric Cancer, is an investigator initiated; phase II, open label, randomised controlled study. This study will be conducted and analyzed by the Gastrointestinal department（Unit III）of the Ruijin Hospital and the project is supported by the Institute of Digestive Surgery, Shanghai, which is a state key research center. This study will be monitored by the Clinical Research Center of the Ruijin hospital (Official body which is responsible to guide and monitor all types of research at Ruijin hospital). Primary endpoint and secondary endpoint is described above. The aim of this study to obtain preliminary result and further conduct a large scale multi-center randomised controlled trial(RCT) study.

Arms: arm 1: A total of four preoperative and four postoperative cycles of FLOT chemotherapy administered

A cycle consists of Day 1 5-fluorouracil(5-FU) 2600mg/M2 administered via an intravenous peripherally inserted central venous catheter(PICC) for 24 hour Leucovorin 200mg/M2 intravenous Oxaliplatin 85mg/ M2 intravenous Docetaxel 50mg/M2 intravenous

Repeated every 15th day arm 2: Three preoperative cycles and three postoperative cycles of SOX chemotherapy administered

A cycle consist of Day 1: Oxaliplatin 130mg/M2 intravenous Day 1-14 Tegafur gimeracil oteracil potassium capsule 80mg/M2 oral (twice daily)

Repeated every 21st day
Interventions: intervention 1: FLOT Chemotherapy intervention 2: SOX Chemotherapy
Intervention descriptions: intervention 1: 5-FU+Leucovorin+Docetaxel+Oxaliplatin intervention 2: Oxaliplatin+Tegafur gimeracil oteracil potassium capsule (TGO)

Protocol documents:
Prot_SAP_000.pdf: 
January 10, 2017 
Cover letter 
 
DRAGON III- Phase 2 research, Neoadjuvant Chemotherapy (FLOT versus SOX) for 
Gastric Cancer, is an investigator-initiated; open-label, randomized controlled study. 
This study will be conducted and analyzed by the Gastrointestinal department（Unit 
III）of the Ruijin Hospital and the project is supported by the Institute of Digestive 
Surgery, Shanghai, which is a state key research center. This study will be monitored 
by the Clinical Research Center of the Ruijin hospital (Official body which is 
responsible to guide and monitor all types of research at Ruijin hospital). 
Over the last 15 years, Dr. Sah has conducted various clinical studies on gastric cancer. 
Professor Zhu is a well-known scholar for gastric cancer in China and has been 
devoted to this field for the last 40 years.  
The main purpose of this study is to compare the safety and efficacy of two main 
streams of chemotherapy (FLOT Versus SOX) for locally advanced gastric cancer 
patients in a high volume center of China. And to obtain preliminary results for 
designing a new phase III multicenter randomized controlled trial.  
 
*Birendra Kumar Sah, MD/Ph D 
Investigators  
Department of General Surgery, Gastrointestinal Surgery Unit, 
Ruijin Hospital Shanghai Jiao Tong University School of Medicine  


Li Jian, Ph D 
Clinical Research Center 
Ruijin Hospital Shanghai Jiao Tong University School of Medicine  
Yan Chao, MD/Ph D 
Department of General Surgery, Gastrointestinal Surgery Unit, 
Ruijin Hospital Shanghai Jiao Tong University School of Medicine 
Li Chen, MD/Ph D 
Department of General Surgery, Gastrointestinal Surgery Unit, 
Ruijin Hospital Shanghai Jiao Tong University School of Medicine 
Yan Min MD 
Department of General Surgery, Gastrointestinal Surgery Unit, 
Ruijin Hospital Shanghai Jiao Tong University School of Medicine 
Prof Liu Bing Ya 
Shanghai Key Laboratory of Gastric Neoplasms 
Shanghai Institute of Digestive Surgery 
*Prof. Zhu Zheng Gang, MD/Ph.D., FACS  
Department of General Surgery, Gastrointestinal Surgery Unit, 
Ruijin Hospital Shanghai Jiao Tong University School of Medicine  
Shanghai Key Laboratory of Gastric Neoplasms 
Shanghai Institute of Digestive Surgery 
* Principal investigator 
 


 
Brief study protocol of the DRAGON III research 
Document update date 2017-1-10 
 
 
Title 
DRAGON III- Phase 2 research:  
Neoadjuvant Chemotherapy (FLOT versus SOX) for Gastric Cancer 
Purpose  
To compare the safety and efficacy of two main streams of chemotherapy (FLOT 
Versus SOX) for locally advanced gastric cancer patients in a high volume center of 
China. To obtain preliminary results for designing a new phase III multicenter 
randomized controlled trial. 
Nature of the study 
Investigator-initiated, phase II, open-label, randomized controlled study.  
Sample size 
This is an exploratory study. The sample size is estimated empirically. Initially, 60 
patients are anticipated to complete the planned chemotherapy and surgery. The 
enrollment of patients is not limited to 60 patients. The principal-investigator can 
decide on the study termination time or the number of patients after discussion among 
investigators. 
 


Randomization  
Patients will be randomized as 1:1 proportion to FLOT or SOX group. A masked 
statistician at the Clinical Research Center of the hospital is responsible for 
randomization. The assignment will be made by telephone contact or text messages 
after the patient met the inclusion criteria and signed the informed consent. 
Endpoints 
Total percentage of patients with pathological complete tumor regression (TRG1a) 
and sub-total tumor regression (TRG1b) in the primary tumor  
Primary Outcome Measure 
Overall survival (OS): Time from randomization to death from any cause 
Secondary Outcome Measures: 
Disease-free survival (DFS): Time from randomization to relapse of the disease  
 
Study design 
 
NAC: Neoadjuvant chemotherapy 


AC: Adjuvant chemotherapy 
RECIST: Response Evaluation Criteria in Solid Tumors  
TRG: Tumour regression grade 
Pre-treatment assessment 
All patients will undergo a full clinical assessment before commencement of the 
treatment, which includes a full medical history, physical examination, a complete 
blood count, clotting analysis, serum liver function, and renal function test, 24-hour 
urinary 
clearance, 
blood 
tumor 
markers 
for 
gastrointestinal 
diseases. 
Electrocardiography, echocardiography, chest radiography, computed tomography 
(CT) of the chest, abdomen, and pelvis, upper gastrointestinal endoscopy are 
mandatory. Specially designed protocol for CT examination will be used for clinical 
staging of gastric cancer, which consists of arterial, venous, and portal phase of 
transverse section images and reconstruction images of the sagittal and coronary 
section). Ultrasonography, Magnetic resonance (MR) are recommended if clinically 
necessary to rule out suspicious distant metastases or retroperitoneal lymph nodes. 
Positron emission tomography (PET) or whole-body bone scintigraphy is 
recommended in suspected cases. Diagnostic laparoscopy is recommended to rule out 
peritoneal metastases. Clinical staging will be performed according to the 
International Union against Cancer (UICC), Tumor–Node–Metastasis (TNM) 
Classification of Stomach, eighth edition.  
Neoadjuvant Chemotherapy 
Patients will be transferred to the department of medical oncology for chemotherapy, 


the standard protocol for chemotherapy will be circulated and timely inspection will 
be performed by investigators and Clinical Research Center to evaluate the 
implementation of the protocol. Preventive antiemetic and dexamethasone are allowed 
before chemotherapy, growth factor, or other supportive medicines are allowed for 
treatment only. Surgical intervention is allowed for acute bleeding or other surgical 
emergencies.  
Patients in the FLOT group will receive four cycles of the standard dose of FLOT 
chemotherapy and the patients in the SOX group receives three cycles of the standard 
dose of TGO plus oxaliplatin before undergoing curative gastrectomy. 
Inclusion criteria 
Age: 18-80 years old  
Sex: all   
Histology 
confirmed 
non-obstructive 
adenocarcinoma 
of 
the 
stomach 
or 
esophagogastric junction.  
Clinical stage: cTNM: stage III or above  
Performance status: Eastern Cooperative Oncology Group ECOG 
≤ 2 (normal to 
symptomatic but in bed less than half the day)  
Clinically fit for systemic chemotherapy and gastric cancer surgery, i.e. adequate 
renal, hepatic, hematologic, and pulmonary function.  
Written informed consent  
Exclusion criteria 
Clinically unfit for systemic chemotherapy and gastric cancer surgery, i.e. 


uncontrolled cardiac disease, or other clinically significant uncontrolled comorbidities, 
unable to undergo general anesthesia 
Confirmed distant metastases  
Locally advanced inoperable disease (Clinical assessment) 
Relapse of gastric cancer  
Malignant secondary disease  
Prior chemo or radiotherapy  
Inclusion in another clinical trial  
Known contraindications or hypersensitivity for planned chemotherapy  
Drop out  
Protocol violation  
Unable to complete planned chemotherapy or surgery for any reason  
Refusal to perform surgery at the same hospital  
Withdrawn by the participant for any reason 
 
Neoadjuvant Treatment  
A cycle consists of  
FLOT Chemotherapy regimen 
Day 1: 5-FU 2600mg/M2 intravenous 
Via  peripherally inserted central catheter (PICC) for 24 hour 
Day 1: Leucovorin 200mg/M2 intravenous  
Day 1: Oxaliplatin 85mg/ M2 intravenous  


Day 1: Docetaxel 50mg/M2 intravenous 
Repeated every 15th day 
 
A cycle consists of 
SOX Chemotherapy regimen 
Day 1: Oxaliplatin 130mg/M2 intravenous  
Day 1-14 Tegafur gimeracil oteracil potassium capsule 80mg/M2 oral (twice daily) 
Repeated every 21st day 
Restaging  
Response to treatment will be evaluated according to the Response Evaluation 
Criteria in Solid Tumors (RECIST version 1.1) guidelines. Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have a reduction in short axis to <10 mm. Partial Response (PR): At 
least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum 
of diameters of target lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on the study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum diameters 
while on the study. The overall response rate (ORR) is defined as the percentage of 


patients who have achieved CR and PR. Disease Control Rate (DCR) is defined as 
the percentage of patients who have achieved CR, PR, and SD. Two specialized 
radiologists will independently evaluate the ORR and DCR. Any conflicting results 
will be settled after discussion among both radiologists and investigators. The 
principal-investigator has the right to decide on the final result. 
 
Surgery 
Surgery is recommended for two to four weeks after completion of the planned 
chemotherapy. The patient will undergo an exploratory laparoscopic examination to 
rule out peritoneal or distant metastases. Surgery will be terminated if there is 
peritoneal or distant metastasis. 
Surgeons who are trained for gastric cancer surgery are allowed to perform the 
surgery. Surgeons will be trained by principal investigators on the implementation of 
protocol guidelines. Japanese gastric cancer treatment guidelines will be followed for 
surgical treatment. Surgical extent is determined by the operating surgeons during 
surgery, standard gastrectomy with curative intent (partial or total gastrectomy with 
D2 lymphadenectomy) is recommended surgical procedure. It involves resection of at 
least two-thirds of the stomach with a D2 lymph node dissection. Gastrectomy with 
combined resection of adjacent involved organs is allowed if required for R0 resection. 
Resection margin: A sufficient resection margin is required when determining the 
resection line in gastrectomy. The proximal margin of at least 3 cm for non-infiltrative 
and 5 cm for those with infiltrative tumors are recommended. Distal gastrectomy with 


gastroduodenostomy or gastrojejunostomy is recommended for the tumors located at 
the antrum or lower part of the stomach body. Total gastrectomy with Roux-en-Y 
esophagojejunostomy is recommended for the proximal tumors. Surgeons are required 
to document whether the procedure is curative or non-curative intent according to the 
definition stated in Japanese gastric cancer treatment guidelines. Non-curative surgery 
is allowed for clinical treatment but those cases will be dropped out for pathological 
analysis. 
Pathological assessment 
After formalin fixation and paraffin embedding, all specimens will have an 
immunohistochemical examination. Pathological assessment will be made according 
to local clinical guidelines that follow Tumor–Node–Metastasis (TNM) Classification 
of Stomach, eighth edition. Assessments include tumor type, Lauren’s classification, 
depth of invasion, the involvement of lymph nodes, resection margins, vessels, and 
nerve invasion. The presence or absence of residual tumor after surgery is described 
as the R status; R0 is a curative resection with negative resection margins; R1 andR2 
is considered non-curative resections. The tumor regression grading (TRG), Becker 
criteria will be used for the evaluation of pathological response in the resected 
specimens.  Pathologists will examine residual vital tumor cells and the remnant of 
the previous tumor as necrosis, fibrosis, or scar as suggested in Becker criteria for 
grading. Two specialized pathologists will independently rate the TRG grading. Any 
conflicting results are settled after re-examination and discussion among both 
pathologists and investigators. The principal-investigator has the right to decide on the 


final result. 
 
Tumor regression grade (TRG), Becker criteria 
Grade 1a: Complete tumor regression: 0% residual tumor per tumor bed  
Grade 1b: Subtotal tumor regression: <10% residual tumor per tumor bed  
Grade 2: Partial tumor regression: 10-50% residual tumor per tumor bed  
Grade 3: Minimal or no tumor regression: >50% residual tumor per tumor bed 
Statistical plan 
General principle: Apply the standard statistical methods to analyze the following 
parameters in both arms 
Timeline for the first and last patient enrolled 
Total number of enrolled cases in two arms 
Eligible cases: Total number of enrolled cases minus drop out cases  
Comparison of basic demographic data (age, sex, BMI, etc) 
Duration of chemotherapy, no. of cycles (non-parametric) 
Reasons for therapy discontinuation 
Resection rates  
Types of surgery (surgical extent)  
Postoperative morbidity and mortality  
Overall Response rate (ORR): Radiological assessment (Recist 1.1) 
Pathological response rate (Tumor regression grading, TRG) 
Overall survival (OS) 


Relapse free survival (RFS) 
Availability of data 
All the data will be kept safe for at least two years after the completion of the research 
and can be provided to any reasonable request according to local rules and 
regulations.