Docetaxel+Oxaliplatin+S-1 (DOS) Regimen as Neoadjuvant Chemotherapy in Advanced Gastric Cancer

Study Overview
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Brief Summary
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Primary Objective: - To compare the 3-year progression free survival (PFS) in the two treatment arms. Secondary Objectives: Overall survival (OS). Postoperative pathological stage and R0 (complete) resection rate. Safety: Toxicities associated with neoadjuvant chemotherapy, surgery, morbidity/mortality, toxicity of adjuvant chemotherapy.

Detailed Description
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Participants in the neoadjuvant chemotherapy arm were treated for 3 cycles (1 cycle is 21 days) before surgery and treated for a year with S-1. Participants in the adjuvant chemotherapy arm underwent surgery and were treated for a year with S-1. All participants were followed during and after the study treatment until death or disease progression, whichever comes first.

Official Title
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A Phase III, Open-labelled, Randomised Study of Neoadjuvant Docetaxel+Oxaliplatin+S-1 (DOS) + Surgery + Adjuvant S-1 Versus Surgery + Adjuvant S-1 in Patients With Resectable Advanced Gastric Cancer

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Docetaxel (XRP6976)
* Drug: Oxaliplatin (SR96669)
* Drug: S-1 (1-(2-tetrahydrofuryl)-5-fluorouracil + 5-chloro-2, 4-dihydroxypyridine (CDHP) (Gimeracil) + Oxo (Oteracil)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants with new histologically confirmed, newly diagnosed, localized gastric or gastro-oesophageal adenocarcinoma, that is considered resectable. Participants with clinical stage (T2-3/N(+), T4/N(+/-):N positive means greater than or equal to [>=] 8 in hour axis). Signed informed consent. Exclusion criteria: Aged less than (<) 20 years or >= 76 years. Performance status >=2 in Eastern Cooperative Oncology Group (ECOG) scale The participants who had the history of other malignancy within the last five years except cured basal cell carcinoma of skin and carcinoma in situ of uterine cervix which had been already successfully treated. Previous surgery on neoplasm of stomach. Participants who did not completely recovered from surgery. Distant metastases (M1) to other organs including distant nodal groups (retropancreatic, para-aortic, portal, retroperitoneal, mesenteric node). severe/unstable angina, coronary artery bypass graft, congestive heart failure, transient ischemic attack within 6 months prior to enrollment in the study. Any previous palliative, adjuvant or neoadjuvant chemotherapy and/or radiotherapy and/or immunotherapy, for the currently treated gastric cancer. Participants with active infection or sepsis. Intolerance of oral taking or malabsorption: lack of physical integrity of the upper gastrointestinal tract or those who have malabsorption syndrome likely to influence absorption of S-1. Ileus, chronic inflammatory intestinal disease or extensive resection of the small intestine and other disorders which limit drug resorption. This includes gastric dumping syndrome, indications of accelerated passage through the small intestine and indications of resorption disorders after intestinal surgery. Greater than or equal to grade 2 severe tumour haemorrhage. Simultaneous participation in another study, or participation in another study within 4 weeks of commencement of this study. Pregnant or lactating participants. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Surgery + Adjuvant Chemotherapy (SC)<br>Participants underwent surgery within 2 weeks after randomization followed by adjuvant chemotherapy with S-1 [(Gimeracil) + Oxo (Oteracil)] 40 milligrams per square meter (mg/m^2) administered orally twice daily, from Day 1 to 28 of each cycle for 1 year, and were followed-up after End-of-Treatment (EOT) until disease progression or death or study cut-off date, whichever comes first (maximum duration: up to 10 years). | Drug: S-1 (1-(2-tetrahydrofuryl)-5-fluorouracil + 5-chloro-2, 4-dihydroxypyridine (CDHP) (Gimeracil) + Oxo (Oteracil)<br>* Pharmaceutical form:Tablet Route of administration: Oral<br>|
| Experimental: Neoadjuvant Chemotherapy +Surgery +Adjuvant chemotherapy (CSC)<br>Participants received neo-adjuvant chemotherapy with Docetaxel 50 mg/m^2 intravenously (IV) for greater than or equal to (>=)1 hour (hr) on Day 1 of each treatment cycle plus Oxaliplatin 100 mg/m^2 IV for >=2 hr on Day 1 of each treatment cycle plus S-1 [(Gimeracil) + Oxo (Oteracil)] 40 mg/m^2 administered orally twice daily from Day 1 to 14, of each treatment cycle followed by surgery approximately 1-3 weeks after completion of neo-adjuvant chemotherapy and adjuvant chemotherapy with S-1 [(Gimeracil) + Oxo (Oteracil)] 40 mg/m^2 administered orally twice daily, from Day 1 to 28 of each cycle for 1 year, and were followed-up after EOT until disease progression or death or study cut-off date, whichever comes first (maximum duration: up to 10 years). | Drug: Docetaxel (XRP6976)<br>* Pharmaceutical form:solution for infusion Route of administration: intravenous<br>Drug: Oxaliplatin (SR96669)<br>* Pharmaceutical form:solution for infusion Route of administration: intravenous<br>Drug: S-1 (1-(2-tetrahydrofuryl)-5-fluorouracil + 5-chloro-2, 4-dihydroxypyridine (CDHP) (Gimeracil) + Oxo (Oteracil)<br>* Pharmaceutical form:Tablet Route of administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With 3-Year Progression-Free Survival (PFS), as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST)1.1 | PFS was defined as the time from randomization to objective tumor progression, or recurrence or death. Progressive disease (PD) was defined as follows: 1) In Neoadjuvant Chemotherapy +Surgery +Adjuvant Chemotherapy (CSC) Arm, PD was determined according to the RECIST 1.1 Criteria during the neo-adjuvant chemotherapy period; 2) Irrespective of curative resection, if an intraoperative distant metastasis was observed or a distant metastasis was reported from pathology, it was considered PD; 3) If residual cancer cells were visually identified at the resection margin during surgery but could not be completely resected (R2), it was considered PD; 4) If residual cancer cells were finally confirmed at the resection margin during postoperative histology (R1), it was considered PD; 5) In case of finding a recurrence/distant metastasis or a new lesion during follow-up after R0 complete resection, it was defined as the first tumor assessment date when it was observed. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. Analyzed using Kaplan-Meier method. | From randomization to date of death due to any cause (maximum duration: up to 10 years) | 
| Number of Participants With Post-Operative Pathological Stage Response | TNM pathological stage was determined according to standardized histopathology and the American Joint Committee on Cancer (AJCC) staging system 7th Edition (Stages 0,IA,IB,IIA,IIB,IIIA,IIIB,IIIC and IV). Stage 0=carcinoma in situ with no metastatic potential; Stage IA=T1N0M0; Stage IB=T2N0M0,T1N1M0; Stage IIA=T3N0M0,T2N1M0,T1N2M0;Stage IIB=T4aN0M0,T3N1M0,T2N2M0,T1N3M0;Stage IIIA=T4aN1M0,T3N2M0,T2N3M0;Stage IIIB=T4bN0-1M0,T4aN2M0,T3N3M0;Stage IIIC=T4bN2-3M0, T4aN3M0 and Stage IV= distant metastases (M1) at diagnosis; where T denotes tumor size where T1: tumor invades lamina propria, muscularis mucosae, or submucosa; T2: invades muscularis propria; T3: invasion of subserosa; T4: T4a: penetrate serosa (visceral peritoneum) T4b: invade adjacent tissue and  N denotes nodes affected where N1:1-2 positive lymph nodes; N2:3-6 positive lymph nodes; N3: 7 or more positive lymph nodes and M denotes metastases where M0: no distant metastases. Higher stages indicates worse outcome. | Up to 10 years | 
| Percentage of Participants With R0 Resection | Tumor condition was explained according to the Residual Tumor (R) Classification: R0; No residual cancer (negative cross-section), R1; Microscopically observed residual cancer (positive cross-section), R2; Macroscopically observed residual cancer. | Up to 10 years | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs were defined as adverse events (AE) that appeared or worsened during the treatment period (up to 30 days after the last dose of the investigational product). SAE was an AE or adverse drug reaction at any dose of the investigational product that corresponded to one of the following: resulting in death or is life threatening; requiring in-patient hospitalization or prolongation of existing hospitalization; resulting in persistent or significant disability of dysfunction; resulting in congenital anomaly or birth defect; important medical event. | From randomization up to 30 days after last dose of study drug (maximum duration: up to 10 years) | 
| Number of Participants With Shift of Laboratory Parameters (Hematology) From Baseline Grade to Worst National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade >=3 | NCI-CTCAE version 4.03 was used to determine Grade(Gr),where Gr refers to severity of AE:Gr 1:mild; asymptomatic/mild symptoms; Gr 2:moderate;minimal; Gr 3:severe/medically significant; Gr 4:life-threatening consequences, Gr 5:death related to AE. Abnormal values for Hemoglobin(Hb)(Anemia) were based on Gr1:<lower limit of normal (LLN)-10.0g/dL; Gr2:<10.0-8.0g/dL; Gr3:<8.0g/dL; Gr4:life-threatening consequences;Gr5:death. Hb increased:Gr 1:increase(incr.) in >0-2g/dL above upper limit of normal(ULN);Gr2: incr. in >2-4g/dL above ULN; Gr3:incr. in >4gm/dL above ULN. White blood cell (WBC) decreased: Gr1:<LLN - 3000/mm^3;Gr2: <3000-2000/mm^3; Gr3:<2000-1000/mm^3;Gr4:<1000/mm^3. WBC (Leukocytosis):Gr3:>100,000/mm^3, Gr4:clinical manifestations of leucostasis;Gr5:Death. Abnormal Neutrophil count (ANC):- Gr1:<LLN-1500/mm^3;Gr2:<1500-1000/mm^3; Gr3: <1000-500/mm^3; Gr4:<500/mm^3. Platelet count decreased: Gr1:<LLN-75,000/mm^3;Gr2:<75,000-50,000/mm^3;Gr3:<50,000-25,000/mm^3;Gr4:<25,000/mm^3. | From Baseline up to 30 days after last dose of study drug (maximum duration: up to 10 years) | 
| Number of Participants With Shift of Laboratory Parameters (Sodium and Potassium Levels) From Baseline Grade to Worst NCI-CTCAE Grade >=3 | NCI-CTCAE version 4.03 was used to determine Gr,where Gr refers to severity of AE: Gr 1: mild; asymptomatic/mild symptoms; Gr 2: moderate; minimal; Gr 3:severe/medically significant; Gr 4:life-threatening consequences, Gr 5:death related to AE. Abnormal values for Sodium (Hyponatremia) were based on Gr1: <LLN-130 mmol/L; Gr3: <130-120 mmol/L; Gr4: <120 mmol/L; life-threatening consequences; Gr5: death. Sodium (Hypernatremia):Gr 1: >ULN-150 mmol/L; Gr2: >150-155 mmol/L; Gr3:>155-160 mmol/L;hospitalization; Gr4: >160 mmol/L; life-threatening consequences; Gr5: Death. Potassium (Hypokalemia): Gr 1: <LLN-3.0 mmol/L; Gr2: <LLN-3.0 mmol/L; symptomatic; intervention indicated; Gr3: <3.0-2.5 mmol/L; hospitalization indicated; Gr4: <2.5 mmol/L; life-threatening consequences; Gr5: Death; Potassium(Hyperkalemia): Gr 1: >ULN-5.5 mmol/L; Gr2: >5.5-6.0 mmol/L; Gr3: >6.0-7.0 mmol/L; hospitalization indicated; Gr4: >7.0 mmol/L; life-threatening consequences; Gr5: Death. | From Baseline up to 30 days after last dose of study drug (maximum duration: up to 10 years) | 
| Number of Participants With Shift of Laboratory Parameters (Calcium, Creatinine and Albumin Levels) From Baseline Grade to Worst NCI-CTCAE Grade >=3 | NCI-CTCAE version 4.03 was used to determine Gr,where Gr refers to severity of AE:Gr 1:mild; asymptomatic/mild symptoms; Gr 2:moderate;minimal; Gr 3:severe/medically significant; Gr 4:life-threatening consequences, Gr 5:death related to AE. Abnormal values for Calcium(Hypocalcemia) were based on Gr1: Corrected serum calcium of <LLN-8.0 mg/dL; Gr2: Corrected serum calcium of <8.0-7.0 mg/dL; Gr3: Corrected serum calcium of <7.0-6.0 mg/dL ; Gr4: Corrected serum calcium of <6.0 mg/dL;Gr5:death. Calcium(Hypercalcemia):Gr 1: Corrected serum calcium of >ULN -11.5 mg/dL; Gr2: Corrected serum calcium of >11.5-12.5 mg/dL; Gr3: Corrected serum calcium of >12.5-13.5 mg/dL; Gr4: Corrected serum calcium of >13.5 mg/dL;Gr5:Death. Creatinine increased: Gr 1: >1-1.5*baseline; >ULN-1.5*ULN; Gr2: >1.5-3.0*baseline; >1.5-3.0*ULN; Gr3: >3.0 baseline; >3.0-6.0*ULN; Gr4: >6.0 x ULN. Albumin(Hypoalbuminemia): Gr 1: <LLN-3 g/dL; Gr2: <3-2 g/dL; Gr3: <2 g/dL; Gr4:life-threatening consequences;Gr5:Death. | From Baseline up to 30 days after last dose of study drug (maximum duration: up to 10 years) | 
| Number of Participants With Shift of Laboratory Parameters (Aspartate Aminotransferase, Alanine Aminotransferase,Blood Bilirubin,Alkaline Phosphatase and Glucose Levels) From Baseline Grade to Worst NCI-CTCAE Grade >=3 | NCI-CTCAE version 4.03 was used to determine Gr, where Gr refers to severity of AE: Gr 1:mild; asymptomatic/mild symptoms; Gr 2:moderate; minimal; Gr 3:severe/medically significant; Gr 4:life-threatening consequences, Gr 5:death related to AE. Abnormal values for Aspartate and alanine aminotransferase increased were based on Gr1: >ULN-3.0*ULN; Gr2: >3.0-5.0*ULN; Gr3: >5.0-20.0*ULN; Gr4: >20.0*ULN. Blood bilirubin increased: Gr1: >ULN-1.5*ULN; Gr2 >1.5-3.0*ULN; Gr3: >3.0-10.0*ULN; Gr4: >10.0*ULN. Alkaline phosphatase increased: Gr1: >ULN-2.5*ULN; Gr2: >2.5-5.0*ULN; Gr3: >5.0-20.0*ULN; Gr4: >20.0*ULN. Glucose (Hypoglycemia): Gr 1: <LLN-55 mg/dL; Gr2: <55-40 mg/dL;Gr3: <40-30 mg/dL; Gr4: <30 mg/dL; Gr5:Death. Glucose (Hyperglycemia): Gr 1: Fasting glucose value >ULN-160 mg/dL; Gr2: Fasting glucose value >160-250 mg/dL; Gr3: >250-500 mg/dL; Gr4: >500 mg/dL; Gr5: Death. | From Baseline up to 30 days after last dose of study drug (maximum duration: up to 10 years) | 
| Number of Participants With Shift of Laboratory Parameters (Creatinine Clearance [Chronic Kidney Disease]) From Baseline Grade to Worst NCI-CTCAE Grade >=3 | NCI-CTCAE version 4.03 was used to determine Gr, where Gr refers to severity of AE: Gr 1: mild; asymptomatic/mild symptoms; Gr 2: moderate; minimal; Gr 3: severe/medically significant; Gr 4:life-threatening consequences, Gr 5:death related to AE. Abnormal values for Creatinine Clearance(Chronic kidney disease) were based on: Gr 1: estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) <LLN-60ml/min/1.73 m^2; Gr2: eGFR or CrCl 59-30 ml/min/1.73 m^2; Gr3: eGFR or CrCl 29-15 ml/min/1.73 m^2; Gr4: eGFR or CrCl <15 ml/min/1.73 m^2; Gr5: Death. | From Baseline up to 30 days after last dose of study drug (maximum duration: up to 10 years) |