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

• ClinicalTrials.gov Identifier: NCT01515748
• Recruitment Status: Active, not recruiting
• First Posted: January 24, 2012
• Results First Posted: March 2, 2020
• Last Update Posted: March 2, 2020
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Gastric Cancer	Drug: Docetaxel (XRP6976); Drug: Oxaliplatin (SR96669); Drug: S-1 (1-(2-tetrahydrofuryl)-5-fluorouracil + 5-chloro-2, 4-dihydroxypyridine (CDHP) (Gimeracil) + Oxo (Oteracil)	Phase 3

Detailed Description:

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 will be followed during and after the study treatment until death or disease progression, whichever comes first.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 530 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 30, 2011
• Actual Primary Completion Date: January 21, 2019
• Estimated Study Completion Date: January 2, 2022

Arms and Interventions

Arm	Intervention/treatment
Surgery + Adjuvant Chemotherapy (SC); 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 8 years).	Drug: S-1 (1-(2-tetrahydrofuryl)-5-fluorouracil + 5-chloro-2, 4-dihydroxypyridine (CDHP) (Gimeracil) + Oxo (Oteracil); Pharmaceutical form:Tablet Route of administration: Oral
Experimental: Neoadjuvant Chemotherapy +Surgery +Adjuvant chemotherapy (CSC); 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 8 years).	Drug: Docetaxel (XRP6976); Pharmaceutical form:solution for infusion Route of administration: intravenous; Drug: Oxaliplatin (SR96669); Pharmaceutical form:solution for infusion Route of administration: intravenous; Drug: S-1 (1-(2-tetrahydrofuryl)-5-fluorouracil + 5-chloro-2, 4-dihydroxypyridine (CDHP) (Gimeracil) + Oxo (Oteracil); Pharmaceutical form:Tablet Route of administration: Oral

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With 3-Year Progression-Free Survival (PFS), as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST)1.1 [ Time Frame: 3 years ]
   PFS was defined as the time from randomization to objective tumor progression, or recurrence or death. Progressive disease (PD) was defined as: 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.

Secondary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: Up to 11 years ]
   Data for this outcome measure will be reported at the time of anticipated last participant last visit results posting (January 2023).
2. Number of Participants With Post-Operative Pathological Stage Response [ Time Frame: Up to 8 years ]
   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.
3. Percentage of Participants With R0 Resection [ Time Frame: Up to 8 years ]
   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.
4. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From randomization up to 30 days after last dose of study drug (maximum duration: up to 8 years) ]
   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.
5. 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 [ Time Frame: From Baseline up to 30 days after last dose of study drug (maximum duration: up to 8 years) ]
   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.
6. Number of Participants With Shift of Laboratory Parameters (Sodium and Potassium Levels) From Baseline Grade to Worst NCI-CTCAE Grade >=3 [ Time Frame: From Baseline up to 30 days after last dose of study drug (maximum duration: up to 8 years) ]
   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.
7. Number of Participants With Shift of Laboratory Parameters (Calcium, Creatinine and Albumin Levels) From Baseline Grade to Worst NCI-CTCAE Grade >=3 [ Time Frame: From Baseline up to 30 days after last dose of study drug (maximum duration: up to 8 years) ]
   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.
8. 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 [ Time Frame: From Baseline up to 30 days after last dose of study drug (maximum duration: up to 8 years) ]
   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.
9. Number of Participants With Shift of Laboratory Parameters (Creatinine Clearance [Chronic Kidney Disease]) From Baseline Grade to Worst NCI-CTCAE Grade >=3 [ Time Frame: From Baseline up to 30 days after last dose of study drug (maximum duration: up to 8 years) ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 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.

Contacts and Locations

Locations

Korea, Republic of

Administrative Office

Seoul, Korea, Republic of

Sponsors and Collaborators

Sanofi

Investigators

• Principal Investigator: Yoon-Koo KANG, MD, PhD; Asan Medical Center

  Study Documents (Full-Text)

Documents provided by Sanofi:

Study Protocol  [PDF] November 12, 2018

Statistical Analysis Plan  [PDF] March 8, 2019

More Information

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01515748
• Other Study ID Numbers: DOCET_R_05153; U1111-1127-0246 ( Other Identifier: UTN ); EFC13833 ( Other Identifier: Sanofi )
• First Posted: January 24, 2012
• Results First Posted: March 2, 2020
• Last Update Posted: March 2, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to participant level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Participant level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com /

Additional relevant MeSH terms:

Stomach Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Docetaxel; Oxaliplatin; Fluorouracil; Tegafur; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs