Diffuse Gastric and Esophagogastric Junction Cancer S-1 Trial (DIGEST)

An Open-Label, Multicenter, Randomized, Phase 3 Study of S-1 and Cisplatin Compared With 5-FU and Cisplatin in Patients With Metastatic Diffuse Gastric Cancer Previously Untreated With Chemotherapy

The purpose of this study is to evaluate the safety and efficacy of S-1 and Cisplatin compared to 5-FU and Cisplatin in treatment of patients with metastatic diffuse gastric and gastro-esophageal junction cancer previously untreated with chemotherapy.

Study Overview

• Status: Terminated
• Conditions: Metastatic Diffuse Gastric Cancer Including Carcinoma of the Gastro-esophageal Junction
• Intervention / Treatment: Drug: S-1 (Tegafur+Gimeracil+Oteracil) /cisplatin (investigational arm); Drug: Fluorouracil/cisplatin (control arm)

Detailed Description

This is an open-label, international, Phase 3 study evaluating the efficacy and safety of the S-1/cisplatin regimen versus the 5-FU/cisplatin regimen in chemotherapy-naïve patients with metastatic diffuse gastric carcinoma including carcinoma of the gastro-esophageal junction. Patients will be randomly assigned to S-1/cisplatin (experimental regimen, Arm A) or 5-FU/cisplatin (control regimen, Arm B).

• Study Type: Interventional
• Enrollment (Actual): 361
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aires, Argentina, 1264
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000KZE
• Belgium
  • Bruxelles, Belgium, 1200
  • Edegem, Belgium, 2650
  • Gent, Belgium, 9000
• Brazil
  • Belo Horizonte, Brazil, 31110-580
  • Fortaleza, Brazil, 60160-230
  • Ijuí, Brazil, 98700-000
  • Porto Alegre, Brazil, 90050-170
  • BA
    • Salvador, BA, Brazil, 41820-021
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
  • SP
    • Barretos, SP, Brazil, 14784-400
    • Ribeirão Preto, SP, Brazil, 14015-130
    • São Paulo, SP, Brazil, 01246-000
    • São Paulo, SP, Brazil, 01406-100
• Bulgaria
  • Pleven, Bulgaria, 5800
  • Vratsa, Bulgaria, 3000
• Croatia
  • Osijek, Croatia, 31000
  • Zagreb, Croatia, 10000
• Estonia
  • Tallinn, Estonia, 11312
  • Tallinn, Estonia, 13419
• Germany
  • Essen, Germany, 45147
• Hungary
  • Budapest, Hungary, 1122
  • Budapest, Hungary, 1032
  • Győor, Hungary, 9024
  • Nyíregyháza, Hungary, 4400
  • Pécs, Hungary, 7624
  • Szeged, Hungary, 6720
  • Székesfehérvár, Hungary, 8000
• Israel
  • Tel Aviv, Israel, 64239
• Italy
  • Ancona, Italy, 60020
  • Candiolo, Italy, 10060
  • Milano, Italy, 20141
  • Modena, Italy, 41100
  • Potenza, Italy, 85100
  • Reggio Emilia, Italy, 42100
  • Rimini, Italy, 47900
• Mexico
  • Chihuahua, Mexico, 31000
  • Mexico City, Mexico, 14080
  • Oaxaca, Mexico, 68000
• Poland
  • Szczecin, Poland, 71-730
  • Warszawa, Poland, 02-781
• Portugal
  • Aveiro, Portugal, 3814-501
  • Coimbra, Portugal, 3000-226
  • Lisboa, Portugal, 1649-035
  • Porto, Portugal, 4200-072
• Romania
  • Baia Mare, Romania, 430031
  • Cluj-Napoca, Romania, 400015
  • Craiova, Romania, 200385
  • Iasi, Romania, 700106
• Russian Federation
  • Barnaul, Russian Federation, 656049
  • Krasnodar, Russian Federation, 350040
  • Moscow, Russian Federation, 115478
  • Pyatigorsk, Russian Federation, 357502
  • Saint Petersburg, Russian Federation, 197022
  • Saint Petersburg, Russian Federation, 197758
  • Saint-Petersburg, Russian Federation, 194214
• South Africa
  • Gauteng
    • Groenkloof Pretoria, Gauteng, South Africa, 0181
    • Pretoria, Gauteng, South Africa, 0002
  • KZN
    • Durban, KZN, South Africa, 4091
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7500
• Spain
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08035
  • Barcelona, Spain, 08907
  • Madrid, Spain, 28046
  • Madrid, Spain, 28034
  • Madrid, Spain, 28007
  • Madrid, Spain, 28033
  • Madrid, Spain, 28050
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
• Ukraine
  • Cherkassy, Ukraine, 18009
  • Chernivtsiy, Ukraine, 58013
  • Dnepropetrovsk, Ukraine, 49102
  • Donetsk, Ukraine, 83092
  • Kharkiv, Ukraine, 61070
  • Kyiv, Ukraine, 3115
  • Lutsk, Ukraine, 43018
  • Lviv, Ukraine, 79031
  • Sumy, Ukraine, 40005
  • Uzhgorod, Ukraine, 88000
  • Zaporizzhya, Ukraine, 69040
• United Kingdom
  • London, United Kingdom, W12 0NN
  • Wales
    • Rhyl, Wales, United Kingdom, LL18 5UJ
• United States
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
  • Texas
    • Dallas, Texas, United States, 75390
    • Houston, Texas, United States, 77030

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has given written Informed Consent.
• Histologically confirmed, unresectable, metastatic diffuse gastric cancer including carcinoma of the gastro-esophageal junction.
• No prior chemotherapy for gastric cancer except adjuvant and/or neo-adjuvant chemotherapy more than 12 months ago.
• Life expectancy of at least 3 months.
• Able to take medications orally.
• Eastern Cooperative Oncology Group performance status 0 to 1.
• Adequate organ function (bone marrow, kidney and liver).

Exclusion Criteria:

• Certain type(s) of non-measurable lesion(s), if the only one(s).
• Certain serious illness or medical condition(s).
• Lost greater than or equal to 10% of body weight in the 3 months proceeding signing the Informed Consent Form.
• Treatment with drugs interacting with S-1, 5-FU, or cisplatin.
• Pregnant or lactating female.
• Known hypersensitivity to fluoropyrimidines or cisplatin.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: S-1+Cisplatin; Participants received S-1 25 milligrams per meter square (mg/m^2) orally twice daily (BID) every 12 hours from Day 1 through Day 21, 1 hour before or after meal with a glass of water; followed by a 7-day rest period from Day 22 to Day 28 in a 28-day cycle. Participants received a single dose of cisplatin 75 mg/m^2 as a 1- to 3-hour intravenous (IV) infusion on Day 1 following the morning dose of S-1 for a maximum of 8 cycles (each cycle of 28 days). Participants received study medication until progression of disease (PD), adverse event (AE), withdrawal of consent, or other reason for discontinuation, whichever happened earlier.	Drug: S-1 (Tegafur+Gimeracil+Oteracil) /cisplatin (investigational arm); 25 mg/m² body surface area (BSA) orally 2 times daily from Days 1 through 21 followed by a 7 day rest period, plus cisplatin 75 mg/m2 BSA on Day 1 each 28 day cycle Number of Cycles: until progression or unacceptable toxicity develops. Treatment with cisplatin is limited to a maximum of 8 cycles.; Other Names: TS-1, Tegafur+Gimeracil+Oteracil
ACTIVE_COMPARATOR: 5FU+Cisplatin; Participants received 5-Fluorouracil (5-FU) 800 mg/m^2 per 24 hours as continuous IV infusion over 120 hours from Day 1 through Day 5 followed by a 16-day rest period on Days 6 through 21 in a 21-day cycle. Participants received a single dose of cisplatin 80 mg/m^2 as a 1- to 3-hour IV infusion on Day 1 prior to the start of the 5-FU infusion on Day 1 for a maximum of 8 cycles (each cycle of 21 days). Participants received study medication until PD, AE, withdrawal of consent, or other reason for discontinuation, whichever happened earlier.	Drug: Fluorouracil/cisplatin (control arm); 5-FU: 800 mg/m2 BSA/24 hours by continuous intravenous infusion (CIV) from Days 1 through 5 plus cisplatin 80 mg/m2 BSA on Day 1 each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. Treatment with cisplatin is limited to a maximum of 8 cycles.; Other Names: TS-1, Tegafur+Gimeracil+Oteracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was defined as the time from randomization to the date of death for the ITT population. Participants who did not die were censored at the date last known to be alive. Analysis was performed by using Kaplan-Meier method.	From the date of randomization until disease progression or death, cut-off date: 15 August 2014 (approximately 40 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	PFS was defined as the time from date of randomization until date of radiological disease progression or death due to any cause. Disease Progression was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, where any of the 3 criteria have been met: 1) at least 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum on study, including the baseline sum, 2) Progression in no-target lesion(s), 3) appearance of new lesion(s) Participants who were alive with no PD were censored at the date of the last tumor assessment. Participants who received new anticancer therapy before disease progression were censored at the date of the last evaluable tumor assessment before new anticancer therapy was initiated. Analysis was performed by using Kaplan-Meier method.	From date of randomization until disease progression or death, cut-off date: 07 March 2014 (approximately 34.7 months)
Time to Treatment Failure (TTF)	TTF was defined as the time from date of randomization until date of PD (clinical or radiologic), or permanent discontinuation of study treatment (S-1 or 5-FU), or death due to any cause. Participates who were still on study treatment at the time of the analysis were censored at the last date the participants was known to be on treatment.	From date of randomization until disease progression, cut-off date: 07 March 2014 (approximately 34.7 months)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)	AE was defined as any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily had to have a causal relationship with the use of the study medication. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment period (from first dose of study medication up to 30 days of last study medication [maximum duration: 35.7 months]).	From first dose of study medication up to 30 days of last study medication (maximum duration: 35.7 months)
Number of Participants With TEAEs With Severity Greater Than or Equal to (>=) Grade 3	An AE was any untoward medical condition that occurred in a participants while participating in a clinical study and does not necessarily had to have a causal relationship with the use of the study medication. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment period (from first dose of study medication up to 30 days of last study medication [maximum duration: 35.7 months]).	From first dose of study medication up to 30 days of last study medication (maximum duration: 35.7 months)
Overall Response Rate (ORR): Percentage of Participants With Overall Response	ORR was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR) based on the Investigator review of the images and application of Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as the disappearance of all target or non-target lesions. Any pathological lymph nodes for target lesions or all lymph nodes for non-target lesions were non-pathological morphologically that was reduced in size in short axis to less than (<) 10 millimeter (mm). PR was defined as target lesions with at least 30% decrease in the sum of diameters, taking baseline sum diameters as reference.	From date of first study medication until cut-off date: 07 March 2014 (approximately 34.7 months)
Duration of Response (DR)	Duration of response was defined as the time (in months) from date of first confirmed response (CR or PR) to date of first progressive disease (PD) or death. Per the RECIST criteria, definitions were as follows: CR was defined as the disappearance of all target or non-target lesions. Any pathological lymph nodes for target lesions or all lymph nodes for non-target lesions were non-pathological morphologically that was reduced in size in short axis to <10 mm. Analysis was performed by using Kaplan-Meier method.	From date of first study medication until cut-off date: 07 March 2014 (approximately 34.7 months)
Time to Tumor Response (TTR)	TTR was defined as the time (in months) from the date of randomization to the date of first observation of response (PR or CR) (whichever status was recorded first). TTR was assessed based on investigator assessment utilizing RECIST 1.1. CR was defined as the disappearance of all target or non-target lesions. Any pathological lymph nodes for target lesions or all lymph nodes for non-target lesions were non-pathological morphologically that was reduced in size in short axis to <10 mm. PR was defined as target lesions with at least 30% decrease in the sum of diameters, taking baseline sum diameters as reference. Analysis was performed by using Kaplan-Meier method.	From date of first study medication until cut-off date: 07 March 2014 (approximately 34.7 months)

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.
• Investigators: Study Director: Taiho Central, Taiho Oncology, Inc. USA

Publications and helpful links

General Publications

• Ajani JA, Abramov M, Bondarenko I, Shparyk Y, Gorbunova V, Hontsa A, Otchenash N, Alsina M, Lazarev S, Feliu J, Elme A, Esko V, Abdalla K, Verma U, Benedetti F, Aoyama T, Mizuguchi H, Makris L, Rosati G; DIGEST Study Group. A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 2017 Sep 1;28(9):2142-2148. doi: 10.1093/annonc/mdx275.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 14, 2011
• Primary Completion (ACTUAL): August 15, 2014
• Study Completion (ACTUAL): August 15, 2014

Study Registration Dates

• First Submitted: January 26, 2011
• First Submitted That Met QC Criteria: January 26, 2011
• First Posted (ESTIMATE): January 28, 2011

Study Record Updates

• Last Update Posted (ACTUAL): May 17, 2022
• Last Update Submitted That Met QC Criteria: April 22, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Gastric Cancer , S-1, Phase 3
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cisplatin; Fluorouracil; Tegafur
• Other Study ID Numbers: TPU-S1303

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No