Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S)

Open Label, Randomised, Multicenter Phase III Study of Adjuvant Chemotherapy in Radically Resected Adenocarcinoma of the Stomach or Gastroesophageal Junction: Comparison of a Sequential Treatment (CPT-11+5-FU/LV --> TXT+CDDP) Versus a 5-FU/LV Regimen

Open label, randomised, multicenter, superiority study for efficacy. Patients with histologically proven adenocarcinoma of the stomach or gastroesophageal junction without gross or microscopic evidence of residual disease after surgery with curative intent and fulfilling all the inclusion/exclusion criteria are eligible for this study.

Study Overview

• Status: Completed
• Conditions: Adenocarcinoma of the Gastroesophageal Junction; Adenocarcinoma of the Stomach
• Intervention / Treatment: Drug: Irinotecan, Leucovorin, 5-Fluorouracil, Docetaxel, Cisplatin; Drug: Leucovorin, 5-Fluorouracil

Detailed Description

Open label, randomised, multicenter, superiority study for efficacy. Patients with histologically proven adenocarcinoma of the stomach or gastroesophageal junction without gross or microscopic evidence of residual disease after surgery with curative intent and fulfilling all the inclusion/exclusion criteria are eligible for this study.

Allocation to treatment will be done centrally using a randomisation scheme and will be stratified by center and nodal involvement (N- vs. N+). Access to random system will be allowed by phone or via web.

All included patients in both groups will received fixed period of 18 weeks of treatment unless unacceptable toxicity or disease relapse during treatment. After cessation of therapy, patients will have a follow-up period while not receiving further treatment. After relapse further chemotherapy is left to the investigator's judgement. When the last patient is randomised, follow-up will be truncated at the achievement of the required number of events.

Time to progression and time to death are the main study outcomes. During the course of the trial, an independent Data and Safety Monitoring Board (DSMB) will advise the Steering Committee on efficacy and/or safety aspects of the study.

• Study Type: Interventional
• Enrollment (Actual): 1100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Arezzo, Italy, 52100
    • Ospedale. S. Donato
  • Benevento, Italy, 82100
    • A.O. "G. Rummo"
  • Bergamo, Italy, 24128
    • Ospedali "Riuniti"
  • Biella, Italy, 13900
    • Ospedale degli Infermi di Biella
  • Bologna, Italy, 40133
    • Ospedale Maggiore-Bellaria
  • Bologna, Italy, 40138
    • A.O.Policlinico "S.Orsola-Malpighi"
  • Brescia, Italy, 25122
    • Ospedale Sant'Orsola - Fatebenefratelli
  • Brescia, Italy, 25124
    • Casa di Cura Poliambulanza di Brescia
  • Brescia, Italy, 25125
    • Spedali Civili
  • Catania, Italy, 95100
    • P.O. Vittorio Emanuele
  • Catania, Italy, 95123
    • Ospedale Garibaldi in Nesima
  • Como, Italy, 22100
    • A.O. Sant'Anna
  • Como, Italy, 22100
    • Ospedale "Valduce"
  • Crema, Italy, 26013
    • A.O. "Ospedale Maggiore" di Crema
  • Cremona, Italy, 26100
    • Azienda Ospedaliera "Istituti Ospitalieri" di Cremona
  • Cuneo, Italy, 12100
    • A.O. "S.Croce e Carle"
  • Ferrara, Italy, 44100
    • Azienda Ospedaliera Universitaria "S.Anna"
  • Firenze, Italy, 50134
    • A.O. Universitaria Careggi
  • Forli, Italy, 47100
    • A.O. "G.B.Morgagni-L.Pierantoni
  • Genova, Italy, 16128
    • E.O. Ospedali Galliera di Genova
  • Genova, Italy, 16132
    • Istituto nazionale Per la Ricerca sul Cancro
  • Lecco, Italy, 23900
    • P.O. "A.Manzoni" di Lecco
  • Livorno, Italy, 57100
    • Azienda USL 6 - P.O. Livorno
  • Lodi, Italy, 26900
    • Ospedale Civile di Casalpusterlengo
  • Lucca, Italy, 55100
    • Ospedale "Campo di Marte"
  • Mantova, Italy, 46100
    • A.O. "C.Poma"
  • Milano, Italy, 20141
    • Istituto Europeo Di Oncologia
  • Milano, Italy, 20132
    • Istituto scientifico universitario San Raffaele
  • Milano, Italy, 20133
    • Istituto Nazionale per la cura dei tumori
  • Milano, Italy, 20153
    • Azienda Ospedaliera "Ospedale San Carlo Borromeo"
  • Milano, Italy, 20157
    • Azienda Ospedaliera "Luigi Sacco" Polo Universitario
  • Milano, Italy
    • Azienda Ospedaliera "San Paolo" Polo Universitario
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria "Federico II"
  • Napoli, Italy, 80131
    • A.O. "D.Cotugno"
  • Napoli, Italy, 80131
    • A.O.R.N. "Antonio Cardarelli"
  • Napoli, Italy, 80131
    • Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Pascale"
  • Novara, Italy, 28100
    • Azienda Ospedaliera "Maggiore della Carità"
  • Padova, Italy, 35128
    • Azienda Ospedaliera di Padova
  • Palermo, Italy, 90127
    • Ospedali "Civico e Benfratelli - G. Di Cristina - Maurizio Ascoli"
  • Palermo, Italy, 90129
    • Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone"di Palermo
  • Parma, Italy, 43100
    • Azienda Ospedaliera Di Parma
  • Pesaro, Italy, 61100
    • A.O."Ospedale S.Salvatore"
  • Pescara, Italy, 65100
    • Ospedale Civile dello "Spirito Santo"
  • Piacenza, Italy, 29100
    • Ospedale Civile di Piacenza
  • Pisa, Italy, 56126
    • Azienda Ospedaliera-Universitaria Pisana
  • Pordenone, Italy, 33170
    • A.O. "Santa Maria degli Angeli"
  • Potenza, Italy, 85100
    • Ospedale "San Carlo"di Potenza
  • Prato, Italy, 59100
    • Ospedale "Misericordia e Dolce"
  • Ravenna, Italy, 48100
    • P.O. di Ravenna - Azienda Unità Sanitaria Locale di Ravenna
  • Reggio Calabria, Italy, 89100
    • A.O. "Bianchi-Melacrino-Morelli"
  • Reggio Emilia, Italy, 42100
    • Arcispedale Santa Maria Nuova
  • Rimini, Italy, 47900
    • Ospedale "Infermi"
  • Roma, Italy, 00161
    • Policlinico Umberto I
  • Roma, Italy, 00133
    • Azienda Ospedaliera Universitaria "Policlinico Tor Vergata"
  • Roma, Italy, 00186
    • Ospedale Fatebenefratelli "San Giovanni Calibita"
  • Roma, Italy, 00189
    • Istituto Nazionale di Riposo e Cura per Anziani
  • Roma, Italy, MD
    • Istituto Dermopatico dell'Immacolata - IRCCS
  • Sassari, Italy, 07100
    • Azienda Unità Sanitaria Locale n°1 Sassari
  • Sassari, Italy, 07100
    • Ospedale Civile di Sassari
  • Sondrio, Italy, 23100
    • A.O. della Valtellina e della Valchiavenna
  • Torino, Italy, 10126
    • Ospedale San Giovanni Battista di Torino
  • Varese, Italy, 21100
    • A.O."Ospedale di Circolo e Fondazione Macchi"
  • Verona, Italy, 37126
    • A.O. Istituti Ospitalieri di Verona
  • Ancona
    • Fabriano, Ancona, Italy, 60044
      • ASL 6 - Fabriano
    • Senigallia, Ancona, Italy, 60019
      • Ospedale Civile di Senigallia
    • Torrette di Ancona, Ancona, Italy, 60020
      • dell'Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I
  • Avellino
    • Ariano Irpino, Avellino, Italy, 83031
      • Presidio Ospedaliero di Ariano Irpino
  • Bergamo
    • Treviglio, Bergamo, Italy, 24047
      • A.O. "Ospedale Treviglio-Caravaggio"
  • Cagliari
    • Monserrato, Cagliari, Italy, 09042
      • P.O. di Monserrato - Policlinico Universitario di Cagliari
    • Monserrato, Cagliari, Italy, 09042
      • P.O. di Monserrato
  • Cosenza
    • Castrovillari, Cosenza, Italy, 87012
      • Ospedale Civile "Ferrari"
    • Lamezia Terme, Cosenza, Italy, 88046
      • Presidio Ospedaliero di Lamezia Terme
    • Paola, Cosenza, Italy, 87027
      • Ospedale "San Francesco" di Paola
  • Cuneo
    • Alba, Cuneo, Italy, 12051
      • P.O. S. Lazzaro
  • Firenze
    • Antella, Firenze, Italy, 50011
      • OSpedale Santa Maria Annunziata
    • Empoli, Firenze, Italy, 50053
      • Ospedale "San Giuseppe"
  • Massa Carrara
    • Carrara, Massa Carrara, Italy, 54033
      • Ospedale Civico di Carrara
  • Milano
    • Monza, Milano, Italy, 20052
      • A.O "San Gerardo" di Monza
    • Rozzano, Milano, Italy, 20089
      • Istituto Clinico Humanitas
    • San Donato Milanese, Milano, Italy, 20097
      • Ospedale IRCCS Policlinico di San Donato
    • Vizzolo Predabissi, Milano, Italy, 20070
      • Presidio Ospedaliero "Serbelloni"di Gorgonzola
  • Modena
    • Carpi, Modena, Italy, 41012
      • Ospedale "B.Ramazzini"
  • Napoli
    • Pozzuoli, Napoli, Italy, 80087
      • Presidio Ospedaliero "Santa Maria delle Grazie"
  • Padova
    • Este, Padova, Italy, 35043
      • Ospedale Civile di Este
  • Perugia
    • Città di Castello, Perugia, Italy, 06012
      • Ospedale di Città di Castello - ASL 1 Umbria
    • Marsciano, Perugia, Italy, 06055
      • Ospedale di Marsciano - Servizio Oncologico
  • Pesaro
    • Fano, Pesaro, Italy, 61032
      • Ospedale "Santa Croce"
    • Penne, Pesaro, Italy, 65017
      • Ospedale Civile "San Massimo"
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • Centro di Riferimento Oncologico - INT
  • Potenza
    • Rionero in Vulture, Potenza, Italy, 85028
      • Centro di Riferimento Oncologico di Basilicata
  • Ravenna
    • Faenza, Ravenna, Italy, 48018
      • P.O. di Faenza
    • Lugo, Ravenna, Italy, 48022
      • P.O. Umberto I di Lugo
  • Reggio Calabria
    • Siderno, Reggio Calabria, Italy, 89048
      • Ospedale Civile di Siderno
  • Salerno
    • Vallo della Lucania, Salerno, Italy, 84078
      • Ospedale "San Luca"
  • Torino
    • Candiolo, Torino, Italy, 10060
      • Istituto per la Ricerca e la Cura del Cancro di Candiolo
  • Udine
    • Latisana, Udine, Italy, 33053
      • Ospedale Civile di Latisana
  • Umbria
    • Terni, Umbria, Italy, 05100
      • Azienda Ospedaliera S. Maria
  • Varallo
    • Saronno, Varallo, Italy, 21047
      • Presidio Ospedaliero di Saronno - A.O. "Ospedale di Circolo di Busto Arsizio"
  • Varese
    • Busto Arsizio, Varese, Italy, 21052
      • A.O. "Ospedale di Circolo di Busto Arsizio"
  • Verona
    • Legnago, Verona, Italy, 37045
      • Ospedale di Legnago
  • Vicenza
    • Montecchio Maggiore, Vicenza, Italy, 36075
      • Ospedale di Montecchio Maggiore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven adenocarcinoma of the stomach or gastroesophageal junction without gross or microscopic evidence of residual disease after surgery with curative intent;
• Subtotal or total gastrectomy with at least D1 dissection;
• Gastroesophageal junction adenocarcinoma extending to the stomach with the center lying 2 to 5 cm below the anatomic esophago-gastric junction;
• Patients with nodal involvement (pN+) or patients without nodal involvement (pN0) with pT2b-3-4. It is recommended to examine at least 15 lymph nodes;
• Age between 18 and 75 years;
• ECOG performance status 0-1;
• No previous chemotherapy and/or radiotherapy;
• Complete staging procedures within 3 months prior to randomization;

• Laboratory requirement (within 8 days prior to randomization):

  • Haematology (Neutrophils > 2.0 x 109 /L, Platelet > 100 x 109 /L, Hemoglobin > 10g/dL);
  • Hepatic function (Total bilirubin < 1 UNL, ASAT (SGOT) and ALAT (SGPT) < 2.5xUNL, Alkaline phosphatase < 2.5xUNL. Patients with ASAT or ALAT > 1.5xUNL associated with alkaline phosphatase > 2.5XUNL are not eligible.)
  • Renal function (Creatinine < 1.5 UNL. In presence of borderline values, the calculated creatinine clearance according to Cockroft-Gault formula, 60 ML/min.
• Recovery from acute effects of surgery. The first infusion of study chemotherapy should be administered 3 to 8 weeks after surgery treatment;
• Written informed consent signed and dated before randomization procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirement.

Exclusion Criteria:

• Non-radical surgery as assessed microscopically (no tumor-free margin of resection, positive biopsy of peritoneal suspicious lesions);
• Synchronous metastases, even curatively resected;
• Pregnant or lactating patients; patients with reproductive potential must implement adequate contraceptive measures;

• Prior or concurrent history of:

  • positive HIV serology,
  • chronic diarrhoea,
  • chronic bowel inflammation or subobstruction,
  • neoplasm other than gastric cancer, except for: curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix,
  • previous history of myocardial infarction within 1 year from study entry,
  • hypersensitivity reaction to polysorbate 80;

• Presence of other systemic disease limiting drug administration and influencing patient survival:

  • uncontrolled hypertension,
  • high-risk uncontrolled arrhythmia,
  • unstable angina pectoris;

• Symptomatic

  • peripheral neuropathy,
  • altered hearing > 2 grade by NCIC-CTG criteria;
• Active uncontrolled infection.
• Definite contra-indications for the use of corticosteroids: unstable diabetes mellitus, active peptic ulcer;

• Concurrent administration of:

  • corticosteroids or equivalent except as use for the prophylactic medication regimen, treatment of acute hypersensitivity reactions or unless chronic treatment (initiated > 6 months prior to study entry) at low doses (< 20mg methylprednisolone or equivalent);
  • any other experimental drug under investigation: concurrent treatment with any other anticancer therapy, growth factors with preventive intent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequential regimen; Sequential treatment with CPT-11 plus Fluorouracil (FU), folinic acid (LV) and Docetaxel (TXT) plus Cisplatin (CDDP)	Drug: Irinotecan, Leucovorin, 5-Fluorouracil, Docetaxel, Cisplatin; Irinotecan (CPT-11) 180 mg/m2, given as 60 min. i.v. infusion on day 1 every 2 weeks followed by; Leucovorin (LV) 100 mg/m2, given as a 2h i.v. infusion on days 1 and 2 every 2 weeks followed by; 5-Fluorouracil (5-FU) 400 mg/m2 given as bolus, and then 5-Fluorouracil (5-FU) 600 mg/m2 given as a 22h continuous infusion on days 1 and 2, every 2 weeks for 4 administrations. After 3 weeks from last infusion: Docetaxel (TXT) 75 mg/m2, given as a 1h i.v. infusion on day 1 followed by; Cisplatin (CDDP) 75 mg/m2, given as a 1h i.v. infusion on.day 1, every 3 weeks, for 3 cycles.
Active Comparator: De Gramont regimen; Fluorouracil (5-FU), folinic acid (LV)	Drug: Leucovorin, 5-Fluorouracil; Leucovorin (LV) 100 mg/m2, given as a 2h i.v. infusion on days 1 and 2 every 2 weeks followed by; 5-Fluorouracil (5-FU) 400 mg/m2 given as bolus, and then 5-Fluorouracil (5-FU) 600 mg/m2 given as a 22h continuous infusion on days 1 and 2, every 2 weeks for 9 administrations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival will be defined as the time from date of randomisation to date of first appearance of local, regional or distant relapse, or death from any cause; patients alive without relapse will be censored at date last known to be alive.	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse events	3 years
OS will be defined as the time from date of randomisation to date of death by any cause, with living patients censored at date last known to be alive	3 years
Toxicity, graded according to the NCI-CTG Expanded Common Toxicity Criteria	3 years

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborators: Aventis Pharmaceuticals; Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori; Gruppo Oncologico Italiano di Ricerca Clinica; Gruppo Oncologico del Nord-Ovest; Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente; Italian Trial in Medical Oncology; Southern Italy Cooperative Oncology Group; Oncotech
• Investigators: Principal Investigator: Emilio Bajetta, MD, Istituto Nazionale Per lo Studio e la Cura dei Tumori Milano

Publications and helpful links

General Publications

• Bajetta E, Floriani I, Di Bartolomeo M, Labianca R, Falcone A, Di Costanzo F, Comella G, Amadori D, Pinto C, Carlomagno C, Nitti D, Daniele B, Mini E, Poli D, Santoro A, Mosconi S, Casaretti R, Boni C, Pinotti G, Bidoli P, Landi L, Rosati G, Ravaioli A, Cantore M, Di Fabio F, Aitini E, Marchet A; ITACA-S (Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach Trial) Study Group. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol. 2014 Jul;25(7):1373-1378. doi: 10.1093/annonc/mdu146. Epub 2014 Apr 12.

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: July 9, 2012
• First Submitted That Met QC Criteria: July 13, 2012
• First Posted (Estimate): July 16, 2012

Study Record Updates

• Last Update Posted (Estimate): July 18, 2014
• Last Update Submitted That Met QC Criteria: July 17, 2014
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: adenocarcinoma of the stomach; adenocarcinoma of the gastroesophageal junction
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Adenocarcinoma; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Docetaxel; Fluorouracil; Leucovorin; Irinotecan; Levoleucovorin
• Other Study ID Numbers: ITACA-S