Clinical trial NCT00646607: FOLFOX-4 3months Versus 6 Months and Bevacizumab as Adjuvant Therapy for Patients With Stage II/III Colon Cancer
Official title: A Randomized Trial Investigating the Role of FOLFOX-4 Regimen Duration (3 Versus 6 Months) and Bevacizumab as Adjuvant Therapy for Patients With Stage II/III Colon Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colon Cancer
Keywords: colorectal neoplasm
high risk
stage II/III
Lead sponsor: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
Sponsor class: OTHER
Collaborators: name: Mario Negri Institute for Pharmacological Research
First posted: 2008-03-28
Enrollment: 3756
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This project consists of two independent, following specific eligibility criteria and different randomisation schemes studies, later on called DURATION study and BEV study. Once randomised in the duration study, patients fulfilling eligibility criteria for BEV study may also be randomized to receive BEV or no BEV, in addition to FOLFOX-4 chemotherapy.

As both are open label studies, there will be no blinding of treatment assignment.

Detailed description: At the present time the standard treatment for resected colon cancer with high possibility of relapse ("high risk" stage II and all stage III) is represented by the regimen FOLFOX (leucovorin, bolus and infusional 5fluorouracil and oxaliplatin), which is able to increase significantly the disease-free survival (DFS) at 3 and 4 years, whereas the advantage for 5-year overall survival (OS) (which is predicted by the previous parameter) could be observed only with a further increase of follow-up. The conventional duration of chemotherapy is today of 6 months (12 courses every 2 weeks), but this long drug exposure increases the risk of long-term neurotoxicity. A reduction of adjuvant chemotherapy under 6 months was proven effective in other cancers (breast, testis...) and is better tolerated by patients in clinical practice. On the other hand, bevacizumab significantly increases OS and all other parameters when combined with standard chemotherapy in advanced disease.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed AJCC/UICC high-risk stage II or stage III colon cancer . High-risk stage III patients (T4, N+, M0, or any T, N2, M0) may also be further randomized in the BEV study (plus or minus BEV)
* Stage II patients have to be considered at high-risk if they fulfill \>1 of the following criteria:

  * T4 tumours,
  * grade \>3,
  * clinical presentation with bowel obstruction or perforation,
  * histological signs of vascular or lymphatic or perineural invasion,
  * \<12 nodes examined
* Age 18 to 75 years
* Curative surgery no less than 3 ( 4 in the BEV study) and no more than 8 weeks prior to randomization
* ECOG performance Status (ECOG-PS) \<1
* Signed written informed consent obtained prior to any study specific procedures

Exclusion Criteria:

* Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections).
* Previous anti-angiogenic treatment for any malignancy; cytotoxic chemotherapy, radiotherapy or immunotherapy for colon cancer
* Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix)
* Lactating women
* Fertile women (\<2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception
* History of clinically relevant psychiatric disability , precluding informed consent
* Clinically relevant cardiovascular disease
* History or presence of other diseases
* Evidence of bleeding diathesis or coagulopathy
* Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes
* Chronic, daily treatment with high-dose aspirin (\>325 mg/day) or clopidogrel (\>75 mg/day)
* Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study

Primary outcomes:
measure: disease free survival (DFS)
timeFrame: time from randomization date to date of local or regional relapse
Secondary outcomes:
measure: overall Survival (OS), Toxicity and incidence of adverse events
timeFrame: from the day of randomisation to the date of death from any cause.
Other outcomes:
Locations:
city: Casale Monferrato
country: Italy
facility: Ospedale Santo Spirito
state: AL
city: Ancona
country: Italy
facility: A.O. Umberto I -Università Località Torrette
state: AN
city: Fabriano
country: Italy
facility: Ospedale Profili
state: AN
city: Ascoli Piceno
country: Italy
facility: Ospedale Mazzoni
state: AP
city: Fermo
country: Italy
facility: Usl 11 Ospedale Murri
state: AP
city: L'Aquila
country: Italy
facility: Università di L'Aquila
state: AQ
city: Arezzo
country: Italy
facility: ASL 8 di Arezzo
state: AR
city: Montevarchi
country: Italy
facility: P.O. Ospedale S.M. Della Gruccia
state: AR
city: Asti
country: Italy
facility: Ospedale Civile
state: AT
city: Altamura
country: Italy
facility: Ospedale di Altamura
state: BA
city: Treviglio
country: Italy
facility: A.O. Treviglio-Caravaggio, P.le Ospedale n1
state: Bergamo
city: Biella
country: Italy
facility: Ospedale degli Infermi
state: BI
city: Benevento
country: Italy
facility: A.O. G.Rummo
state: BN
city: Brescia
country: Italy
facility: Fondazione Poliambulanza
state: BS
city: Brescia
country: Italy
facility: Ospedale S.Orsola Fatebenefratelli
state: BS
city: Brescia
country: Italy
facility: Spedali Civili
state: BS
city: Iseo
country: Italy
facility: Azienda M.Mellini-Chiara
state: BS
city: Manerbio
country: Italy
facility: Ospedale di Manerbio
state: Bs
city: Bolzano
country: Italy
facility: Ospedale Regionale
state: BZ
city: Iglesias
country: Italy
facility: Ospedale S.Barbara - Asl 7
state: CA
city: Monserrato
country: Italy
facility: Policlinico Universitario
state: CA
city: Caserta
country: Italy
facility: A.O. S.Sebastiano
state: CE
city: Lanciano
country: Italy
facility: AUSL di Lanciano-Vasto
state: CH
city: Alba
country: Italy
facility: Ospedale S.Lazzaro
state: CN
city: Cuneo
country: Italy
facility: A.O. S.Croce e Carle
state: CN
city: Como
country: Italy
facility: Ospedale S.Anna
state: CO
city: Como
country: Italy
facility: ospedale Valduce
state: CO
city: Erba
country: Italy
facility: Ospedale Fatebenefratelli Sacra Famiglia
state: CO
city: Cremona
country: Italy
facility: Azienda Istituti Ospitalieri
state: CR
city: Catania
country: Italy
facility: Azienda Ospedaliera
state: CT
city: Lamezia Terme
country: Italy
facility: ASL 6 - Ospedale Civile
state: CZ
city: Empoli
country: Italy
facility: ASL 11
state: FI
city: Firenze
country: Italy
facility: Ospedale S.M.Annunziata-ASL FI
state: FI
city: Firenze
country: Italy
facility: A.O. Ospedale Careggi - Università
state: FI
city: Cesena
country: Italy
facility: Ospedale M.Bufalini
state: FO
city: Forlì
country: Italy
facility: A.O. Morgagni-Pierantoni
state: FO
city: Genova
country: Italy
facility: A.O. Ospedale S.Martino
state: GE
city: Genova
country: Italy
facility: Istituto Nazionale ricerca Cancro
state: GE
city: Genova
country: Italy
facility: Università-Ospedale san Martino
state: GE
city: Lecco
country: Italy
facility: Azienda Ospedaliera di Lecco
state: LC
city: Livorno
country: Italy
facility: Azienda Usl-6 Università
state: LI
city: Casalpusterlengo
country: Italy
facility: Ospedale di Casalpusterlengo
state: LO
city: Gaeta
country: Italy
facility: Centro Oncologico Conti
state: Lt
city: Latina
country: Italy
facility: Azienda USL LT3
state: LT
city: Lido di Camaiore
country: Italy
facility: Ospedale Unico Versilia
state: LU
city: Messina
country: Italy
facility: A.O. Università-Policlinico
state: ME
city: Gorgonzola
country: Italy
facility: Ospedale Serbelloni
state: MI
city: Legnano
country: Italy
facility: Azienda Ospedaliera
state: MI
city: Magenta
country: Italy
facility: Azienda Ospedale Civile
state: MI
city: Milano
country: Italy
facility: A.O. Ospedale Fatebenefratelli
state: MI
city: Milano
country: Italy
facility: A.O. san Paolo
state: MI
city: Milano
country: Italy
facility: Casa di Cura Igea
state: MI
city: Milano
country: Italy
facility: Istituto dei Tumori
state: MI
city: Milano
country: Italy
facility: Istituto di Ricerca S.Raffaele
state: MI
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
state: MI
city: Milano
country: Italy
facility: Ospedale Luigi Sacco
state: MI
city: Milano
country: Italy
facility: Ospedale S.Carlo Borromeo
state: MI
city: Monza
country: Italy
facility: A.O. s.Gerardo
state: MI
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: MI
city: Sesto San Giovanni
country: Italy
facility: Multimedica
state: MI
city: Mantova
country: Italy
facility: A.O. Ospedale carlo Poma
state: MN
city: Carpi
country: Italy
facility: Ospedale ramazzini
state: MO
city: Carrara
country: Italy
facility: USL 1 di Massa e Carrara
state: MS
city: Palermo
country: Italy
facility: Ospedale Oncologico M.Ascoli
state: PA
city: Palermo
country: Italy
facility: Policlinico Giaccone
state: PA
city: Piacenza
country: Italy
facility: Azienda Ospedale Civile
state: PC
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
state: PD
city: Penne
country: Italy
facility: Ospedale Santo Spirito
state: PE
city: Pescara
country: Italy
facility: Ospedale Santo Spirito
state: PE
city: Città di Castello
country: Italy
facility: ASL 1
state: PG
city: Aviano
country: Italy
facility: Centro Riferimento
state: PN
city: Pordenone
country: Italy
facility: A.O. S.Maria degli Angeli
state: PN
city: Prato
country: Italy
facility: Ospedale ASL 4
state: PO
city: Parma
country: Italy
facility: Azienda Ospedaliera
state: PR
city: Fano
country: Italy
facility: Ospedale Santa Croce
state: PS
city: Pesaro
country: Italy
facility: A.O. S.Salvatore
state: PS
city: Potenza
country: Italy
facility: Azienda Ospedaliera San Carlo
state: PZ
city: Rionero in Volture
country: Italy
facility: Centro Riferimento Oncologico Basilicata
state: PZ
city: Faenza
country: Italy
facility: Ospedale per gli Infermi
state: RA
city: Lugo
country: Italy
facility: Ospedale Umberto I
state: RA
city: Ravenna
country: Italy
facility: A.O. Santa Maria delle Croci
state: RA
city: Reggio calabria
country: Italy
facility: Azienda Ospedali Riuniti
state: RC
city: Reggio Emilia
country: Italy
facility: A.O. Santa maria Nuova-Spallanzani
state: RE
city: Roma
country: Italy
facility: Ospedale S.Camillo
state: RM
city: Roma
country: Italy
facility: Policlinico Militare Celio
state: RM
city: Roma
country: Italy
facility: Università Policlinico Umberto I
state: RM
city: Roma
country: Italy
facility: Ospedale Sant'Andrea
state: RM
city: Cattolica
country: Italy
facility: Azienda ospedaliera
state: RN
city: Rimini
country: Italy
facility: Ospedale degli Infermi
state: RN
city: Rovigo
country: Italy
facility: AULSS 18 di Rovigo
state: RO
city: Sondalo
country: Italy
facility: Ospedale Morelli
state: SO
city: Sondrio
country: Italy
facility: A.O. Valtellina e Chiavenna
state: SO
city: Pietra Ligure
country: Italy
facility: A.O. Santa Corona
state: SV
city: Candiolo
country: Italy
facility: Università degli Studi
state: TO
city: Torino
country: Italy
facility: Ospedale S.Giovanni Bosco
state: TO
city: Latisana
country: Italy
facility: Ospedale Civile
state: UD
city: Castellanza
country: Italy
facility: Casa di Cura Santa Maria
state: VA
city: Montecchio Maggiore
country: Italy
facility: Ulss 5 Ovest Vicentino
state: VI
city: Negrar
country: Italy
facility: Ospedale Negrar
state: VR
city: Bergamo
country: Italy
facility: Ospedali Riuniti, Largo Barozzi, 1
city: Castellamare di Stabbia
country: Italy
facility: Ospedale S.Leonardo
city: Firenze
country: Italy
facility: A.O. Careggi-Università, Viale Pieraccini, 17
city: Napoli
country: Italy
facility: Fondazione Pascale - Istituto Tumori
city: Napoli
country: Italy
facility: Istituto Tumori- Pascale
city: Napoli
country: Italy
facility: Università federico II
city: Napoli
country: Italy
facility: A.O. Cardarelli
city: Napoli
country: Italy
facility: Azienda Ospedaliera
city: Napoli
country: Italy
facility: Ospedale S.Gennaro
city: Novara
country: Italy
facility: A.O. Ospedale Maggiore della carità
city: Roma
country: Italy
facility: Università Campus Biomedico, Via Emilio Longoni, 83
city: Roma
country: Italy
facility: A.O. S.Giovanni Calabita Fatebenefratelli
Study officials:
affiliation: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
name: Roberto Labianca, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
name: Alberto Sobrero, MD
role: STUDY_CHAIR
References:
citation: Gallois C, Shi Q, Meyers JP, Iveson T, Alberts SR, de Gramont A, Sobrero AF, Haller DG, Oki E, Shields AF, Goldberg RM, Kerr R, Lonardi S, Yothers G, Kelly C, Boukovinas I, Labianca R, Sinicrope FA, Souglakos I, Yoshino T, Meyerhardt JA, Andre T, Papamichael D, Taieb J. Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials. J Clin Oncol. 2023 Feb 1;41(4):803-815. doi: 10.1200/JCO.21.02726. Epub 2022 Oct 28.
citation: Iveson TJ, Sobrero AF, Yoshino T, Souglakos I, Ou FS, Meyers JP, Shi Q, Grothey A, Saunders MP, Labianca R, Yamanaka T, Boukovinas I, Hollander NH, Galli F, Yamazaki K, Georgoulias V, Kerr R, Oki E, Lonardi S, Harkin A, Rosati G, Paul J. Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer. J Clin Oncol. 2021 Feb 20;39(6):631-641. doi: 10.1200/JCO.20.01330. Epub 2021 Jan 13.
citation: Sobrero A, Lonardi S, Rosati G, Di Bartolomeo M, Ronzoni M, Pella N, Scartozzi M, Banzi M, Zampino MG, Pasini F, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Zagonel V, Maiello E, Barni S, Rulli E, Labianca R; TOSCA Investigators. FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial. J Clin Oncol. 2018 May 20;36(15):1478-1485. doi: 10.1200/JCO.2017.76.2187. Epub 2018 Apr 5.
citation: Lonardi S, Sobrero A, Rosati G, Di Bartolomeo M, Ronzoni M, Aprile G, Massida B, Scartozzi M, Banzi M, Zampino MG, Pasini F, Marchetti P, Cantore M, Zaniboni A, Rimassa L, Ciuffreda L, Ferrari D, Barni S, Zagonel V, Maiello E, Rulli E, Labianca R; TOSCA (Three or Six Colon Adjuvant) Investigators. Phase III trial comparing 3-6 months of adjuvant FOLFOX4/XELOX in stage II-III colon cancer: safety and compliance in the TOSCA trial. Ann Oncol. 2016 Nov;27(11):2074-2081. doi: 10.1093/annonc/mdw404. Epub 2016 Aug 29.