Sequential Treatment Strategy for Metastatic Colorectal Cancer

NCT01878422 | Completed Phase 3

• 2 other identifiers: IRST153.012007-004539-44
• Study Type: interventional
• Target: 376
• Locations: 1 country
• Sites: 23

Brief Summary

Study Design: This is a pragmatic study on the management strategy for patients with metastatic colorectal cancer (CRC) who are candidates for CT, independently of any previous adjuvant therapy received. The aim of this study is to define the role of new target molecules in combination with CT in first- and second line treatment. First line study: Eligible patients were randomized to either treatment: Arm A: FOLFIRI or FOLFOX + Bevacizumab, cycle to be repeated every 2 weeks

• BEVACIZUMAB: Day 1,1st cycle 5 mg/kg IV infusion of 90 min Day 1, 2nd cycle if well tolerated, 5 mg/kg IV infusion of 60 min Day 1, 3rd cycle and subsequent cycles if well tolerated, 5 mg/kg IV infusion of 30 min after 5-Fluorouracile (FU) bolus
• FOLFIRI Day 1: Irinotecan 180 mg/m2 IV infusion 30-90 min Day 1,2: L-Folinic acid 100 mg/m2 IV infusion of 2 hours 5-Fluorouracil 400 mg/m2 as a bolus 5-Fluorouracil 600 mg/m2 continuous IV infusion of 22 hours - FOLFOX Day 1: Oxaliplatin 85 mg/m2 IV infusion of 2hours Day 1,2: L-Folinic acid 100 mg/m2 IV infusion of 2 hours 5-Fluorouracil 400 mg/m2 as a bolus 5-Fluorouracil 600 mg/m2 continuous IV infusion of 22 hours Arm B: FOLFIRI or FOLFOX, cycle to be repeated every 2 weeks If FOLFIRI: FOLFIRI as specified in arm A without Bevacizumab If FOLFOX: FOLFOX as specified in arm A without Bevacizumab Duration of Therapy For both arms, CT was repeated until progressive disease (PD) or unacceptable toxicity occurs. If unacceptable CT-related toxicity occurs in ARM A, in the absence of PD patients stopped CT and continued with only bevacizumab 5 mg/kg as a 30-min infusion every 2 weeks until progression or intolerable toxicity occurred. Second line - it is divided in two different studies (2A and 2B): Study 2A: Patients from arm A and Kras Wild Type were randomized to:
• Arm C: FOLFIRI or FOLFOX (the CT schedule not received in 1st line trial, as defined in arm B)
• Arm D: FOLFIRI or FOLFOX (the CT schedule not received in 1st line trial, as described in arm B) plus CETUXIMAB CETUXIMAB 1st cycle Day 1 400 mg/m2 infusion of 120 min 2 hrs before CT infusion 1st cycle Day 8 and subsequent cycles 250 mg/m2 infusion of 60 min 1 hr before CT infusion Patients from arm A and Kras Mutant were treated according to arm C. Study 2B: Patients from arm B and Kras Wild Type were randomized to:
• Arm E: FOLFIRI or FOLFOX (the CT schedule not received in the 1st line trial, as defined in arm B) plus BEVACIZUMAB
• Arm F: FOLFIRI or FOLFOX (the CT schedule not received in the first-line trial, as defined in arm B) plus BEVACIZUMAB and CETUXIMAB; cycle to be repeated every 2 weeks, whilst cetuximab will be administered weekly.
• BEVACIZUMAB 2nd day of 1st cycle 5 mg/kg IV infusion of 90 min 2nd day of 2 nd cycle if well tolerated, 5 mg/kg IV infusion of 60 min 2nd day of 3 rd cycle and subsequent cycles if well tolerated, 5 mg/kg IV infusion of 30 min after the end of 5-FU bolus on the 2nd day
• CETUXIMAB 1st cycle Day 1 400 mg/m2 infusion of 120 min 2 hr before CT infusion 1st cycle Day 8 and subsequent cycles 250 mg/m2 infusion of 60 min 1 hr before CT infusion If cetuximab will be stopped for any of the reasons specified in this protocol, bevacizumab will be administered as defined in arm A of the 1st line study Patients from arm B and Kras Mutant were treated according to arm E. Objectives of study The primary objective of the 1st line study is to determine whether the addition of bevacizumab to a poly-chemotherapy (polyCT) regimen (FOLFIRI or FOLFOX) improves efficacy in terms of progression-free survival (PFS). The secondary objectives of the 1st line study are to determine the Overall Response Rate (ORR) and the safety profile of the treatments administered. The primary objective of the 2nd line studies is to determine, separately for each study, whether the addition of cetuximab to a polyCT schemes (FOLFOX or FOLFIRI), or to polyCT schemes plus bevacizumab, improves efficacy in terms of PFS.The secondary objectives of the 2nd line studies are to determine the ORR, the overall survival (OS) and the safety profile of the treatments administered.

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS) of first and second line treatment strategy

  To compare the Progression Free Survival (PFS) between different treatment arms in patients of first line treatment and, subsequently, the same analisys will be performed in patients treated in second line therapy.

  6 years

Secondary Outcomes (3)

• Overal Response Rate (ORR) of first and second line treatment strategy

  6 years

• Overal Survival (OS) of second line treatment

  6 years

• Number of partecipants with adverse events as a measure of safety and tolerability

  6 years

Study Arms (6)

Arm A: FOLFIRI or FOLFOX + Bevacizumab

EXPERIMENTAL

* BEVACIZUMAB: Day 1,1st cycle 5 mg/kg IV infusion of 90 min Day 1, 2nd cycle if well tolerated, 5 mg/kg IV infusion of 60 min Day 1, 3rd cycle and subsequent cycles if well tolerated, 5 mg/kg IV infusion of 30 min after 5-FU bolus * FOLFIRI Day 1: Irinotecan 180 mg/m2 IV infusion 30-90 min Day 1,2: L-Folinic acid 100 mg/m2 IV infusion of 2 hours 5-Fluorouracil 400 mg/m2 as a bolus 5-Fluorouracil 600 mg/m2 continuous IV infusion of 22 hours \- FOLFOX Day 1: Oxaliplatin 85 mg/m2 IV infusion of 2hours Day 1,2: L-Folinic acid 100 mg/m2 IV infusion of 2 hours 5-Fluorouracil 400 mg/m2 as a bolus 5-Fluorouracil 600 mg/m2 continuous IV infusion of 22 hours

Drug: Arm A: FOLFIRI or FOLFOX + Bevacizumab

Arm B: FOLFIRI or FOLFOX

EXPERIMENTAL

If FOLFIRI: FOLFIRI as specified in arm A without Bevacizumab If FOLFOX: FOLFOX as specified in arm A without Bevacizumab

Drug: Arm B: FOLFIRI or FOLFOX

Arm C: FOLFIRI or FOLFOX

EXPERIMENTAL

Arm C: FOLFIRI or FOLFOX: for patients from arm A: FOLFIRI or FOLFOX (the CT schedule not received in 1st line trial, as defined in arm B)

Drug: Arm B: FOLFIRI or FOLFOX

Arm D: FOLFIRI or FOLFOX plus CETUXIMAB

EXPERIMENTAL

Arm D: FOLFIRI or FOLFOX plus CETUXIMAB: for patients from arm B: FOLFIRI or FOLFOX (the CT schedule not received in 1st line trial, as described in arm B) plus CETUXIMAB

Drug: Arm D: FOLFIRI or FOLFOX plus CETUXIMAB

Arm E: FOLFIRI or FOLFOX plus BEVACIZUMAB

EXPERIMENTAL

for patients from arm B: FOLFIRI or FOLFOX (the CT schedule not received in the 1st line trial, as defined in arm B) plus BEVACIZUMAB

Drug: Arm A: FOLFIRI or FOLFOX + Bevacizumab

Arm F: FOLFIRI or FOLFOX plus BEVACIZUMAB and CETUXIMAB;

EXPERIMENTAL

for patients from arm B: FOLFIRI or FOLFOX (the CT schedule not received in the first-line trial, as defined in arm B) plus BEVACIZUMAB and CETUXIMAB; cycle to be repeated every 2 weeks, whilst cetuximab will be administered weekly.

Drug: Arm F: FOLFIRI or FOLFOX plus BEVACIZUMAB and CETUXIMAB

Interventions

Arm A: FOLFIRI or FOLFOX + Bevacizumab DRUG

Arm A: FOLFIRI or FOLFOX + Bevacizumab or Arm E: FOLFIRI or FOLFOX plus BEVACIZUMAB

Also known as: Arm E: FOLFIRI or FOLFOX plus BEVACIZUMAB

Arm A: FOLFIRI or FOLFOX + Bevacizumab; Arm E: FOLFIRI or FOLFOX plus BEVACIZUMAB

Arm B: FOLFIRI or FOLFOX DRUG

Arm B: FOLFIRI or FOLFOX or Arm C: FOLFIRI or FOLFOX

Also known as: Arm C: FOLFIRI or FOLFOX

Arm B: FOLFIRI or FOLFOX; Arm C: FOLFIRI or FOLFOX

Arm D: FOLFIRI or FOLFOX plus CETUXIMAB DRUG

Arm D: FOLFIRI or FOLFOX plus CETUXIMAB

Also known as: FOLFIRI or FOLFOX plus CETUXIMAB

Arm D: FOLFIRI or FOLFOX plus CETUXIMAB

Arm F: FOLFIRI or FOLFOX plus BEVACIZUMAB and CETUXIMAB DRUG

Arm F: FOLFIRI or FOLFOX plus BEVACIZUMAB and CETUXIMAB

Also known as: FOLFIRI or FOLFOX plus BEVACIZUMAB and CETUXIMAB

Arm F: FOLFIRI or FOLFOX plus BEVACIZUMAB and CETUXIMAB;

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed untreated metastatic or locally advanced, non resectable CRC; previous adjuvant chemotherapy for CRC or neoadjuvant/adjuvant chemoradiotherapy for rectal cancer is permitted but must have been completed at least 6 months prior to enrolment;
• Resected CRC patients who have developed metastases do not require separate histological or cytological confirmation unless \> 5 yrs have elapsed between primary surgery or primary tumor stage I;
• Evaluation of Kras status from the primary tumor or metastases
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST criteria)
• Age ≥ 18 years and \< 70 years with Performance Status (ECOG) ≤ 2 or age \> 70 years with ECOG ≤ 1;
• Estimated life expectancy of at least 12 weeks;
• Adequate hematological, hepatic and renal function, as follows: hemoglobin ≥ 9 g/dl,absolute neutrophil count ≥1,500/μL, platelets ≥100,000/μL, total bilirubin ≤1.5 x upper limit of normal (ULN),alkaline phosphatase, aspartate aminotransferase (AST(SGOT)) and alanine aminotransferase (ALT(SGPT)) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases present), serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance \>50 mL/min (calculated on the basis of Standard Cockcroft and Gault Formula, urinary excretion (if protein \> 30 mg/dL or +1, patients must have ≤ 1 g of protein/24 hours)
• Either international normalized ratio (INR) or activated partial thromboplastin time (APTT) \< 1.5 x ULN and D-dimer within normal range (if abnormal, thromboembolic events must be excluded);
• Negative pregnancy test no more than 7 days before randomization; test pregnancy can be omitted only in women without any reproductive potential (e.g.: postmenopausal women, i.e. amenorrhoea ≥2 years or with previous hysterectomy or bilateral ovariectomy). Women of child-bearing potential and men must agree to use adequate contraception at the time of randomization and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician and coordinating centre (CC) immediately; women in lactation period must be excluded;
• Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Prior treatment with cetuximab, bevacizumab or other anti Epidermal Growth Factor Receptor (antiEGFR) or anti-angiogenesis agents;
• Prior chemotherapy or immunotherapy for metastatic or advanced disease;
• Participation in another clinical trial with any investigational agents ≤ 30 days prior to study randomization;
• Contraindications or hypersensitivity to study drugs;
• Treatment with other concomitant antineoplastic drugs;
• Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix);
• Symptomatic brain or central nervous system metastases or clinically relevant central nervous diseases (for example: primary brain tumor, uncontrolled convulsions with medical therapy, carcinomatous meningitis);
• Grade \> 1 peripheral neuropathy (as defined by the National Cancer Institute - Common Toxicity Criteria for Adverse Effects (NCI CTCAE) v3.0);
• Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular accidents ≤ 6 months prior to randomization), myocardial infarction (≤ 1 year prior to randomization), uncontrolled hypertension whilst receiving chronic medication, unstable angina, New York Heart Association (NYHA) grade II or more congestive heart failure,or serious cardiac arrhythmia requiring medication;
• Malabsorption syndrome or lack of physical integrity of the gastrointestinal tract. Diverticulitis. Patients with colostomy or ileostomy may enter at the investigator's discretion. History of trachea-oesophageal fistula or any other type of fistula (e.g. abdominal), gastrointestinal perforation, intra-abdominal abscess;
• Interstitial pneumonia or extensive symptomatic fibrosis of the lungs;
• Serious, non-healing wound, ulcer, or bone fracture; significant traumatic injury in the 4 weeks prior to enrolment (complete recover must have occurred);
• Major surgery (e.g. laparotomy) in the 4 weeks prior to study randomization;
• Minor surgery in the 2 weeks prior to study randomization. Insertion of a central vascular access device for chemotherapy infusion must be done at least 2 days prior to the start of treatment. Patients will be randomized only if they have recovered from all surgery related toxicities;
• Bleeding diathesis or coagulopathy;

Sponsors & Collaborators

• Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS: lead

Study Sites (23)

Dipartimento Oncologia Ematologia - Policlinico S.Orsola-Malpighi - Università di Bologna

Bologna, BO, Italy

Location

Ist. di Ematologia e Oncologia Medica "L. e A. Seragnoli" - Università di Bologna

Bologna, BO, Italy

Location

Ospedale Bellaria-Maggiore, AUSL Città di Bologna

Bologna, BO, Italy

Location

P.O. San lazzaro

Alba, CN, Italy

Location

Ospedale Buffalini - ASL Cesena

Cesena, FC, Italy

Location

Irccs Irst

Meldola (FC), FC, 47014, Italy

Location

Azienda Ospedaliero - Università di Ferrara

Ferrara, FE, Italy

Location

Ospedale Vito Fazzi

Lecce, LE, Italy

Location

Ospedale Ramazzini - ASL Modena

Carpi, MO, Italy

Location

Centro Oncologico Modenese - Policlinico di Modena

Modena, MO, Italy

Location

Ospedale degli Infermi - AUSL di Ravenna

Faenza, RA, Italy

Location

Ospedale Civile di Lugo -AUSL di Ravenna

Lugo, RA, Italy

Location

Ospedale S.Maria delle Croci

Ravenna, RA, Italy

Location

ospedale Civile Cattolica

Cattolica, RN, Italy

Location

Ospedale Infermi - Azienda USL di Rimini

Rimini, RN, Italy

Location

AOU S.Giovanni Battista di Torino (Molinette) Presidio San Lazzaro

Torino, TO, Italy

Location

Azienda Sanitaria Ospedaliera S. Giovanni Battista - Molinette

Torino, TO, Italy

Location

Ospedale Cardinal Massaia

Asti, Italy

Location

Azienda ULSS 1 di Belluno

Belluno, Italy

Location

Ospedale A.Perrino

Brindisi, Italy

Location

Azienda Osp. Maggiore della Carità

Novara, Italy

Location

Azienda Ospedaliero Universitaria di Parma

Parma, Italy

Location

Ospedale di Piacenza, ASL Piacenza

Piacenza, Italy

Location

Related Publications (5)

• Petracci E, Passardi A, Biggeri A, Valgiusti M, Monti M, Frassineti GL, Nanni O, Scarpi E. Baseline and Longitudinal Neutrophil-to-Lymphocyte Ratio as Prognostic Factor for Metastatic Colorectal Cancer: A Secondary Analysis of the ITACa Randomized Trial. JCO Precis Oncol. 2024 Jan;8:e2300256. doi: 10.1200/PO.23.00256.

  PMID: 38295317 DERIVED

• Casadei Gardini A, Scarpi E, Valgiusti M, Monti M, Ruscelli S, Matteucci L, Bartolini G, Vertogen B, Pagan F, Rovesti G, Frassineti GL, Passardi A. Prognostic role of a new index (multi inflammatory index) in patients with metastatic colorectal cancer: results from the randomized ITACa trial. Ther Adv Med Oncol. 2020 Sep 28;12:1758835920958363. doi: 10.1177/1758835920958363. eCollection 2020.

  PMID: 33062063 DERIVED

• Casadei-Gardini A, Scarpi E, Ulivi P, Palladino MA, Accettura C, Bernardini I, Spallanzani A, Gelsomino F, Corbelli J, Marisi G, Ruscelli S, Valgiusti M, Frassineti GL, Passardi A. Prognostic role of a new inflammatory index with neutrophil-to-lymphocyte ratio and lactate dehydrogenase (CII: Colon Inflammatory Index) in patients with metastatic colorectal cancer: results from the randomized Italian Trial in Advanced Colorectal Cancer (ITACa) study. Cancer Manag Res. 2019 May 10;11:4357-4369. doi: 10.2147/CMAR.S198651. eCollection 2019.

  PMID: 31191000 DERIVED

• Passardi A, Scarpi E, Tamberi S, Cavanna L, Tassinari D, Fontana A, Pini S, Bernardini I, Accettura C, Ulivi P, Frassineti GL, Amadori D. Impact of Pre-Treatment Lactate Dehydrogenase Levels on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer. PLoS One. 2015 Aug 5;10(8):e0134732. doi: 10.1371/journal.pone.0134732. eCollection 2015.

  PMID: 26244985 DERIVED

• Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, Ruscelli S, Mucciarini C, Lorusso V, Ragazzini A, Frassineti GL, Amadori D. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015 Jun;26(6):1201-1207. doi: 10.1093/annonc/mdv130. Epub 2015 Mar 3.

  PMID: 25735317 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Folfox protocol; Bevacizumab; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Dino Amadori

  IRST IRCCS, Meldola

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2013
• First Posted: June 17, 2013
• Study Start: November 1, 2007
• Primary Completion: March 1, 2014
• Study Completion: June 11, 2016
• Last Updated: January 31, 2025

Record last verified: 2025-01

Locations

IT (23)