First-line Irinotecan, Lederfolin and 5FU (FOLFIRI) and Bevacizumab in Patients With Advanced Colorectal Cancer (CENTRAL)

First-line FOLFIRI and Bevacizumab in Patients With Advanced Colorectal Cancer Prospectively Stratified According to Serum LDH

Bevacizumab in combination with chemotherapy represents a standard of care for first-line treatment in patients with advanced colorectal cancer. Molecular predictive factors for bevacizumab efficacy have not yet been identified therefore selection of patients more likely to benefit from such a treatment approach is not possible. Retrospective analyses suggested that LDH serum levels may influence the clinical activity of anti-angiogenetic drugs. Primary aim of our clinical trial will be to prospectively ascertain whether bevacizumab in combination with chemotherapy has an improved clinical activity in patients with high LDH serum levels compared to patients with normal LDH serum levels

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer Stage II
• Intervention / Treatment: Drug: Bevacizumab and FOLFIRI

Detailed Description

The VEGF-driven tumour pathway has been demonstrated to represent a novel therapeutic target for an innovative class of antineoplastic agents. Among these antiangiogenetic-targeted treatment modalities the anti-VEGF monoclonal antibody bevacizumab has become a new standard of care for first-line treatment of metastatic colorectal cancer. The biological link between hypoxia, LDH levels and the tumour-driven angiogenesis pathway through the abnormal activation of the hypoxia Inducible factor 1 α (HIF1-α) is well established. HIF1-α is a key transcription factor that up-regulates a series of genes involved in glycolytic metabolism, angiogenesis, cell survival and erythropoiesis Accordingly to this biological assumption Azuma et al (Azuma et al 2007) demonstrated that high LDH serum levels were associated with tumour over-expression of VEGFA and VEGFR-1. As a clinical consequence it has been speculated that LDH levels may represent an indirect indicator of activated tumour angiogenesis and ultimately of worse prognosis We previously analysed the role of LDH pre-treatment serum levels in colorectal cancer patients receiving first-line bevacizumab in metastatic colorectal cancer treated with first-line bevacizumab were eligible. A control group including all consecutive patients treated with chemotherapy alone was also considered. Pre-treatment LDH serum levels were collected for all cases

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy, 60100
    • A.O. Universitaria - Ospedali Riuniti
  • Benevento, Italy, 82100
    • A.O. Ospedale G.Rummo
  • Brescia, Italy, 25124
    • Istituto Ospedaliero Fondazione Poliambulanza
  • Milano, Italy, 20141
    • IRCCS Istituto Europeo di Oncologia
  • Milano, Italy, 20122
    • Ospedale Maggiore Policlinico
  • Roma, Italy, 00186
    • A.O. S.Giovanni Calabita Fatebenefratelli
  • Bergamo
    • Treviglio, Bergamo, Italy, 24047
      • A.O. Treviglio-Caravaggio, P.le Ospedale n1
  • MI
    • Milano, MI, Italy, 20100
      • A.O. Ospedale S.Paolo
  • Massa Carrara
    • Carrara, Massa Carrara, Italy, 54033
      • Ospedale Civile
  • PD
    • Padova, PD, Italy, 35124
      • Istituto Oncologico Veneto
  • PS
    • Fano, PS, Italy, 61032
      • Ospedale Santa Croce
  • PZ
    • Potenza, PZ, Italy, 85100
      • Azienda Ospedaliera San Carlo
  • RM
    • Roma, RM, Italy, 00186
      • Università Policlinico Umberto I

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:

• Written informed consent
• No prior treatment for advanced disease (adjuvant therapy allowed)
• age < 75 years < 18 years
• Histologically/cytologically confirmed advanced, colorectal cancer
• At least one lesion measurable with CT or MRI scan
• Performance Status (ECOG) 0-1 at study entry)
• Life expectancy of at least 6 months
• Neutrophils count =/> 1.5 x 109/L, platelets count =/> 100 x 109/L, HGB =/> 10 g/dL
• total bilirubin < 1.5 x UNL • SGOT and SGPT =/< 2.5 x UNL (=/< 5 x UNL in patients with liver metastases)
• Creatinine < 1.5 x UNL

Exclusion Criteria:

• CNS metastases
• Severe cardiovascular disease
• Uncontrolled infections
• Radiotherapy within 4 weeks of study entry
• Any experimental drug administered within 4 weeks of study entry
• Known hypersensitivity to study drug
• Known drugs or alcohol abuse
• Pregnant or lactating women (serum Betahcg test)
• Other tumours, except in situ melanoma or cervix cancer if radically removed
• Incapability to sign informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Bevacizumab and FOLFIRI; Bevacizumab 5 mg/kg d1 q14 in combination with FOLFIRI (Irinotecan, leucovorin, 5FU I.V.bolus and 5FU I.V. c.i.)

Drug: Bevacizumab and FOLFIRI; The CENTRAL trial is a biologically enriched prospective phase II clinical trial in which patients treated with first-line modified FOLFIRI and bevacizumab will be prospectively stratified according to LDH serum levels. After written informed consent patients will be enrolled. Patients will be considered evaluable for study aim if response rate was radiologically evaluated at least once during treatment course. Treatment will be administered until progression, patients' withdrawal of consent, unacceptable toxicity; Other Names: 5FU; Folinic acid; CPT11

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	Response rate to ascertain whether bevacizumab in combination with chemotherapy could determine an improved response rate in patients with high LDH serum levels compared to patients with normal LDH serum levels	RR will be evaluated every 12 weeks for 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	Progression free survival to ascertain whether bevacizumab in combination with chemotherapy could determine an improved progression survival in patients with high serum LDH levels compared to patients with normal LDH serum levels	18 months: time from the start of the treatment until PD or death
evaluation of serum IL-8, bFGF, HGF, PlGF, SDF-1, MCP-3	Methods described by Kopetz et al (Kopetz, JCO 2010)	every 12 weeks for 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
RECIST criteria and those defined by Chun	Radiological Criteria defined by Chun (Chun et al, JAMA 2009)	every12 weeks for 18 months

Collaborators and Investigators

• Sponsor: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
• Collaborators: Azienda Ospedaliero, Universitaria Ospedali Riuniti
• Investigators: Study Chair: Stefano Cascinu, PhD, GISCAD Foundation

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: March 21, 2013
• First Submitted That Met QC Criteria: May 14, 2013
• First Posted (Estimate): May 15, 2013

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: July 14, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: colorectal cancer; LDH; advanced disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 2012-005048-46