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

Phase 2

Completed

• Conditions: Colorectal Cancer Stage II
• Interventions: Drug: Bevacizumab and FOLFIRI

• Registration Number: NCT01853813
• Lead Sponsor: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente

Brief Summary

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

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 Timeline

• Study First Submitted: 2013-03-21
• Study Start: 2013-05
• Study First Submitted QC: 2013-05-14
• Study First Posted: 2013-05-15
• Primary Completion: 2015-05
• Status Verified: 2015-07
• Study Completion: 2015-07
• Last Update Submitted: 2015-07-14
• Last Update Posted: 2015-07-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 85

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Bevacizumab and FOLFIRI	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.)

Primary Outcome Measures

Name	Time	Method
Response Rate	RR will be evaluated every 12 weeks for 24 months	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

Secondary Outcome Measures

Name	Time	Method
Progression free survival	18 months: time from the start of the treatment until PD or death	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
evaluation of serum IL-8, bFGF, HGF, PlGF, SDF-1, MCP-3	every 12 weeks for 18 months	Methods described by Kopetz et al (Kopetz, JCO 2010)

Trial Locations

Locations (13)

A.O. Treviglio-Caravaggio, P.le Ospedale n1; 🇮🇹 Treviglio, Bergamo, Italy

Ospedale Civile; 🇮🇹 Carrara, Massa Carrara, Italy

Istituto Oncologico Veneto; 🇮🇹 Padova, PD, Italy

A.O. Ospedale S.Paolo; 🇮🇹 Milano, MI, Italy

Ospedale Santa Croce; 🇮🇹 Fano, PS, Italy

Azienda Ospedaliera San Carlo; 🇮🇹 Potenza, PZ, Italy

Università Policlinico Umberto I; 🇮🇹 Roma, RM, Italy

A.O. Universitaria - Ospedali Riuniti; 🇮🇹 Ancona, Italy

Istituto Ospedaliero Fondazione Poliambulanza; 🇮🇹 Brescia, Italy

Ospedale Maggiore Policlinico; 🇮🇹 Milano, Italy

A.O. Ospedale G.Rummo; 🇮🇹 Benevento, Italy

IRCCS Istituto Europeo di Oncologia; 🇮🇹 Milano, Italy

A.O. S.Giovanni Calabita Fatebenefratelli; 🇮🇹 Roma, Italy