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

Colorectal Cancer Stage II Clinical Trial

— CENTRAL  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01853813
• Other study ID #: 2012-005048-46
• Status: Completed
• Phase: Phase 2
• First received: March 21, 2013
• Last updated: July 14, 2015
• Start date: May 2013
• Est. completion date: July 2015

Study information

• Verified date: July 2015
• Source: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: July 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer Stage II
• Colorectal Neoplasms

Intervention

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

Locations

Country	Name	City	State
Italy	A.O. Universitaria - Ospedali Riuniti	Ancona
Italy	A.O. Ospedale G.Rummo	Benevento
Italy	Istituto Ospedaliero Fondazione Poliambulanza	Brescia
Italy	Ospedale Civile	Carrara	Massa Carrara
Italy	Ospedale Santa Croce	Fano	PS
Italy	A.O. Ospedale S.Paolo	Milano	MI
Italy	IRCCS Istituto Europeo di Oncologia	Milano
Italy	Ospedale Maggiore Policlinico	Milano
Italy	Istituto Oncologico Veneto	Padova	PD
Italy	Azienda Ospedaliera San Carlo	Potenza	PZ
Italy	A.O. S.Giovanni Calabita Fatebenefratelli	Roma
Italy	Università Policlinico Umberto I	Roma	RM
Italy	A.O. Treviglio-Caravaggio, P.le Ospedale n1	Treviglio	Bergamo

Sponsors (2)

Lead Sponsor	Collaborator
Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente	Azienda Ospedaliero, Universitaria Ospedali Riuniti

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	RECIST criteria and those defined by Chun	Radiological Criteria defined by Chun (Chun et al, JAMA 2009)	every12 weeks for 18 months	No
Primary	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	Yes
Secondary	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	Yes
Secondary	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	No