Clinical trial NCT01853813: First-line Irinotecan, Lederfolin and 5FU (FOLFIRI) and Bevacizumab in Patients With Advanced Colorectal Cancer
Official title: First-line FOLFIRI and Bevacizumab in Patients With Advanced Colorectal Cancer Prospectively Stratified According to Serum LDH
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer Stage II
Keywords: colorectal cancer
advanced disease
LDH
Lead sponsor: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
Sponsor class: OTHER
Collaborators: name: Azienda Ospedaliero, Universitaria Ospedali Riuniti
First posted: 2013-05-15
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Response Rate
timeFrame: RR will be evaluated every 12 weeks for 24 months
Secondary outcomes:
measure: Progression free survival
timeFrame: 18 months: time from the start of the treatment until PD or death
measure: evaluation of serum IL-8, bFGF, HGF, PlGF, SDF-1, MCP-3
timeFrame: every 12 weeks for 18 months
Other outcomes:
measure: RECIST criteria and those defined by Chun
timeFrame: every12 weeks for 18 months
Locations:
city: Treviglio
country: Italy
facility: A.O. Treviglio-Caravaggio, P.le Ospedale n1
state: Bergamo
city: Carrara
country: Italy
facility: Ospedale Civile
state: Massa Carrara
city: Milano
country: Italy
facility: A.O. Ospedale S.Paolo
state: MI
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
state: PD
city: Fano
country: Italy
facility: Ospedale Santa Croce
state: PS
city: Potenza
country: Italy
facility: Azienda Ospedaliera San Carlo
state: PZ
city: Roma
country: Italy
facility: Università Policlinico Umberto I
state: RM
city: Ancona
country: Italy
facility: A.O. Universitaria - Ospedali Riuniti
city: Benevento
country: Italy
facility: A.O. Ospedale G.Rummo
city: Brescia
country: Italy
facility: Istituto Ospedaliero Fondazione Poliambulanza
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: IRCCS Istituto Europeo di Oncologia
city: Roma
country: Italy
facility: A.O. S.Giovanni Calabita Fatebenefratelli
Study officials:
affiliation: GISCAD Foundation
name: Stefano Cascinu, PhD
role: STUDY_CHAIR
References: