First-line FOLFOXIRI In Combination With Bevacizumab For Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a single-arm, open-label, multicentre phase II study evaluating the safety and efficacy of the combination of the G.O.N.O. FOLFOXIRI regimen with bevacizumab as first-line treatment of metastatic colorectal cancer.

Official Title
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Open-label, Multicenter, Phase II Study Of First-line Biweekly Irinotecan, Oxaliplatin And Infusional 5-FU/LV (FOLFOXIRI) In Combination With Bevacizumab In Patients With Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Irinotecan
* Drug: Oxaliplatin
* Drug: 5-fluorouracil/leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed colorectal adenocarcinoma Unresectable and measurable metastatic disease (RECIST criteria) Male or female, aged > 18 years and ≤ 75 years ECOG Performance Status (PS) < 2 if aged < 71 years ECOG PS = 0 if aged 71-75 years Life expectancy of more than 3 months Adequate haematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL INR ≤ 1.5 and aPTT ≤ 1.5 x ULN within 7 days prior to starting study treatment Adequate liver function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN) Serum Creatinine ≤ 1.5 x ULN Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24- hour urine must demonstrate ≤ 1 g of protein in 24 hours Previous adjuvant chemotherapy is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse At least 6 weeks from prior radiotherapy and 4 weeks from surgery Exclusion Criteria: Prior palliative chemotherapy Prior treatment with bevacizumab Bowel obstruction (or subobstruction) History of inflammatory enteropathy or extensive intestinal resection (> hemicolectomy or extensive small intestine resection with chronic diarrhea) Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria Presence or history of CNS metastasis Active uncontrolled infections Active disseminated intravascular coagulation Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, or anticipation of the need for major surgery during the course of the study Central Venous Access Device (CVAD) for chemotherapy administration inserted within 2 days prior to study treatment start Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin cancer or in situ carcinoma of the cervix Clinically significant cardiovascular disease, for example cerebrovascular accidents (CVA) (≤ 6 months before treatment start), myocardial infarction (≤ 6 months before treatment start), unstable angina, NYHA ≥ grade 2 chronic heart failure (CHF), uncontrolled arrhythmia Uncontrolled hypertension 24-hour urine protein > 1 g if dipstick > 2+ History of thromboembolic or hemorrhagic events within 6 months prior to treatment Evidence of bleeding diathesis or coagulopathy Serious, non healing wound/ulcer or serious bone fracture No therapeutic anticoagulation or antiplatelet agents or NSAID with anti-platelet activity (aspirin ≤ 325 mg/day allowed) Pregnancy or lactation Fertile women (< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOXIRI plus bevacizumab<br>BEVACIZUMAB 5 mg/Kg i.v. followed by IRINOTECAN 165 mg/sqm i.v. over 1 hr followed by OXALIPLATIN 85 mg/sqm i.v. over 2 hr concomitantly with l-LV 200 mg/sqm over 2 hrs followed by 5FU 3.200 mg/sqm c.i. over 48 hrs starting on day 1. Cycles repeated every 2 weeks | Drug: Bevacizumab<br> <br> Drug: Irinotecan<br> <br> Drug: Oxaliplatin<br> <br> Drug: 5-fluorouracil/leucovorin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS was calculated from the day of treatment start to the first observation of disease progression or death from any cause. | PFS rate at 10 months from study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (RR) | Response evaluation was performed every 8 weeks from the day of treatment start until disease progression for each enrolled patient for the full lenght of the study. Response evaluation was performed according to RECIST criteria. Responses were subsequently confirmed by a central review. | 2007-2010 | 
| Overall survival (OS) | OS was calculated from the day of treatment start until death from any cause for each enrolled patient for the full lenght of the study, censoring patients who had not died at the last date known to be alive. | 2007-2010 | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | During the full lenght of first-line treatment, number of enrolled patients reporting adverse events was recorded. Adverse events were evaluated according to National Cancer Institute Common Toxicity Criteria (version 3.0). | 2007-2010 | 
| Evaluation of potential surrogate markers predictive of bevacizumab activity | During first-line therapy and at disease progression. | 2007-2010 |