Efficacy of FOLFOX+Bevacizumab in Combination With Irinotecan in the Treatment of Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the efficacy of Irinotecan in combination with FOLFOX+Bevacizumab versus FOLFOX+Bevacizumab alone in the first-line treatment of patients with metastatic colorectal cancer.

Detailed Description
-----------------
5-Fluorouracil and oxaliplatin (FOLFOX-Regimen) in combination with bevacizumab is regarded as standard first-line treatment in metastatic colorectal cancer [Saltz et al., 2008]. Current studies established the role of the FOLFOXIRI regimen [Souglakos et al., 2006, Falcone et al., 2007]. A further intensification of the therapy seems feasible yielding response rates up to 84% and a disease control rate up to 100% [Falcone, 2008, Santomaggio, 2009, Masi, 2010]. This trial evaluates the activity of an intensified first-line therapy for metastatic colorectal cancer compared to standard treatment.

Official Title
-----------------
FOLFOX and Bevacizumab With or Without Irinotecan in First-line Treatment for Metastatic Colorectal Cancer. A Randomized Phase II Study

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: Oxaliplatin, 5FU/LV, Bevacizumab
* Drug: 5FU/LV, Oxaliplatin, Bevacizumab, Irinotecan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with histologically confirmed diagnosis of stage IV (UICC) colorectal cancer (primary tumor may be present) Patients with at least one measurable lesion, with size > 1 cm (RECIST v1.1) ECOG Performance status ≤ 2 (ECOG 2, only if tumor related) Patients, who are able to tolerate intensive first lien treatment as judged by the investigator Life expectancy > 3 months Age ≥ 18 years Haematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin 9 g/dl or 5.59 mmol/l Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and aPTT < 1.5 ULN within 7 days prior to registration. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of registration. Adequate liver function as measured by serum transaminases (AST & ALT) ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN) and total bilirubin ≤ 1.5 x ULN Adequate renal function: Serum creatinine ≤ 1.5 x ULN Signed, written informed consent Exclusion Criteria: Patients with histologically confirmed diagnosis of stage IV (UICC) colorectal cancer (primary tumor may be present) Patients with at least one measurable lesion, with size > 1 cm (RECIST v1.1) ECOG Performance status ≤ 2 (ECOG 2, only if tumor related) Patients, who are able to tolerate intensive first lien treatment as judged by the investigator Life expectancy > 3 months Age ≥ 18 years Haematologic function: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin 9 g/dl or 5.59 mmol/l Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and aPTT < 1.5 ULN within 7 days prior to registration. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of registration. Adequate liver function as measured by serum transaminases (AST & ALT) ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN) and total bilirubin ≤ 1.5 x ULN Adequate renal function: Serum creatinine ≤ 1.5 x ULN Signed, written informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FOLFOX+Bevacizumab<br>bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1) I-LV at a dose of 200 mg/m2 iv over two hours (day 1) 5-FU at a dose of 3200 mg/ m2 iv over 48 hours (day 1-3) | Drug: Oxaliplatin, 5FU/LV, Bevacizumab<br>* bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1) I-LV at a dose of 200 mg/m2 iv over two hours (day 1) 5-FU at a dose of 3200 mg/ m2 iv over 48 hours (day 1-3)<br>* Other names: 5-FU;|
| Experimental: FOLFOX+Bevacizumab+Irinotecan<br>bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) irinotecan at a dose of 165 mg/m2 iv over two hours (day 1) oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1) I-LV at a dose of 200 mg/m2 iv over two hours (day 1) 5-FU at a dose of 3200 mg/ m2 iv over 48 hours (day 1-3) | Drug: 5FU/LV, Oxaliplatin, Bevacizumab, Irinotecan<br>* bevacizumab at a dose of 5 mg/kg iv over 30 to 90 min (day 1) irinotecan at a dose of 165 mg/m2 iv over two hours (day 1) oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1) I-LV at a dose of 200 mg/m2 iv over two hours (day 1) 5-FU at a dose of 3200 mg/ m2 iv over 48 hours (day 1-3)<br>* Other names: Irinotecan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival rate |  | 9 months after first study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tumour response according to RECIST v 1.1 |  | until progression of disease for a maximum of two years after end of treatment | 
| Secondary resection rate |  | for a maximum of two years after end of treatment | 
| Progression free survival rate |  | until progression of disease for a maximum of two years after end of treatment | 
| Overall survival |  | until death for a maximum of two years after end of treatment | 
| Adverse events | Toxicity of study medication | 18 months after the date of last study drug administration | 
| Quality of Life evaluated by questionnaire | Quality of Life evaluated using questionnaire EORTC QLQ-30 | Until end of treatment (maximum 2 years after first study drug administration) |