FOLFOXIRI Compared to FOLFOX in First Line Treatment of Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of the study is to evaluate if the exposure to all the three active cytotoxic agents (FOLFOXIRI regimen) is superior in terms of progression-free survival to conventional chemotherapy with the FOLFOX regimen as first-line treatment of chemo-naive metastatic colorectal cancer patients. A second primary aim is to evaluate the response rate, safety and tolerability of the chemotherapy of FOLFOXIRI regimen in this patient population. Patients will be randomized to two therapy groups: Experimental arm A: Chemotherapy with FOLFOXIRI Standard arm B: Chemotherapy with FOLFOX

Detailed Description
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Survival of patients with metastatic colorectal cancer is correlated with the proportion of patients who receive all the three active drugs , but not with the proportion of patients who receive any second-line therapy. A superior efficacy in PFS,ORR and OS of FOLFOXIRI has been reported with acceptable toxicity. Moreover,evidence suggests that continuous dosing metronomic chemotherapy may be more efficacious than interval-chemotherapy. Therefore, a way to improve the outcome of metastatic colorectal cancer patients could be to administer a maintenance first-line regimen containing the three active agents.

Official Title
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Phase II Randomized Controlled Trial of FOLFOXIRI Compared to FOLFOX in First Line Treatment of Chemo-naive Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: FOLFOXIRI
* Drug: FOLFOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent obtained before any study specific procedures. -Subjects must be able to understand and willing to sign a written informed consent. Male or female subjects ≥ 18 years ≤ 75 years of age Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2.(ECOG PS 0-2 for≥18 years ≤ 65 years of age ，ECOG PS 0-1 for >65 years of age) Histological or cytological documentation of adenocarcinoma of the colon or rectum. All other histological types are excluded. There must be documentation by PET/CT scan, CT scan, MRI, or intraoperative palpation (at the time of resection of the primary colorectal tumor, if applicable) that the patient has evidence of metastases (Histologic confirmation of metastasis is not required.). At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria measured within 4 weeks prior to registration. No previous chemotherapy or target therapy for metastatic disease (adjuvant chemotherapy for non-metastatic disease is allowed if terminated more than 6 months ago). In case of previous radiotherapy, at least one measurable lesion should be located outside the irradiated field. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: Leukocytes ≥ 3.0 x109/ L, absolute neutrophil count (ANC) ≥ 1.5 x109/ L, platelet count ≥ 100 x109/ L, hemoglobin (Hb) ≥9g/ dL. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN. Alkaline phosphatase limit ≤ 5x ULN. Amylase and lipase ≤ 1.5 x the ULN. Serum creatinine ≤ 1.5 x the ULN. Calculated creatinine clearance or 24 hour creatinine clearance ≥ 50 mL/ min. Exclusion Criteria: Previous palliative chemotherapy for metastatic disease，previous adjuvant chemotherapy including irinotecan or oxaliplatin within 6 months before random assignment. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization. Life expectancy > 12 weeks; Extended field radiotherapy within 4 weeks or limited field radiotherapy within 2 weeks prior to randomization. Subjects must have recovered from all therapy-related toxicities. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks before start of study medication. Congestive heart failure ≤ New York Heart Association (NYHA) class 2. Significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment or a history of ventricular arrhythmia Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication. Any evidence of active infection. History of interstitial pneumonitis or pulmonary fibrosis Pregnancy or lactation at the time of study entry. Known dihydropyrimidine dehydrogenase (DPD) deficiency Any illness or medical conditions that are unstable or could jeopardize the safety of the subjects and his/her compliance in the study. Active inflammatory bowel disease or other bowel disease causing chronic diarrhoea Subjects with known allergy to the study drugs or to any of its excipients. Current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study. Continuous use of immunosuppressive agents (except the use of corticosteroids as anti-emetic prophylaxis/treatment).

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOXIRI<br>FOLFOXIRI | Drug: FOLFOXIRI<br>* irinotecan* 165 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 3200 mg/m² cont. inf. 46h all on day 1 of each 2 weeks cycle *reduced in UGT1A1 7/7 patients<br>* Other names: 5-Fluorouracil;|
| Active Comparator: FOLFOX<br>FOLFOX | Drug: FOLFOX<br>* oxaliplatin 85 mg/m² + leucovorin 400 mg/m² +5-FU 400mg/m² bolus iv.+ 5-FU 2400 mg/m² cont. inf. 46h all on day 1 of each 2 weeks cycle<br>* Other names: 5-Fluorouracil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival after induction and maintenance chemotherapy (PFS1) | Progressions are evaluated every 8 weeks according to WHO criteria and reviewed by an independent panel at the end of follow up (36 months). | up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival after re-introduction of chemotherapy (PFS2) |  | up to 24 months | 
| Response rate during re-introduction of chemotherapy | (CR + PR rate according to RECIST) | up to 12 months | 
| Early tumor shrinkage rate in 8 weeks after induction treatment |  | 8 weeks | 
| Overall survival |  | up to 5 years | 
| toxicity and safety | Number of participants with adverse events as a measure of safety and tolerability according to NCI CTC 4.0 | up to 24 months | 
| QLQ (QLQ C30) - scores according to EORTC QLQ-C30 scoring manual (Quality of life) |  | up to 36 months | 
| Translational research |  | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, Metastatic colorectal cancer, FOLFOXIRI, FOLFOX, Oxaliplatin, irinotecan, Leucovorin, 5-FU