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

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

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

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.

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).