Irinotecan and raltitrexed are active against advanced colorectal cancer (ACC), act through different mechanisms, and have only partially overlapping toxicity profiles. The purpose of this study is to evaluate efficacy and safety of irinotecan plus raltitrexed as second-line treatment in advanced colorectal cancer patients.

The standard initial treatment for patients with advanced colorectal cancer (ACC) not amenable for surgical resection is palliative 5-fluorouracil (5-FU)-based chemotherapy. However, response rates are low and prognosis remains poor, with median survival times about one year. Until recently, second-line therapy options were limited.

Irinotecan is a semisynthetic camptothecin derivate that acts as a DNA-topoisomerase-1 inhibitor,its most frequent toxic effects are diarrhea, neutropenia and cholinergic syndrome. Raltitrexed is a quinazoline folate-based specific thymidylate synthase inhibitor, its clinical activity in this setting is similar to that of modulated 5-FU regimens but with a better toxicity profile (mainly asthenia and increased serum transaminase levels). There seems to be no cross-resistance between 5-FU and raltitrexed. Irinotecan and raltitrexed have different toxicity profiles and modes of action. Both drugs are active as single agents and may be given as a short 3-weekly infusion, thus obviating complex schedules or the need for implantable venous access devices. Preclinical studies have demonstrated a pronounced sequence-dependent synergy between SN-38 (the active metabolite of irinotecan) and raltitrexed. It seems then interesting to explore the feasibility and therapeutic potential of this association.

With this background, the investigators have performed this study to evaluate efficacy and safety of irinotecan plus raltitrexed as second-line treatment in advanced colorectal cancer patients.

Inclusion Criteria:

• life expectancy of at least 3 months;
• histological and/or cytological confirmation of ACC;
• disease progression while on first-line palliative oxaliplatin & fluoropyrimidine chemotherapy or relapse within 6 months after adjuvant oxaliplatin & fluoropyrimidine chemotherapy;
• wash-out time of 4 weeks after the last chemotherapy infusion or radiotherapy，and observed lesions not in the radiotherapy target；
• at least one measurable objective tumor lesion by spiral CT examination, the maximum diameter ≥ 1cm（according to RECIST 1.1）；
• ECOG performance status 0-1；
• satisfactory main organ function，laboratory test must meet the following criteria: hemoglobin (HGB) ≥90g/L, neutrophil count（ANC） ≥1.5×109/L, platelet count（PLT） ≥90×109/L, Serum creatinine（CR）≤1.5 upper normal limitation (UNL)，creatinine clearance rate (CCr) ≥60ml/min, total bilirubin (TBil) ≤1.5 upper normal limitation (UNL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 UNL (For patients with liver metastasis, the AST/ALT must be ≤5.0 UNL);
• For women with child bearing potential, a negative serum or urine pregnancy test result should be obtained before enrollment
• written informed consent.

Exclusion Criteria:

• prior exposure to irinotecan or raltitrexed;
• chronic enteropathy on unresolved bowel obstruction;
• Pregnant or lactated women;
• previous malignant disease other than carcinoma in situ of the cervix or basal cell carcinoma of the skin;
• Concurrent administration of any other investigational drug, or have been enrolled in other clinical trial with investigational drug treatment within the 30 days of start of study treatment；
• cerebral metastases or leptomeningeal carcinomatosis;
• severe or uncompensated concomitant medical conditions.
• Unsuitable for the study or other chemotherapy determined by investigator.