Study of S-1 and Oxaliplatin (SOX) Versus Capecitabine and Oxaliplatin (COX) in Patients With Advanced Colorectal Cancer

A Randomized Phase III Study of SOX vs. COX in Patients With Advanced Colorectal Cancer

Primary objective :

To compare the combination of S-1 and oxaliplatin(SOX) to the combination of capecitabine and oxaliplatin(COX) therapy for advanced or metastatic colorectal carcinoma.

Secondary objectives :

1. To evaluate and compare the efficacy (overall survival and response rate) in the two treatment groups.
2. To evaluate and compare the quality of life of the patients and safety profiles of the two treatment groups.

• The urgent need for new effective therapy with better safety profile for metastatic colorectal cancer patients and promising results observed so far in trials with S-1 combined with oxaliplatin in gastrointestinal cancer including colorectal cancer strongly warrants the comparison of S-1 combined with oxaliplatin to capecitabine combination with oxaliplatin acknowledged as a standard regimen in a first-line treatment for advanced colorectal cancer patients.
• Recently, a Phase I study was completed, indicating recommended dose as S-1 100 mg/m2/day1-14 and oxaliplatin (130 mg/m2/day1), repeated every 3 weeks. However, in the phase II study using the above recommended dose, delayed toxicities of thrombocytopenia and anemia were observed. These delayed toxicities were also reported in a phase II study using S-1 90 mg/m2/day plus oxaliplatin 130 mg/m2/day1 in advanced gastric cancer. At 2007 GI ASCO, the interim data of S-1(80 mg/m2/day1-14) plus oxaliplatin (130 mg/m2/day1) combination, repeated every 3 weeks, was presented, showing promising antitumor activity with favourable safety profile. Among 18 patients, there were only two patients with Grade 3 thrombocytopenia and one with Grade 3 neutropenia. Response rate was 57.1 % and disease control rate was 92.9 %. Considering these results and Japanese data which showed that enhanced efficacy was not observed with S-1 over 90 mg/m2/day and oxaliplatin combination, S-1 80 mg/m2/day 1-14 and oxaliplatin 130 mg/m2/D1, repeated every 3 weeks, will be tested in this study.

Inclusion Criteria:

• Histologically documented colorectal adenocarcinoma
• Age over 18 years old
• Performance status (ECOG scale): 0-2
• Measurable or evaluable disease
• Patients can take food and drugs orally
• Adequate organ functions
• Life expectancy ≥ 3 months
• Patients should sign a written informed consent before study entry

Exclusion Criteria:

• Tumor type other than adenocarcinoma
• Second primary malignancy
• Prior systemic therapy (for instance, cytotoxic chemotherapy or active/passive immunotherapy) for advanced or metastatic colorectal cancer
• Adjuvant or neo-adjuvant treatment for non-metastatic (M0) disease has been completed within 6 months prior to initiation of study treatment.
• Prior radiotherapy was administered to target lesions selected for this study, or radiotherapy to the non-target lesions has been completed within 4 weeks before randomization.
• Presence of CNS metastasis
• Obvious peritoneal seeding or bowel obstruction disturbing oral intake
• Symptomatic peripheral neuropathy
• Major surgery within 4 weeks prior to study treatment start, or lack of complete recovery from the effects of major surgery. The patient received curative operation or RFA for metastatic disease.
• Serious illness or medical conditions
• Receiving a concomitant treatment with drugs interacting with S-1, capecitabine or oxaliplatin, as follows;flucytosine, a fluorinated pyrimidine antifungal agent phenytoin warfarin etc.
• Received any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment with study drug.
• Pregnant or lactating woman
• Women of child bearing potential not using a contraceptive method
• Sexually active fertile men not using effective birth control during medication of study drug and up to 6 months after completion of study drug if their partners are women of child-bearing potential
• Any patients judged by the investigator to be unfit to participate in the study