TS-1 in Combination With Calcium Folinate in Patients With Heavily Pre-treated mCRC

Simon's optimal two-stage design will be used to determine the sample size for this study.

• Stage I: >1/9: The first 9 evaluable patients enrolled, >1 (or ≥2) responders are required in order to enter the second stage, otherwise the trial will be terminated at the first stage due to futility.

• Stage II: Total >8/34: For the total 34 evaluable patients, >8 (or ≥9) responders are required to conclude the effectiveness of the study regimen.

The primary endpoint will be disease control rate which will be presented in frequency tabulation with two-sided 95% confidence interval (using binomial estimation).

The secondary endpoints are described as follows:

* ORR will be presented in frequency tabulation with two-sided 95% confidence interval;
* TTP will be estimated by Kaplan-Meier method with two-sided 95% confidence interval;
* OS will be estimated by Kaplan-Meier method with two-sided 95% confidence interval;
* Incidence of adverse events (AEs), serious adverse events (SAEs) \[Safety and Tolerability\] : assessed by CTCAE v4.0. Safety parameters will only be analyzed on the safety analysis set and be presented in frequency tabulation.

• S-1+leucovorin (Drug), also known as TS-1+calcium folinate: Eligible patients will receive TS-1 orally 40-60 mg (depending on patient's body surface area (BSA)) in combination with calcium folinate 30 mg twice a day for 7 days in a 2-week cycle. The treatment will be administered until disease progression, intolerable toxicity, or consent withdrawal during any time of the study.

Primary outcomes

• Disease Control Rate (DCR) [6 months(an expected average)]: Documented objective response (OR) (defined as partial response \[PR\] or complete response \[CR\]), assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at any time during trial participation by Investigator assessment

Secondary outcomes

• Objective Response Rate (ORR) [6 months(an expected average)]: the rate of completely response \[CR\] and partial response \[PR\] patients according to RECIST version 1.1. criteria
• Time to Progression (TTP) [until disease progression, intolerable toxicity, 12 months(an expected average)]: Participants follow-up for disease progression occur. Maximum follow-up time is 12 months after the initial administration of the last subject
• Overall survival (OS) [at death or at the end of study, 24 months(an expected average)]: median time between the start date of study treatment and the date of the death
• Incidence of adverse events (AEs), serious adverse events (SAEs) [Safety and Tolerability] [From the date of study entry until 30 days after the last dose of study treatment]: assessed by the NCI-CTCAE (Common Toxicity Criteria for Adverse Effects) v4.0 and within some subgroups of patients

Sex: All, ages: 20 Years to any

Inclusion Criteria:

1. histologically or cytologically confirmed colorectal adenocarcinoma;
2. metastatic and unresectable disease;
3. presence of at least one measurable tumor lesion which is defined as lesion that can be measured in at least one dimension (longest diameter) with a minimum size of:

   1. 10mm by CT scan and MRI (no less than double the slice thickness and a minimum of 10mm);
   2. 20mm by conventional techniques;
4. previously treatment to

   1. fluoropyrimidine, oxaliplatin and irinotecan;
   2. at least one targeted therapy
5. adequate hematopoietic function which is defined as below:

   1. hemoglobin ≥ 9 g/dL;
   2. absolute neutrophil count (ANC) ≥ 1,500/mm3;
   3. platelet count ≥ 100,000/mm3;
6. adequate hepatic function which is defined as below:

   1. total bilirubin ≤ 2 times upper limit of normal (ULN);
   2. hepatic transaminases (ALT and AST) ≤ 3 x ULN. If there are known liver metastases, ALT or AST must be ≤ 5 x ULN;
7. adequate renal function which is defined as below:

   a. serum creatinine ≤ 1.5 x ULN;
8. age of 20 years or above;
9. ECOG performance status 0-2;
10. life expectancy of at least 12 weeks;
11. ability to take oral medication;
12. ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. history or known presence of brain metastasis;
2. presence of mental disease or psychotic manifestation;
3. significant medical conditions that is contraindicated to study medication or render patient at high risk from treatment complications based on investigator's discretion;
4. presence of diarrhea ≥ grade 2 in common terminology criteria for adverse event version 4.0 (CTCAE v4.0);
5. other malignancy within the past 5 years (different site or histology) except for adequately treated basal or squamous cell skin cancer or cervical cancer in situ;
6. recent (within 30 days prior to study treatment) treatment of another investigational drug;
7. pregnant women or nursing mothers, or positive pregnancy test for women of childbearing potential. Patients with childbearing potential should have effective contraception for both the patient and his or her partner during the study.

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• Hung-Chih Hsu, Principal investigator, Chang Gung Memorial Hospital, Linkou, Taiwan