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

A Phase II Study Assessing Efficacy and Safety of TS-1 in Combination With Calcium Folinate in Patients With Heavily Pre-treated Metastatic Colorectal Cancer

Primary Objective:

To determine disease control rate (DCR) of TS-1® in patients with heavily pre-treated metastatic colorectal cancer

Secondary Objectives:

• To determine objective response rate (ORR)
• To determine time to progression (TTP)
• To determine overall survival (OS)
• To assess incidence of adverse events (AEs), serious adverse events (SAEs) [Safety and Tolerability]

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.

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.