| Eligibility |
Inclusion Criteria:
1. Phase Ib: Subjects with a histologically-confirmed, advanced/recurrent colorectal
cancer who have progressed on two prior standard chemotherapies Phase II:
Histologically or cytologically confirmed colorectal cancer patient who had progressed
on, were intolerant of, or were inappropriate for the treatment with fluoropyrimidine,
oxaliplatin, irinotecan and targeted agents (If the subject received adjuvant
chemotherapy after curative surgery and lymph node dissection for colorectal cancer,
the adjuvant chemotherapy is considered to be the first-line palliative chemotherapy
if the disease recurred during adjuvant chemotherapy or within 6 months after the
completion of adjuvant chemotherapy.)
2. Permit previous 2 lines of anti-VEGF blockades
3. Patient has evaluable disease as per RECIST 1.1. (Measurable lesions are not mandatory
for study inclusion.)
4. Age = 19 years old of male and female
5. ECOG performance status (PS) 0-1
6. Adequate bone marrow and organ function as defined by the following laboratory values:
- Absolute neutrophil count (ANC) = 1.0 x 109/L
- Hemoglobin = 9.0 g/dL
- Platelet = 75 x 109/L
- Serum creatinine = ULN (upper limit of normal) x 1.5 or serum creatinine
clearance > 30 mL/min
- Total bilirubin: = 2.0 × ULN, Subjects with a bile duct obstruction will be
eligible if they meet the criteria after appropriate bile drainage
- Phase Ib: Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) = 3
x ULN (regardless of liver metastases)
- Phase II: AST and ALT = 3 x ULN if liver metastases are absent, or AST and ALT =
5 x ULN if liver metastases are present.
7. Adequate cardiac function: QTc =480 msec; if QTc exceeds 480 msec, subjects can be
enrolled if the average QTc value is less than 480 msec by measuring 3 times
consecutively in total.
8. The subject is able to swallow and retain oral medication
9. Serum ß-HCG test negative within 14 days before the first administration of the study
treatment (women of childbearing potential only).
10. Requirement for contraception must be observed by the subject.
11. Life expectancy of at least 3 months
12. Subject has signed the Informed Consent Form (ICF) prior to any screening procedures
being performed.
Exclusion Criteria:
1. Patient has a known or suspicious hypersensitivity to fluoropyrimidines.
2. Any cytotoxic chemotherapy from a previous treatment regimen within 14 days. If the
subject received an investigational drug from another clinical trial, the subject can
be enrolled after 2 weeks of last administration and more than 5 x half-life of the
investigational drug. If monoclonal antibody therapy including anti VEGF agent was
given, the subject can be enrolled after four weeks after the last does.
3. Patients with complete or partial dihydropyrimidine dehydrogenase deficiency.
4. Serious uncontrolled intercurrent infections
5. Serious intercurrent medical or psychiatric illness, including active cardiac disease
- Acute coronary syndrome within the 6 months prior to the initiation of study drug
(including myocardial infarction or unstable angina, Coronary Artery Bypass Graft
surgery, percutaneous coronary intervention and stenting)
- Heart failure = grade 2 by New York Heart Association (NYHA) functional
classification or that requires treatment
- Ejection fraction (EF) <50% on multi-gated acquisition (MUGA) scan or
echocardiography examination. MUGA scan or echocardiography is not required as a
screening test if there is no current suspicious symptom and past history of
heart failure.
- Persistent uncontrolled hypertension as defined by: systolic >180 mmHg or
diastolic >100 mmHg despite medical treatment. Initiation or adjustment of
antihypertensive medication(s) is allowed prior to screening.
- Current or past history of clinically significant cardiac arrhythmia, atrial
fibrillation, and/or conduction abnormality (e.g. congenital long QT syndrome,
complete AV block)
- Any risk factors that prolong QTc or increase the probability of arrhythmia,
including medication (e.g. heart failure, hypokalemia, congenital long QT
syndrome, history of Torsades de Pointes)
6. Active central nervous system (CNS) lesions (i.e., those with radiologically unstable
or symptomatic brain lesions). For those who receive radiation or surgical treatment,
the subject can be enrolled if the subject is maintained without steroid therapy and
the evidence of CNS disease progression for more than 4 weeks. However, patients with
leptomeningeal metastases are excluded.
7. History of other primary cancer. Exceptions are as follows:
- Adequately treated non-melanoma skin cancer (basal cell or squamous cell
carcinoma), curatively treated in situ cancer of the cervix or stage I bladder
cancer, completely resected thyroid cancer without distant metastasis in which
all treatment has been completed (Appropriate wound healing is required prior to
clinical trial enrollment)
- Other curatively treated solid tumors except for gastric cancer with no evidence
of disease recurrence at least 36 months before participating in this trial
8. Patient has not recovered to = grade 1 (except alopecia) from related adverse effects
of any prior antineoplastic therapy.
9. Radiotherapy with a wide field (more than 30% of the bone marrow) of radiation within
4 weeks or radiotherapy with a limited field of radiation for palliation within 2
weeks of the first dose of study treatment.
10. Patient who has undergone major surgery = 4 weeks prior to starting study treatment or
who has not recovered from adverse effects of such procedure.
11. Patient has a known positive serology for human immunodeficiency virus (HIV), active
Hepatitis B, and/or active Hepatitis C infection. Hepatitis B carriers may be enrolled
if prophylactic use of an antiviral agent with minimal interaction with CYP3A4 is
administered to inhibit HBV activation (e.g., entecavir, adefovir)
12. Concomitant medication of strong or moderate inducers or inhibitors of CYP3A4 before
the first dose of study treatment (In this case, if the drug is stopped for more than
1 week and changed to another drug that does not affect CYP3A4, then the subject can
be enrolled.)
13. People who are taking BCRP inhibitors, allopurinol, soribudin, brivudine or within 4
weeks of stopping, and taking tegafur/gimeracil/oteracil or within 7 days of stopping
14. History of allogeneic bone marrow transplantation or organ transplantation
15. As judged by the Investigator, all other symptoms and associated disease for which the
investigator determined that participation in this study is contraindicated (e.g.
Infection/inflammation; severe liver dysfunction; bilateral diffuse interstitial lung
disease; uncontrolled renal disease; unstable heart and lung disease; hemorrhagic
disease; intestinal obstruction; unable to swallow oral pills; social and
psychological problems, etc.)
16. Medical, psychiatric, cognitive, or other conditions that may interfere with the
ability of the subject to understand the subject information, provide the informed
consent, follow the protocol process, or complete the clinical trial
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