A Phase I/IIa Dose-Escalation Study Evaluating the Safety, Tolerability and Efficacy of LEAC-102 in Combination with FOLFOX + Bevacizumab/Cetuximab in Subjects with Advanced Colorectal Cancer

Inclusion Criteria:

1. Subjects aged at least 20 years old
2. Histologically or cytologically confirmed measurable and/or evaluable advanced (stage III/IV) colorectal cancer that can be accurately assessed by CT/MRI scan (RECIST v1.1) for which regimen of FOLFOX + Bevacizumab/Cetuximab is arranged by the investigator
3. Subjects may be treatment naïve, or may have received therapy for colorectal cancer.
4. ECOG performance status ≤ 2 and life expectancy ≥ 12 months Note: ECOG = Eastern Cooperative Oncology Group
5. Dated and signed informed consent

Exclusion Criteria:

1. Primary CNS malignancies or clinically active CNS metastases Note: CNS = central nervous system

2. Ascertained hypersensitivity to any component of investigational product or FOLFOX + Bevacizumab/Cetuximab that the subject will be treated

3. Any of the following hematologic abnormalities:

   1. Hemoglobin < 10.0 g/dL,
   2. ANC < 1,500/μL,
   3. Platelets < 100,000 /μL Note: ANC = absolute neutrophil count

4. Any of the following serum chemistry abnormalities:

   1. Total bilirubin > 1.5 × ULN,
   2. AST or ALT > 2.5 × ULN,
   3. Gamma-GT > 2.5 x ULN,
   4. Alk-P > 2.5 x ULN,
   5. serum albumin < 3.0 g/dL,
   6. creatinine > 1.5 × ULN,
   7. any other ≥ Grade 3 laboratory abnormality at baseline (other than those listed above)

   Note: ULN = upper limit of normal. AST = aspartate transaminase, ALT: alanine transaminase, Gamma-GT = Gamma-glutamyl transferase, Alk-P = alkaline phosphatase

5. Requirement for ongoing systemic steroid, or immunosuppressive agents

6. Uncontrolled nausea or vomiting or any symptom that would prevent the ability to comply with daily oral LEAC-102 treatment

7. Active clinically serious infection

8. Known history of HIV or hepatitis B or C Note: HIV = human immunodeficiency virus

9. Uncontrolled psychiatric disorder or altered mental status precluding informed consent or necessary testing

10. Consumption of herbal preparations/supplements (except for a daily multivitamin/mineral supplement not containing herbal components) within 2 weeks prior to the start of Cycle 1 of FOLFOX + Bevacizumab/Cetuximab administration

11. Significant cardiovascular disease, including:

    1. Active clinically symptomatic left ventricular failure
    2. Active hypertension (diastolic blood pressure > 100 mmHg). Subjects with a history of hypertension must have been on stable doses of anti-hypertensive drugs for ≥ 4 weeks prior to start of Cycle 1 of FOLFOX + Bevacizumab/Cetuximab administration
    3. Uncontrolled hypertension: Blood pressure >140/90 mmHg on more than 2 antihypertensive medications
    4. Myocardial infarction, severe angina, or unstable angina within 12 weeks prior to start of Cycle 1 of FOLFOX + Bevacizumab/Cetuximab administration
    5. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation)

12. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent

13. Has received an investigational agent within 4 weeks of entering this study

14. With any condition judged by the investigator that entering the trial may be detrimental to the subject

15 Female with childbearing potential who is lactating or has positive urine pregnancy test at Screening visit

16. Subject with either gender refuses to adopt at least two forms of birth control (at least one of which must be a barrier method) during the study and until 30 days after study treatment.

Note: Acceptable forms include:

1. Established use of oral, injected or implanted hormonal methods of contraception.
2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
3. Barrier methods of contraception: Condom OR Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository

17. Subjects with grade 2 or above chronic neuropathy

18. Subjects with known dihydropyrimidine dehydrogenase (DPD) deficiency.