Regorafenib Plus FOLFIRI With Irinotecan Dose Escalated in Patients With Previously Treated Metastatic Colorectal Cancer

A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with metastatic colorectal cancer (mCRC).

Primary objective:

Progression-free survival

Secondary objective:

Overall survival, best objective response, disease control rate, time to progression, duration of treatment and adverse events

Number of Subjects: 153 patients with metastatic colorectal cancer treated with regorafenib and FOLFIRI as a third- or fourth-line setting.

Plan of the Study:

1. This is a prospective, multicenter, randomized in a 2:1 ratio, controlled study.
2. Study Schedule Study date: the time getting approval letter issued by both regulatory authority and institutional review board (IRB). Duration of the study: 4 years.
3. Duration of Treatment: Treatment was administered until disease progressed.

Eligibility Criteria:
Inclusion Criteria:

1. Cyto-/histological confirmed mCRC
2. Patients who have been previously treated with, or are not considered candidates for, other locally approved standard treatment(s) and for whom the decision has been made per investigator's routine treatment practice to prescribe regorafenib as 3rd line (RAS mutant) or 4th line (RAS wild type) therapy
3. Aged no less than 20 years, at the time of acquisition of informed consent
4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-1
5. Patients with measurable or non-measurable disease in the colon or rectum, according to RECIST criteria version 1.1
6. Life expectancy more than 12 weeks
7. Women with childbearing potential must agree to perform adequate contraception measures since informed consent till a least 12 weeks after the last study drug administration.

   The investigators or designee are requested to advise the patient to achieve adequate birth control.
8. Adequate organ and bone marrow function as defined below:

   * Total bilirubin \<= 1.5 x the upper limit of normal (ULN)
   * Alanine amino-transferase (ALT) and aspartate amino-transferase (AST) \<= 2.5 x ULN (\<= 5 x ULN for patients with liver metastases)
   * Alkaline phosphatase (ALP) \<= 2.5 x ULN (\<= 5 x ULN for patients with liver metastases)
   * Amylase and lipase \<= 1.5 x ULN
   * Serum creatinine \<= 1.5 x ULN
   * Glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m2, according to the modified diet in renal disease (MDRD) abbreviated formula
   * International normalized ratio (INR)/partial thromboplastin time (PTT) \<= 1.5 x ULN
   * Platelet counts \>= 100,000/mm3
   * Hemoglobin level \>= 9 g/dL
   * Absolute neutrophil counts \>= 1,500/mm3
9. Ability to understand and willingness to sign written Informed Consent Form (ICF)

Exclusion Criteria:

1. Prior treatment with regorafenib within 28 days
2. Other concurrent cancer or prior treatment for other carcinomas within the last five years, except curatively treated non-melanoma skin cancer, superficial bladder tumors, and cervical cancer in-situ
3. Extended field radiotherapy within 28 days or limited radiotherapy within 14 days prior to randomization
4. Major surgery within 28 days prior to start of study treatment (diagnostic biopsy, laparotomy, line placement is not considered as major surgery)
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction in the past 12 months, active gastrointestinal bleeding, central nervous system disorders or psychiatric illness/social situation that would limit compliance with study requirements or judged to be ineligible for the study by the investigator
6. History of myocardial infarction, deep venous or arterial thrombosis, or cardiovascular accident (CVA) during the last 6 months
7. Uncontrolled cardiac arrhythmias, unstable angina, or newly-onset angina within 3 months prior to study entry
8. Uncontrolled hypertension despite optimal management (systolic blood pressure \> 150 mmHg or diastolic pressure \> 90 mmHg)
9. Patients with known central nervous system (CNS) metastases
10. Having received any investigational agents or participating in any investigational drug study within 4 weeks prior to study enrollment
11. Pregnant or breast-feeding female (a pregnancy test must be performed on all female patients with child-bearing potential within 7 days of treatment initiation, and the result must be negative)
12. Inability to take oral medications
13. Poor compliance as judged by the investigator