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

Kaohsiung Medical University

Status and phase: Unknown; Phase 2

Conditions: Metastatic Colorectal Cancer

Treatments: Genetic: UGT1A1 genotyping (TA7/TA7); Drug: Leucovorin and 5-FU; Drug: Regorafenib; Genetic: UGT1A1 genotyping (TA6/TA6); Genetic: UGT1A1 genotyping (TA6/TA7)

Study type: Interventional

Funder types: Other

Identifiers

NCT03880877

KMUHIRB-F(II)-20190032

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 153 estimated patients

Sex: All

Ages: 20 to 85 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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153 participants in 2 patient groups

Regorafenib plus FOLFIRI

Experimental group

Description:

Regimen for treatment consists of irinotecan (180 mg/m2 as a 120-min IV infusion for UGT1A1 genotyping (TA6/TA6) and UGT1A1 genotyping (TA6/TA7); 120 mg/m2 as a 120-min IV infusion for UGT1A1 genotyping (TA7/TA7)), followed by Leucovorin (400 mg/m2 IV infusion over 2 hours), and fluorouracil (5-FU) (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks. After every 2 cycles of each different dose of irinotecan, if adverse events (AEs) are under the grade 2, we will escalate the dose of 30 mg/m2. The estimated maximal dose of irinotecan is 260 mg/m2 for UGT1A1 genotyping (TA6/TA6); 240 mg/m2 for UGT1A1 genotyping (TA6/TA7); 180 mg/m2 for UGT1A1 genotyping (TA7/TA7). Regorafenib is administered at adjusted dosage of 120 mg daily for 3 weeks in a 4-week cycle.

Treatment:

Genetic: UGT1A1 genotyping (TA6/TA7)

Genetic: UGT1A1 genotyping (TA6/TA6)

Genetic: UGT1A1 genotyping (TA7/TA7)

Drug: Leucovorin and 5-FU

Drug: Regorafenib

Regorafenib

Active Comparator group

Description:

Regorafenib is administered at adjusted dosage of 120 mg daily for 3 weeks in a 4-week cycle.

Treatment:

Drug: Regorafenib